Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]([C:9]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:12]([NH2:13])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S-:22][C:23]#[N:24].[Na+].O.Cl>CC1C=CC=CC=1C>[O:2]([C:9]1[CH:10]=[C:11]([CH:19]([CH3:21])[CH3:20])[C:12]([NH:13][C:23]([NH2:24])=[S:22])=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N
Reactant: N#C[S-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1NC(N)=S
Temperature: 25 °C
Yield: 95.9 %

Procedure:
305 g (1 mol) of 4-phenoxy-2,6-diisopropylaniline hydrochloride, 97 g (1.2 mol) of sodium thiocyanate, 10 ml of water and 10 ml of concentrated hydrochloric acid are suspended in 800 ml of o-xylene. The mixture is heated to 90° C. over 6 hours, during which time 2 ml of concentrated hydrochloric acid are added after 3 hours and then after each further hour. Thereafter the reaction mixture is cooled to room temperature and the product is isolated by filtration, washed with water and dried, giving 315 g (96% of theory) of N-(4-phenoxy-2,6-diisopropylphenyl)thiourea in the form of pale grey crystals which melt at 219°-221° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:32])[C@H:21]([N:29]=[C:30]=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.COC(=O)C(N=C=O)CC1C=CC=CC=1>C1COCC1>[CH3:18][O:19][C:20](=[O:32])[C@H:21]([NH:29][C:30]([O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][C:10]=2[CH:12]=1)=[O:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCc1ccc2oc(-c3ccccc3)cc2c1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Agent: COC(=O)C(Cc1ccccc1)N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of 2-phenyl-benzofuran-5-carboxylic acid methyl ester 27 (0.7 g, 2.8 mmol) in THF (15 ml) was added dropwise a solution of lithium aluminum hydride (1M in THF) (3.6 ml, 3.6 mmol) at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hrs. The mixture was cooled to 0° C., diluted with ether and sodium sulfate decahydrate was added. After filtration the solids were washed with ether, and the organic layer was washed and dried. Evaporation of the solvent and purification by chromatography yielded (2-phenyl-benzofuran-5-yl)-methanol (0.55 g). A mixture of (2-phenyl-benzofuran-5-yl)-methanol (0.5 g, 2.23 mmol), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.55 g, 2.68 mmol), triethylamine (0.74 ml, 5.35 mmol) and THF (15 ml) was heated at 50° C. for 6 hrs. Additional (R) 2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.15 g) was added, and the mixture was stirred at 50° C. overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. After extraction and evaporation of the solvent, the residue was purified by chromatography to give about 0.76 g of (R)-3-phenyl-2-(2-phenyl-benzofuran-5-ylmethoxycarbonylamino)-propionic acid methyl ester 28.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C(C)=CC=CC=1C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:24])[C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:25](=[O:27])[CH3:26])[CH:6]=1)=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 50 °C

Procedure:
A flask charged with 3-(3-amino-isoxazol-5-yl)-6-chloro-4-phenyl-1H-quinolin-2-one (example 59)(22 mg, 0.063 mmol), acetic anhydride (9 mg, 0.082 mmol), 2,6-lutidine (11 mg, 0.10 mmol), DMAP (10 mg, 0.082 mmol) and DMF (0.5 mL) was heated at 50° C. for 2 hrs. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 40-100% CH3CN in 0.1% TFA/H2O over 30 mins to give 15 mg (60%) the title cpd. 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.80 (s, 1H), 7.68 (m, 1H), 7.46 (m, 4H), 7.30 (m, 2H), 6.96 (m, 2H), 2.04 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H14ClN3O3 379.1, found 380.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][NH:11][CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH:17](I)([CH3:19])[CH3:18]>[Ag]=O.CC(C)=O>[CH:17]([N:11]1[CH2:12][CH2:13][CH:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1cccc(C2=CCCNC2)c1
Reactant: CC(C)I
