Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[S:19])SC)([OH:4])(=[O:3])=[O:2].[N-:20]=[N+:21]=[N-:22].[Na+]>>[S:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:16]([SH:19])=[N:22][N:21]=[N:20]1)([OH:4])(=[O:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCCCCCCCCS(=O)(=O)O
Agent: [Na+]
Product: O=S(=O)(O)CCCCCCCCCCn1nnnc1S

Procedure:
Methyl 10-sulfodecyldithiocarbamate (31.4 g., 0.096 mol.) is reacted with 6.5 g. (0.1 mol.) of sodium azide as described above to give 1-(10-sulfodecyl)tetrazole-5-thiol.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:8]=[CH:9][C:10]=1[F:11])(=O)C.S(Cl)(Cl)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C1COCC1.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]2[CH:8]=[CH:9][C:10]([F:11])=[C:5]([OH:4])[CH:6]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=O)Oc1cc(/C=C/C(=O)O)ccc1F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(/C=C/c1ccc(F)c(O)c1)Nc1cccc(Cl)c1
Temperature: 35 °C
Yield: 33.8 %

Procedure:
A solution (E)-3-(3-acetoxy-4-fluoro-phenyl)-acrylic acid (0.17 g, 0.76 mmol) and thionyl chloride (0.069 mL, 0.95 mmol) in dry THF (2 mL) was stirred at 55° C. for 3 hrs. Then a further aliquot of thionyl chloride (0.008 mL, 0.11 mmol) was added and the mixture was stirred at reflux temperature for additional 1.5 hrs. After cooling to about 35° C., a solution of 3-chloro-aniline (0.204 mL, 1.90 mmol) dry THF (0.5 mL) was added dropwise. After stirring at RT for 16 hrs, the reaction mixture was diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was then dried over sodium sulphate and evaporated. The resulting raw material was taken up without further purification with THF (2 mL), and a 3N methanolic solution of hydrochloric acid (4 mL-12 mmols) was added to the so obtained solution. The resulting mixture was stirred at RT for 16 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a light yellow residue that was sequentially triturated with toluene, ethyl ether and dichlorometane. After the last filtration and drying, 75 mg of the title (E)-N-(3-chloro-phenyl)-3-(4-fluoro-3-hydroxy-phenyl)-acrylamide were obtained, as a light yellow powder.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of 12.0 g (75.42 mmol) of 3,4-difluoronitrobenzene (2) in 150 mL of acetonitrile was treated with 16.24 g (188.6 mmol) of piperazine, followed by warming at reflux for 3 hours. The solution was cooled to ambient temperature and was concentrated in vacuo. The residue was diluted with 200 mL of water and was extracted with ethyl acetate (3×250 mL). The combined organic layers were extracted with water (200 mL) and saturated NaCl solution (200 mL), followed by drying (Na2SO4). The solution was concentrated in vacuo to afford an orange oil which was chromatographed over 450 g of 230-400 mesh silica gel eluting initially with dichloromethane until the least polar fractions had eluted and then elution was continued with 2% (v/v) methanol-chloroform and then with 10% (v/v) methanol-chloroform. These procedures afforded 13.83 g (81%) of the desired piperazine derivative 3, mp=68.5°-71° C.
Reaction SMILES: C[CH:2](C)[CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].NCCC[OH:22]>>[OH:22][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)CCNc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: NCCCO
Product: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1

