Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:15][N:13]([CH3:14])[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=3)=[O:29])=[CH:3][CH:4]=2)=[O:7])[CH2:9]1
Reactant: CN(C)C1CCN(C(=O)c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc(NC(=O)c3ccc4ccccc4n3)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
A mixture of 1-(4-aminobenzoyl)-3-dimethylamino-pyrrolidine (46 mg, 0.2 mmol), quinoline-2-carbonyl chloride (38 mg, 0.2 mg) and diisopropyl ethyl amine (0.1 mL, 0.6 mmol) in CH2Cl2 is stirred at room temperature for 5 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by reverse-phase semi-preparative HPLC, using the same HPLC conditions described in Example 1, to give the title compound as a white powder (10mg), identified by HPLC and mass spectral analyses. Retention Time, MS [366.2 m/e (M+H)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: OCc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-chlorodibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydro-dibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:11][C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[Cl:38]>CN(C=O)C>[Cl:38][C:32]1[C:33]([Cl:37])=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:4]1[C:5]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[C:6]=2[N:7]=[C:3]1[CH:2]([F:1])[F:22]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)F)[nH]c12
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(Cl)c1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A mixture of methyl 2-(difluoromethyl)-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 68 (1000 mg, 3.2 mmol), K2CO3 (884 mg, 6.4 mmol) and 1-(bromomethyl)-2,3-dichlorobenzene (926 mg, 3.8 mmol) in DMF (30 mL) was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was poured into water (100 mL) and filtered, the filter cake was collected and purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the desired product (1.4 g, 93%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 3.16 (s, 4H), 3.74 (s, 4H), 3.92 (s, 3H), 5.77 (s, 2H), 6.21 (d, 1H, J=7.5 Hz), 7.20-7.58 (m, 5H); LC-MS: m/e=470 [M+1]+
Reaction SMILES: [C:1]1([CH3:36])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH3:36])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (E)-ethyl 8-(2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)oct-2-enoate (step 1)(60 mg, 0.124 mmol) and 10% Pd/C (66.0 mg, 0.062 mmol) in MeOH (10 ml) placed under an atmosphere of hydrogen at 0.35 bar pressure and stirred at room temperature overnight. The mixture was filtered through Celite® (filter material) and washed through with MeOH. The filtrated was concentrated in vacuo and purification of the crude product by chromatography on silica eluting with iso-hexane/EtOAc afforded the title compound as a pale yellow oil;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[O:16])[C:13](=[O:24])[N:12]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:11]3[CH2:35][CH2:36][C:37](=[O:38])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].OO.S([O-])(O)(=O)=[O:42].[K+].O>C(O)C.C[Re](=O)(=O)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH:18]3[CH2:19][CH2:20][S:21](=[O:42])[CH2:22][CH2:23]3)=[O:16])[C:13](=[O:24])[N:12]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:11]3[CH2:35][CH2:36][C:37](=[O:38])[C:10]2=3)=[CH:7][CH:8]=1)#[N:2]
Reactant: O=S(=O)([O-])O
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCSCC2)cc1
Agent: C[Re](=O)(=O)=O
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=O)CC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-(4-cyanophenyl)-2,5-dioxo-N-(tetrahydro-2H-thiopyran-4-yl)-1-(3-(tri-fluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxamide (example 42.7, 94 mg, 0.18 mmol) in ethanol (1.0 mL) is cooled at −78° C. with an acetone/dry ice bath. Aqueous hydrogen peroxide (36%, 87 μL, 1.0 mmol) is added, and the mixture is stirred at −78° C. for 30 min Methyltrioxorhenium(VII) (1 mg, 4 μmol) is a) added, and the mixture is stirred at −78° C. for 30 min Another portion of methyltrioxo-rhenium(VII) (1 mg, 4 μmol) is added, and the mixture is stirred at −78° C. for 1 h. Aqueous potassium hydrogen sulfate solution (10%, 0.5 mL) and water is (10 mL) is added, and the mixture is filtered. The precipitate is dissolved in N,N-dimethylformamide, and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 40 mg; ESI mass spectrum [M+H]+=557; Retention time HPLC: 0.96 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])(=[O:22])=[O:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])(=[O:21])=[O:22])[N:11]([CH3:31])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)C(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(S(=O)(=O)C(F)(F)C(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 94 %