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CC(C)N1CCC=C(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2.2 g of 3-(3-trifluoromethyl-phenyl)-1,2,5,6-tetrahydropyridine, 18 ml of acetone, 1.18 g of silver oxide and 1.4 ml of isopropyl iodide was stirred for 12 hours at room temperature and after the addition of 0.7 ml of isopropyl iodide and 0.5 g of silver oxide, the mixture was stirred another 3 hours at room temperature and was filtered. The filtrate was evaporated to dryness to obtain 2.9 g of raw product which was chromatographed over silica gel. Elution with an 85-10-5 cyclohexane-chloroform-triethylamine mixture yielded 2.21 g of 1-isopropyl-3-(3-trifluoromethyl-phenyl)-1,2,5,6-tetrahydropyridine in the form of a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[C:4](F)=[C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[N:7][C:6]2=[C:13]([C:16]#[N:17])[C:14]=1[CH3:15].C(N(CC)CC)C.[CH3:27][N:28]([CH3:34])[C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CSC>[CH:10]1([C:8]2[O:9][C:5]3[C:6](=[C:13]([C:16]#[N:17])[C:14]([CH3:15])=[C:3]([N:2]([CH3:19])[CH3:1])[C:4]=3[N:31]3[CH2:32][CH2:33][C@H:29]([N:28]([CH3:34])[CH3:27])[CH2:30]3)[N:7]=2)[CH2:12][CH2:11]1
Reactant: Cc1c(N(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CSC
Solvent: CCN(CC)CC
Product: Cc1c(N(C)C)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
6-Dimethylamino-2-Cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-321) (34 mg, 0.10 mmol) was dissolved in dimethyl sulfide (4 ml), then triethylamine (29 μl, 0.20 mmol) and (3S)-3-(dimethylamino)pyrrolidine (27 μl, 0.21 mmol) were added, followed by stirring under nitrogen atmosphere at 100° C. for 24 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (20 mg, 64%) as a white crystal.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:54](=[O:62])[NH:55][S:56]([CH:59]([CH3:61])[CH3:60])(=[O:58])=[O:57])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45](O)=[O:46])=[CH:42][C:41]4[CH:48]=[C:49]([O:52][CH3:53])[CH:50]=[CH:51][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:63][N:64]1[CH2:73][CH2:72][C:67]2([NH:71][CH2:70][CH2:69][CH2:68]2)[CH2:66][CH2:65]1>CN(C=O)C.CO>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:54]([NH:55][S:56]([CH:59]([CH3:61])[CH3:60])(=[O:57])=[O:58])=[O:62])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]([N:71]4[C:67]5([CH2:66][CH2:65][N:64]([CH3:63])[CH2:73][CH2:72]5)[CH2:68][CH2:69][CH2:70]4)=[O:46])=[CH:42][C:41]4[CH:48]=[C:49]([O:52][CH3:53])[CH:50]=[CH:51][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reactant: CN1CCC2(CCCN2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(C(=O)N1CCCC13CCN(C)CC3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
HATU (30 mg, 0.079 mmol) was added to a stirring solution of 13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (34 mg, 0.063 mmol) and 8-methyl-1,8-diazaspiro[4.5]decane (24 mg, 0.16 mmol) in DMF (0.5 mL) and TEA (100 μL, 0.72 mmol) and the reaction mixture was stirred at rt for 1 h (complete by LCMS). The reaction mixture was diluted with MeOH, filtered and purified by preparative HPLC (CH3CN/H2O w/10 mM NH4OAc) to yield 13-cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (19.7 mg, 0.029 mmol, 46% yield) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ ppm 1.10-2.20 (m, 22H), 2.76 (s, 3H), 2.67-3.49 (m, 9H), 3.91 (s, 3H), 3.86-4.00 (m, 1H), 4.27-4.45 (m, 1H), 5.07-5.20 (m, 1H), 6.91 (s, 1H), 7.03 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.73 (dd, J=8.4, 1.5 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 8.26 (br s, 1H). LC-MS retention time: 2.64 min; m/z 671 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[C:4]=1[C:5]([NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)=[O:6].C(O)(=O)C.[CH3:36][C:37]([CH3:39])=O.C([BH3-])#N.[Na+]>CO>[CH:37]([N:10]1[CH2:11][CH2:12][CH2:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[C:20]([C:28]([F:31])([F:29])[F:30])=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:3]=2[O:2][CH3:1])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)([CH3:39])[CH3:36]
Reactant: CC(C)=O