Procedure:
4-(3-Hydroxy-propylamino)-3-nitro-benzonitrile was prepared as described for 4-(3-methyl-butylamino)-3-nitro-benzonitrile using 3-amino-propan-1-ol.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:20][CH2:19]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 105 °C
Yield: 40.4 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-cyclopropyl-3-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (137 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)—N-cyclopropyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (85.3 mg, 0.184 mmol, 40.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.45-0.61 (m, 2H) 0.61-0.76 (m, 2H) 1.83-2.05 (m, 3H) 2.08-2.25 (m, 1H) 2.44-2.49 (m, 4H) 2.80 (td, J=7.33, 3.79 Hz, 1H) 3.08 (br. s., 4H) 3.54-3.66 (m, 1H) 3.91-4.06 (m, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.02 (t, J=8.84 Hz, 1H) 7.49-7.69 (m, 3H) 8.31 (d, J=4.04 Hz, 1H) 10.44 (s, 1H). [M+H] calc'd for C25H29FN6O2, 465. found, 465.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:65]=[C:64]([Cl:66])[C:63]([Cl:67])=[C:62]([Cl:68])[CH:61]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].[NH2:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76]>C(Cl)Cl>[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:61]=[C:62]([Cl:68])[C:63]([Cl:67])=[C:64]([Cl:66])[CH:65]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46]([NH:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:76])([CH3:78])[CH3:77])=[O:47]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)NCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between water and CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a brown solid (200 mg, 39%): 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J=5.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.6, 9.2 Hz, 1H), 6.84 (t, J=6.0 Hz, 1H), 6.76 (t, J=15.6 Hz, 1H), 4.84-4.80 (m, 1H), 3.24-3.20 (m, 2H), 3.11-3.08 (m, 2H), 1.30 (s, 9H); ESIMS m/z 628.80 ([M+H]+); IR (thin film) 3365, 1701, 1167, 699, 555 cm−1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[H-].[Na+].C(OP([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(OCC)=O)C.CN(C)C=O>O>[CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:4]=[N:3]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1cc(C=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cnn(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A mixture of 1-methyl-1H-pyrazole-4-carbaldehyde (2.59 g), sodium hydride (60% in oil, 1.13 g), ethyl diethylphosphonoacetate (5.8 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (2E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate (2.72 g, 64%) as crystals from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 43-44° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:18][OH:19]>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:19][CH3:18])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C(=O)Cl)cc1
Reactant: CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(C(=O)OC)cc1

Procedure:
4-Octylbenzoyl chloride (obtained by reacting 4-octylbenzoic acid with thionyl chloride) is esterified with methanol in the presence of an equimolar amount of triethylamine and 0.1 mol % of DMAP. Customary work-up followed by purification by distillation affords methyl 4-octylbenzoate as a colorless liquid, b.p. 112° C./0.25 mbar.
Reaction SMILES: O.[SH-].[Na+].[Cl:4][CH2:5][C:6]1([CH3:15])[O:10][N:9]=[C:8]([S:11]([CH3:14])(=O)=O)[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrC[C:30]1[C:31]([C:37]([F:40])([F:39])[F:38])=[N:32][N:33]([CH3:36])[C:34]=1[Cl:35]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:35][C:34]1[N:33]([CH3:36])[N:32]=[C:31]([C:37]([F:40])([F:39])[F:38])[C:30]=1[CH2:14][S:11][C:8]1[CH2:7][C:6]([CH2:5][Cl:4])([CH3:15])[O:10][N:9]=1
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1Cl
Reactant: CC1(CCl)CC(S(C)(=O)=O)=NO1
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1Cl
Reaction time: 2 h
Yield: 91.1 %

Procedure:
1.2 g (15.0 mmoles) of sodium hydrosulfide hydrate (purity: 70%) was added into a solution of 2.1 g (10.0 mmoles) of 5-chloromethyl-5-methyl-3-methylsulfonyl-2-isoxazoline dissolved in 20 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Then, there were added 2.1 g (15.0 mmoles) of anhydrous potassium carbonate, 2.3 g (15.0 mmoles) of Rongalit and 2.8 g (10.0 mmoles) of 4-bromomethyl-5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.3 g (yield: 100.0%) of 3-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline.
Reaction SMILES: [C:1]([C:4](=[CH:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:2][C:1]1[O:3][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC=C(C(C)=O)C(=O)OCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccoc1C
Yield: 23.7 %