Procedure:
A mixture of 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole (3.0 g, 0.0071 mole), methyl iodide (1.5 g, 0.011 mole), potassium carbonate (1.5 g, 0.011 mole), and dimethylformamide (30 ml) was stirred for 50 hours at room temperature in a stoppered flask. The mixture was then poured into water, and after the oil crystallized, the solid was collected and washed with water. There was obtained 2.9 g of colorless crystals, mp 122°-124°. Recrystallization from heptane (125 ml) gave 2.5 g (81%) of colorless prisms, mp 125°-126.5°.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[O-2].[Mg+2].C1COCC1>C(OCC)C>[CH3:12][C:6]([CH3:13])([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:5][CH:4]=[CH:3][CH2:2][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)CC(C)(C)CC=CCCl
Reactant: NCCN1CCNCC1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(C)CC=CCNCCN1CCNCC1

Procedure:
In a similar manner to Example 4, 10 g (4.95 mmol) of 1-chloro-5,5,7,7-tetramethyl-2-octene, 64 g (495 mmol) of 1-(2-aminoethyl)piperazine, 10 g (248 mmol) of magnesium oxide and 30 ml of THF are refluxed for 4 h. The mixture is diluted with 300 ml of diethyl ether and extracted once each with 5% strength aqueous NaOH and water, concentrated and dried at 40° C./1 mbar. Yield: quantitative.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:15][CH2:16][CH2:17][CH3:18])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][CH:44]=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][CH2:44][N:15]([C@@H:13]([CH3:14])[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=2)[CH2:16][CH2:17][CH3:18])[CH2:35][CH2:34]1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCCC=O)CC1
Reactant: CCCN[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCN(CCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
A mixture of [(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamine hydrochloride (2.05 g, 7.03 mmole), triethylamine (0.98 mL, 7 mmole), 5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.0 g, 7.03 mmole), and sodium triacetoxyborohydride (2.23 g, 10.5 mmole) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 15 hours. The mixture was concentrated, and the residue was partitioned between diethyl ether and saturated sodium carbonate. The organic phase was dried (magnesium sulfate) and concentrated to give 4-(4-{[(S)-2-(4-methane-sulfonylphenyl)-1-methylethyl]propyl-amino}butyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.6 g) as a heavy syrup. M+H=524. The hydrochloride salt was recrystallized from acetone/diethyl ether, m.p. 156–158° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](C1C=C(B(O)O)C=CC=1)=[O:22]>>[CH:21]([C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1)=[O:22]
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=Cc1cccc(B(O)O)c1
Product: O=Cc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1

Procedure:
In a manner similar to that described above for Compound 12, the tricyclic bromide (381 mg, 1.44 mmol) and 3-formylbenzeneboronic acid (345 mg, 2.16 mmol) were coupled to yield 2-(3-formylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one 15, 346 mg (83%), as a tan solid. 1H NMR (300 MHz, d6-DMSO) δ 2.86 (m, 2H), 3.16 (m, 2H), 7.01 (t, 1H, J=7.8 Hz), 7.34 (d, 1H, J=7.3 Hz), 7.50 (m, 2H), 7.73 (m, 2H), 7.85 (br t, 1H), 7.94 (s, 1H), 9.88 (s, 1H), 11.50 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Cl.[OH-].[Na+].CCOC(C)=O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][CH2:14][C:15](=[O:16])[CH2:20][CH2:21]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC4(CC3)OCCO4)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of 8-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane (0.97 g, 2.36 mmol) in 1,4-dioxane (16 mL) was slowly added concentrated HCl (24 mL) and the resulting solution was stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and the pH was adjusted to 12 by careful addition of an aqueous solution of NaOH (50% w/v). EtOAc was added, the layers were separated and the aqueous layer was extracted further with EtOAc. The combined organic layers were dried (Na2SO4), then concentrated in vacuo to give the title compound as a yellow solid (0.9 g, 100%).
Reaction SMILES: C([O:5][C:6](=[O:22])/[CH:7]=[CH:8]/[C:9]1[CH:21]=[N:20][C:12]2[NH:13][C:14](=[O:19])[CH2:15][N:16]([CH3:18])[CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:16]1[CH2:17][C:11]2[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:22])=[O:5])[CH:21]=[N:20][C:12]=2[NH:13][C:14](=[O:19])[CH2:15]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)OC(C)(C)C)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 163.9 %