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCN(C(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 35.7 mg (0.08 mmol) rac-2-methoxy-N-(3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide in methanol were added 28 ul (0.48 mmol) acetic acid, 59 ul (0.8 mmol) acetone and finally 30 mg (0.4 mmol) sodium cyanoborohydride. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed once with a 1N NaOH solution, once with water and once with brine. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 33 mg (85%) of the title compound as a white foam. MS (m/e): 489.4 (M+H).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH3:12][C:13](=O)[CH2:14][C:15](=O)[CH3:16]>C(O)(C)C>[CH3:12][C:13]1[CH:14]=[C:15]([CH3:16])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)n(-c2ccc(C(=O)O)cc2)n1
Yield: 99.8 %

Procedure:
4-Hydrazinylbenzoic acid (251a, 2 g, 13.2 mmol) and pentane-2,4-dione (1.35 mL, 13.2 mmol) were dissolved in isopropanol (40 mL) and refluxed for 15 hours. The solvent was removed under reduced pressure to afford 252a as a white solid (2.85 g, 99% yield). 1H NMR: (DMSO) δ 8.04 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 6.14 (s, 1H), 2.39 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47]>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiophene-3-carboxylic acid (2.75 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for 15 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DRPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)thiophene-3-amide. LCMS: retention time 3.69 min, MH+ 344. NMR: δH [2H6]-DMSO 10.06,(1H, b), 8.34,(1H, m), 8.29,(1H, d), 7.70,(1H, dd), 7.66,(1H, dd), 7.62,(1H, dd), 7.30,(1H, d), 2.34,(3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[NH:16][C:17](=[O:27])[N:18]3[CH2:23][CH2:24][C:25]#[N:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]#[C:37][CH3:38].Cl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:35][C:36]#[C:37][CH3:38])[C:17](=[O:27])[N:18]3[CH2:23][CH2:24][C:25]#[N:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[nH]c(=O)n3CCC#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(=O)n(CCC#N)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
4-[9-(2-Cyano-ethyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (623 mg) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (300 mg) and 1-bromo-2-butyne (0.18 mL) were then added to this solution. The reaction solution was stirred at room temperature for 19 hours, then water (20 mL) and 1 N hydrochloric acid (5 mL) were added. This was then twice extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine. The resulting organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (484 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:14][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Clc1cncc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cncc(Cl)n2)cc1

Procedure:
2,6-Dichloropyrazine (2.98 g, 20.0 mmol), [4-(methylsulfonyl)phenyl]boronic acid (2 g, 10.0 mmol), tetrakis(triphenylphospine)palladium (1.15 g, 1.0 mmol), potassium phosphate (10.2 g, 48 mmol) and dimethylformamide (90 ml) were heated to 80° C. for 16 hours. The solvent was removed in vacuo and the product was dissolved in chloroform and filtered through celite. The filtrate was washed with water then separated. The residue was purified by column chromatography eluting with a mixture of ethylacetate:hexane (4:6) to afford the title compound. MS (ES+) m/e 270 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11])([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[C:5]=1[OH:11])([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cccc(O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a solution of 3-nitrobenzene-1,2-diol (2.78 g) and 3,4-dihydro-2H-pyrane (1.81 g) in benzene (39 ml) was added p-toluenesulfonic acid monohydrate (5 mg) at ambient temperature, and the mixture was stirred for 24 hours. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-methanol) and crystallized with n-hexane to give 2-nitro-6-(tetrahydropyran-2-yloxy)phenol (2.32 g).