Procedure:
A mixture of 3.12 g (0.02 mole) ethyl 2-acetyl-2-butenoate and 3.56 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 19 hours. After cooling, the insoluble succinimide was removed by filtration and the solution concentrated by rotary evaporation. Distillation of the crude product gave 0.73 g (24%) of ethyl 2-methyl-3-furoate, bp 87°-9° C. (20 mm).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[CH2:94]([N:96]1[CH:100]=[C:99]([CH2:101][CH2:102][NH2:103])[N:98]=[CH:97]1)[CH3:95]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:34]1([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH:25][C:4]2[N:3]=[C:2]([NH:103][CH2:102][CH2:101][C:99]3[N:98]=[CH:97][N:96]([CH2:94][CH3:95])[CH:100]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCn1cnc(CCN)c1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCc5cn(CC)cn5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with 2-(1-ethyl-1H-imidazol-4-yl)-ethylamine (intermediate CD). MS (ES+) m/e 647.42 (MH+).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][C:20]([NH2:29])([CH3:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH3:28][C:20]([NH:29][C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:19])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NC(C)(C)Cc3ccccc3)c(=O)c2=O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) in ethanol (3 mL) was added 1,1-dimethyl-2-phenyl-ethylamine (0.182 g, 1.22 mmol). The mixture was stirred at 70° C. overnight then filtered hot through a pad of silica gel. The filtrate was concentrated and the resulting residue was recrystallized from ethyl acetate/hexanes to give 0.170 g (83%) of the title product as a tan solid: m.p. 150-151° C.; 1H NMR (DMSO-d6) δ 8.28(s,1H), 8.00(m,2H), 7.28(m,2H), 7.26(m,1H), 7.13(m,2H), 7.09(m,2H), 3.82(s,3H), 3.10(s,2H), 1.42(s,6H); IR (KBr) 3420, 2950, 1775, 1715, 1650, 1570, 1410, 1252, 1200, 1045, 850, 740, 700, 602, 530 cm−1; MS (m/z) 335 [M+].
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]=[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[CH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[OH-].[Na+]>CCOCC.O>[CH2:1]([NH:4][CH2:5][CH2:6][CH:7]=[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[CH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[CH3:2]
Reactant: CC(=O)NCCC=C1c2ccccc2C=Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCNCCC=C1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(3-Acetamidopropylidene)-5H-dibenzo[a,d]cycloheptene is dissolved in absolute ether. The solution is added dropwise to a stirred solution of lithium aluminum hydride in ether, containing 1.25 molar equivalents of the hydride. The mixture is stirred for 2 hours at room temperature, then for 15 hours at reflux. The mixture is then cooled and stirred while water is added cautiously, followed by sodium hydroxide solution. The ether layer is separated, washed with water and dried over sodium sulfate. The product is obtained by evaporation of the ether and purified by vacuum distillation.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.CS([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)(=O)=O>CN(C=O)C>[F:3][C:4]([F:16])([F:17])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:26]2[CH:25]=[CH:24][N:23]=[CH:22][CH:27]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)c1ccccn1
Reactant: OCCc1ccc(OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(CCOc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of about one gram of 60% NaH (dispersion in oil) in 20 mL of dry DMF was added 5.2 g (0.023 m) of 2-[4-(2,2,2-trifluoroethoxy)phenyl]ethanol. The mixture was stirred at room temperature for 40 minutes, then 3.1 g (0.02 m) of methylsulfonyl pyridine was added. The mixture was stirred at room temperature overnight, then DMF was evaporated in vacuo, and the residue was diluted with water and extracted with CH2Cl2. The CH2Cl2 layer was separated, washed with saturated NaCl solution and filtered through phase separating paper. The product was concentrated to yield 6.2 g of crude product, which was adsorbed onto silica gel and chromatographed over silica gel 60 (230-400 mesh) using CH2Cl2 →50% EtOAc/CH2Cl2 to give the title product as an oil. Yield 2.5 g.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([OH:19])[CH3:18].O>CN(C=O)C>[OH:19][CH2:17][CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(O)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCO)cc1
Yield: 80.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, bromoethanol (450 mg, 3.6 mmol) were added. The mixture was heated to reflux for 3 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution, dried with Na2SO4. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 2/1); 400 mg (yield 80%) of pure product of the title were obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[C:7]([O:11][C:12](=[O:15])[NH:13][NH2:14])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([NH:13][N:14]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:15])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCC(=O)CC
Reactant: CC(C)(C)OC(=O)NN
Product: CCC(CC)=NNC(=O)OC(C)(C)C