Procedure:
A suspension of (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid tert-butyl ester (0.59 g, 1.9 mmol) in CH2Cl2 (7 mL) was treated with TFA (7 mL). After stirring at room temperature under N2 for 45 min, the clear tan solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl in dioxane (10 mL, 4.0 M) and sonicated until the oil was converted to a fine off-white solid. After stirring under N2 for 20 min, the solid was isolated by filtration, washed with Et2O, and dried under vacuum for several hours to give the title compound (0.77 g, quantitative) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.27 (bs, 1H), 11.28 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.32 (d, J=1.9 Hz, 1H), 7.65 (d, J=16.1 Hz, 1H), 6.63 (d, J=16.1 Hz, 1H), 4.32 (s, 2H), 3.82 (s, 2H), 2.89 (s, 3H); MS (ESI) m/e 248 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][C@@H:19]1[CH2:31][CH2:32][OH:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][C@@H:19]1[CH2:31][CH:32]=[O:33])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 653.8 %

Procedure:
Combine a solution of oxalyl chloride (0.1.83 mL, 21.0 mmol) in dichloromethane (20 mL) with a solution of dimethyl sulfoxide (2.34 mL, 33.0 mmol) in dichloromethane (10 mL) at −78° C. and stir for 15 minutes. Add a solution of (S)-2-(1,4-dibenzylpiperazin-2-yl)ethanol (0.60 g, 1.82 mmol) in dichloromethane (10 mL) at −78° C. via cannula. Stir at −78° C. for one hour, add triethylamine (10.5 mL, 75.0 mmol) and warm to room temperature overnight. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 6% 2N ammonia-methanol in dichloromethane to obtain the title compound (3.66 g, 11.9 mmol, 79%) as a brown oil: mass spectrum (APCI): m/z=309.4 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C:21]([F:24])([F:23])[F:22])[C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:27]>>[CH2:1]([O:8][C@H:9]([C:21]([F:23])([F:22])[F:24])[C@@H:10]([NH:13][C:14]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:20])[C:11]([OH:27])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)[C@H](OCc1ccccc1)C(F)(F)F
Reactant: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)[C@H](OCc1ccccc1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2S,3S)-3-(benzyloxy)-4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (1.47 g, 4.2 mmol) in acetone (80 mL) was added Jone's reagent (8.2 mL) at 0° C. The mixture was stirred at the same temperature for 3 h until the starting material was completely consumed, then the reaction was quenched by adding isopropanol (5 mL). The reaction mixture was extracted with EtOAc. The extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave the crude (2R,3S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (1.56 g), which was used directly for the following reaction. 1H NMR (400 MHz, CD3OD, δ in ppm) 7.25˜7.34 (m, 5H), 4.76 (d, J=10.9 Hz, 1H), 4.70 (d, J=10.9 Hz, 1H), 4.53 (d, J=6.4 Hz, 1H), 4.32 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=O)[CH2:14][CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:20][CH:17]3[CH2:19][CH2:18]3)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2CN(Cc3ccccc3)CC12
Reactant: NC1CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2C[C@@H]3CC[C@H](NC4CC4)[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (0.578 g, 2.68 mmol), cyclopropylamine (0.189 mL, 2.68 mmol), and acetic acid (10 mL) were combined in dichloromethane (20 mL). PS-Cyanoborohydride (1.147 g, 2.68 mmol) was added. The reaction was stirred at room temperature for 2 hours, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was applied to a silica gel column and was eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compounds.
Reaction SMILES: COC([C:5]1([CH2:25][CH:26]=[CH2:27])[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24])=O.[Br-].[Li+]>CN(C)C=O.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]2[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[NH:7][C:6](=[O:24])[C@H:5]2[CH2:25][CH:26]=[CH2:27])=[CH:13][CH:14]=1
Reactant: C=CCC1(C(=O)OC)C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C(=O)Nc2ccccc2C[C@@H]1c1ccc(OC)cc1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-3-(2-propenyl)-2H-1-benzazepin-2-one (4.56 g, 12.48 mmol), lithium bromide (6.18 g, 71.13 mmol) and α-aminothiophenol (3.12 g, 24.96 mmol) in 38 ml of dry dimethylformamide was heated to 137° C. (oil bath temperature) under argon for 51/2 hours. The reaction mixture was cooled to room temperature and diluted with water (250 ml total volume). The precipitate was collected by filtration, rinsed with 1M hydrochloric acid, saturated aqueous potassium carbonate solution, water, and dried in vacuo with phosphorous pentoxide to give 3.5 g of a white solid. Recrystallization from methanol (3 crops) yielded 3.03 g of white needles, melting point 169°-171° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].P(Cl)(Cl)Cl.[C-:24]#[N:25].[Na+].CS(C)=O>O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][C:24]#[N:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [C-]#N
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClP(Cl)Cl
Solvent: O
Product: CCCCC[C@H]1CC[C@H](c2ccc(CC#N)cc2)CC1