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>O1CCCC1.CO>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:4](=[S:3])[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:6]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)n(C(=O)OC(C)(C)C)c(=S)n2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (60% in oil) (5.55 g; 138 mmol) is added in small portions at 10° C., with stirring, to a solution of 2-mercapto-5-methoxybenzimidazole (10 g; 55.5 mmol) in solution in 400 ml of tetrahydrofuran under argon. The reaction mixture is then stirred for 30 minutes at 0° C., and then BOC2O (26.64 g; 122 mmol) is added in one go. Stirring of the reaction mixture is then carried out for 18 hours at ambient temperature. The reaction mixture is diluted with methanol, filtered over Celite and then concentrated to dryness. The residue obtained is subsequently taken up in a 1/1 mixture of petroleum ether/isopropyl ether. The solid which precipitates is then suction-filtered off to yield the title product in the form of a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[O:21][CH:22]=1>>[CH:23]1([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: ClCc1coc(C2CCCCC2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1cn(CCCc2ccc(OCc3coc(C4CCCCC4)n3)cc2)cn1
Yield: 38 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-cyclohexyloxazole to give 2-cyclohexyl-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 38%. Recrystallization from ether-hexane gave colorless prisms, mp 46-47° C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.COCCOC>C(OCC)(=O)C>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Reactant: C1CCNC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(N3CCCC3)cc12
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A vial was charged with 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (100 mg, 0.236 mmol), Pd-PEPPSI® (3 mg, 0.005 mmol), potassium tert-butoxide (40 mg, 0.354 mmol) and purged with argon for 15 min. Pyrrolidine (24 μl, 0.283 mmol) and dry 1,2-dimethoxyethane (1 ml) were added and the solution was heated at 80° C. for 18 hours. The mixture was diluted with ethyl acetate washed with a saturated aqueous solution of ammonium chloride, water and brine, dried over sodium sulfate and purified by flash chromatography over silica gel (cyclohexane/dichloromethane: 0-80%) to yield 2-isoquinolin-3-yl-6-(pyrrolidin-1-yl)-chromen-4-one O-tert-butyl oxime (64 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:21]=[CH:22][C:23](O)=O>>[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(C=CC(=O)O)cc(Br)c1OC
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(Br)c(OC)c(OC)c3)nc2n(CCC)c1=O
Yield: 66.6 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 1.5 g (6.64 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.10 g (7.31 mmol) of 3-bromo-4,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.11 g (yield 67%) of Compound 60 as white needles.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=1[F:27].[CH2:28]1[O:31][C@@H:29]1[CH3:30]>C1COCC1>[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[C:16]([CH2:28][C@H:29]([OH:31])[CH3:30])[C:15]=1[F:27]
Reactant: C[C@@H]1CO1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](O)Cc1c(C(=O)NC(C)(C)C)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (11.7 mL, 82.0 mmol) in THF (200 mL) was treated with n-butyllithium (33 mL, 82 mmol) at 0° C. The solution was stirred for 30 min before being cooled to −78° C. Next, a solution of 4-bromo-N-tert-butyl-3-fluorobenzamide (9.0 g, 33 mmol) in THF (100 mL) was added. The solution was then warmed to −40° C. and maintained there for 1 h. Next, (R)-(+)-propylene oxide (6.9 mL, 98 mmol) was added and the solution warmed to 0° C. After 1 h, the ice bath was removed and the solution was allowed to warm to rt. LC/MS indicated desired product present. The solution was quenched with MeOH, diluted with brine (200 mL), and extracted with EtOAc (300 mL). The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude material was purified using a 340 g Biotage SNAP (0-60% Hexanes: EtOAc) cartridge to yield the title compound. LC-MS: m/z 332.08 (M+H)+.