Procedure:
B-20a is prepared analogously to B-19a starting from 3-pentanone (1.23 mL, 11.6 mmol) and tert-butylcarbazate (1.53 g, 11.6 mmol). Yield: 2.26 g.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([C@@H:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)[NH:18][CH:19]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]([NH:29][C@@H:30]([CH:34]([CH3:36])[CH3:35])[C:31](O)=[O:32])=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[N:16]=[C:17]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:31](=[O:32])[C@@H:30]([NH:29][C:27](=[O:28])[O:26][CH3:25])[CH:34]([CH3:36])[CH3:35])[NH:18][CH:19]=3)=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: Brc1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4)n3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(Br)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of (S)-4-(4′-bromo-[1,1′-biphenyl]-4-yl)-2-(pyrrolidin-2-yl)-1H-imidazole hydrochloride (423 mg, 1.045 mmol) in DMF (5 mL) is sequentially added (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (201.5 mg, 1.150 mmol), DIPEA (405.2 mg, 546.1 μL, 3.135 mmol) and HATU (596.2 mg, 1.568 mmol) under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 2 hours and diluted with saturated aqueous NaHCO3 (10 mL). The reaction mixture is extracted with EtOAc (5×10 mL), and the combined organic layer are washed with H2O (3×10 mL), and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (2 to 20% methanol in CH2Cl2) to give methyl ((S)-1-((S)-2-(4-(4′-bromo-[1,1′-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (462 mg, 84%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C1COCC1.[CH2:14](Br)[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)c1cccs1
Reactant: CC(C)CBr
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(=O)O)s1
Temperature: -78 °C
Reaction time: 5 h
Yield: 28.2 %

Procedure:
To a solution of 2-thiophene-carboxylic acid (4.16 g, 32.1 mmol) in THF (200 mL) tert. butyllithium (49 mL, 1.7 M solution in pentane, 83.6 mmol) is slowly added at −78° C. The mixture is stirred at −78° C. for 30 min before isobutylbromide (22.7 g, 160.7 mmol) is carefully added. The mixture is stirred at −78° C. for 5 h, then at rt for 16 h. The reaction is quenched by the addition of water (400 mL). The mixture is acidified and extracted with EA. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on reverse phase silica gel to give the title compound (1.67 g) as a brownish oil; LC-MS: tR=0.91 min, 1H NMR (CDCl3): δ 0.96 (d, J=6.7 Hz, 6H), 1.94 (hept, J=6.7 Hz, 1H), 2.72 (d, J=7.0 Hz, 2H), 6.80 (d, J=3.8 Hz, 1H), 7.73 (d, J=3.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(-c2cncc(Cl)n2)cc1
Temperature: 25 °C
Yield: 308.1 %

Procedure:
To a mixture of 2,6-dichloropyrazine (3 g, 20 mmol), sodium carbonate (5.5 g, 52 mmol) and 4-chlorophenylboronic acid (3.79 g, 3.36 mmol) in dimethoxyethane (140 mL) and water (70 mL) under nitrogen was added tetrakis(triphenylphosphine) palladium (0) (0.46 g). The resulting mixture was heated at reflux for 18 h under nitrogen. The reaction mixture was allowed to cool to room temperature and diluted with water (150 mL) and extracted with dichloromethane (2×200 mL). The organic solution was passed through a hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ (Si, 90 g) 9:1 cyclohexane:EtOAc afforded the title compound as a white solid (2.33 g).