Procedure:
27.9 g of 4-(trans-4-pentylcyclohexyl)benzyl chloride (obtained by chloromethylation of trans-4-pentyl-1-phenylcyclohexane or by esterification of 4-(trans-4-pentylcyclohexyl)benzoic acid, reduction of the methyl or ethyl ester obtained to give 4-(trans-4-pentylcyclohexyl)benzyl alcohol and reaction with PCl3) was added within 15 minutes at 60°, with stirring, to a mixture of 5.5 g of NaCN and 40 ml of dimethyl sulfoxide. The mixture was heated at 70° for 6 hours, cooled down, poured into water and 4-(trans-4-pentylcyclohexyl)phenylacetonitrile was obtained, m.p. 53°, c.p. -19°.
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17](Cl)[CH3:18])=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Cl)c1ccc(C(=O)c2cccs2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C#N)c1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C

Procedure:
A suspension of 4.9 parts of sodium cyanide in 55 parts of dimethyl sulfoxide is stirred while heating to 60° C. Then there are added at once 8.5 parts of p-(1-chloroethyl)phenyl 2-thienyl ketone and stirring at 60° C is continued for 4h.30. The reaction mixture is poured onto water and the product is extracted with ether. The organic layer is washed with water, dried, filtered and evaporated, yielding p-(2-thenoyl)hydratroponitrile as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][O:12][CH:13]([O:17][CH3:18])[C:14](=O)[CH3:15].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH:14]([NH:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:15]
Reactant: COc1cccc(CN)c1
Reactant: COC(OC)C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(CNC(C)C(OC)OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.7 %

Procedure:
(3-Methoxyphenyl) methanamine (100 g, 730 mmol, 1 equiv.) and 1,1-dimethoxypropan-2-one (172.2 g, 1.46 mol, 2 equiv.) were dissolved in acetic acid (1.8 L). Anhydrous sodium sulfate (207 g, 1.46 mol, 2 equiv.) was added. The mixture was stirred for 1.5 hour at room temperature. Sodium triacetoxyborohydride (463 g, 2.19 mmol, 3 equiv.) was added in portions over 40 minutes. The mixture was stirred for an additional 2 hours. Most of the acetic acid was removed under reduced pressure. The resulting black oil was dissolved in ethyl acetate (2 L) and saturated aqueous sodium bicarbonate (1 L) was added slowly followed by solid potassium carbonate to adjust the pH to 7. The organic layer was separated, dried over sodium sulfate and filtered. The filtrate was concentrated under reduce pressure to give a black oil which was purified by silica gel chromatography to give the title compound (120 g, ˜85% purity by LC/MS, 68% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N[CH2:34][CH2:35][OH:36].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:34][CH2:35][OH:36])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCO)C1
Yield: 55 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2-amino-ethanol, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (60 mg, 55%); LCMS (method B): RT=3.25 min, M+H+=490.