Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[OH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.[OH-].[Na+].Cl>C(O)CC>[OH:7][CH2:8][CH2:9][N:10]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:12][OH:13]
Reactant: OCCNCCO
Reactant: COC(=O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: O=C(O)CN(CCO)CCO

Procedure:
Methyl bromoacetate (152.98 grams, 1 mole) is dissolved in 1-propanol (500 ml.) and bis-(2-hydroxyethyl)amine (105.14 grams, 2 moles) and triethylamine (111.1 grams, 1.1 moles) are added and the mixture is stirred and heated at reflux for 3 hours. The mixture is treated with 10 normal sodium hydroxide (110 ml., 1.1 moles) and the solvents are removed by distillation in vacuo. The residue is filtered and the solid is washed with 1-propanol. The combined filtrates are dissolved in ethanol (400 ml) and 10 normal sodium hydroxide (130 ml, 1.3 moles) is added. The mixture is stirred and heated at reflux for 3 hours. The mixture is acidified with 12 normal hydrochloric acid (108 ml, 1.3 moles). Upon cooling, N,N-bis-(2-hydroxyethyl)aminoacetic acid separates and is collected by filtration, and is washed with a 50% aqueous ethanol and dried.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6][C@@H:5]1[OH:25])[CH3:2].[CH2:26](O)[CH2:27][OH:28].C([O-])([O-])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:26]1[CH2:27][O:28][C:14]2([CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([C:18](=[O:23])[CH2:17][C@:15]23[CH3:16])[C@:20]2([CH3:22])[C@H:7]([CH2:6][C@H:5]([OH:25])[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21]2)[CH2:8][CH2:9]4)[O:24]1
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O
Reactant: OCCO
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@@]2(C)[C@H]3CCC23OCCO3)C[C@@H]1O
Reaction time: 8 h

Procedure:
A solution of 2β-ethoxy-3α-hydroxy-5α-androstane-11,17-dione (8 g) in chloroform (80 ml) containing ethylene glycol (13 ml), ethyl orthoformate (8.3 ml) and p-toluene sulphonic acid (160 mg) was kept at room temperature overnight. The reaction mixture was washed with sodium bicarbonate solution and water, dried (Na2SO4) and evaporated in vacuo. Purification of the residual froth (8.6 g) by preparative thin layer chromatography over silica (acetone-petroleum ether 3:7) and crystallization from ethyl acetate-petroleum ether afforded the title compound m.p. 142°-145°, [α]D +18.2°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].CCN(CC)CC>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (121 mg, 0.28 mmol), isobutyryl chloride (30 mg, 0.29 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (1 mL) was allowed to stir at r.t. for 2 h then concentrated in vacuo. The resulting residue purified by column chromatography (Si-PCC, MeOH:DCM, 0-6%) followed by triturating with Et2O affording 824 as a white solid (86 mg, 61%). LCMS (method I): RT 3.42 min, [M+H]+ 503.2. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.30-7.22 (2 H, m), 4.50-4.20 (4 H, brd s), 4.41 (1 H, t, J=8.45 Hz), 4.32-4.21 (1 H, m), 3.98 (1 H, dd, J=8.63, 5.41 Hz), 3.90-3.80 (5 H, m), 3.76 (3 H, s), 3.34 (2 H, q, J=7.49 Hz), 3.28-3.25 (1 H, m), 3.16-3.11 (2 H, m), 2.47-2.46 (1 H, m), 1.44 (3 H, t, J=7.48 Hz), 1.12 (6 H, dd, J=6.82, 2.82 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C(OO)(=[O:17])C.OO>C(O)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Fc1ccc(Br)cc1-c1cccnc1
Reactant: CC(=O)OO
Agent: OO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [O-][n+]1cccc(-c2cc(Br)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-(5-bromo-2-fluorophenyl)pyridine (2.52 g, 10.0 mmol) and peracetic acid (3.37 ml of a 36-40 wt % solution in acetic acid) in tetrahydrofuran (40 ml) was stirred at ambient temperature for 1 h and then heated at 50° C. for 2 h. Hydrogen peroxide (35 wt % solution in water, 1 ml) was added and the mixture heated at 50° C. for a further hour. The solvent was removed in vacuo and the residue diluted with water and layered with ethyl acetate. Solid sodium hydrogencarbonate was added to pH 8. The layers were separated and the organic layer washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (2-5%) gave 3-(5-bromo-2-fluorophenyl)pyridine-1-oxide as a white solid (2.00 g, 75%): δH (400 MHz, CDCl3) 7.09-7.14 (1H, m), 7.35-7.43 (2H, m), 7.52-7.57 (2H, m), 8.22-8.25 (1H, m), 8.42 (1H, t, J 1).
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=O)[CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:2].[CH3:14][CH:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:16]([C:18]1C=C(O)[CH:21]=[C:22]([CH:24]=1)[OH:23])[CH3:17]>>[CH2:1]([CH:3]1[C:7]2[C:21]3[C:22]([OH:23])=[CH:24][C:18]([CH:16]([CH:15]([CH3:14])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:17])=[CH:13][C:12]=3[O:11][C:9](=[O:10])[C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CCOC(=O)C1CCC(CC)C1=O
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CCC3CC

Procedure:
5-Ethyl-2-carboethoxycyclopentanone is reacted with 5-(3-methyl-2-octyl)-resorcinol to produce 1-ethyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c] [l]benzopyran.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:22])[N:9]2[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH:23]1([NH:29][C:30]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(N(CC)CC)C.C(Cl)Cl>[Si:15]([O:14][CH2:13][CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([C:39]([F:41])([F:42])[F:40])=[CH:38][C:30]=3[NH:29][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:22])([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1NC1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21

Procedure:
A methylene chloride solution of 7-amino-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydroquinolin-2(1H)-one, 2-(cyclohexylamino)-4-(trifluoromethyl)benzoic acid, 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide hydrochloride, dimethylaminopyridine and triethylamine was allowed to undergo the reaction at room temperature. By post-treating the reaction liquid, N-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]-2-(cyclohexylamino)-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Br:23][C:24]1[CH:25]=[C:26]2[CH2:32][C:31](=[O:33])[NH:30][C:27]2=[N:28][CH:29]=1>>[Br:23][C:24]1[CH:25]=[C:26]2[C:27]([NH:30][C:31](=[O:33])/[C:32]/2=[CH:21]\[C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=2[CH3:1])=[N:28][CH:29]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ncc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 60 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyrid in-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 22 (59 mg, yield 60%) as an orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[C:12]([O:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2.O.O.[OH-].[Li+]>CO>[CH3:29][N:2]([CH3:1])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:12]([O:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)N(C)C)c2c(c(C)c1OC)COC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Yield: 94.6 %

Procedure:
To a solution of 0.3 g (0.74 mmol) of methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate in 7.4 ml of 4:1 methanol:water was added 0.13 g (2.96 mmol) of lithium hydroxide monohydrate. The solution was heated at 50°-60° C. for 4 hours. Upon cooling, the reaction was partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to (E)-6-[1,3- dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]- 4-methyl-4-hexenoic acid. Recrystallization from hexane-ethyl acetate gave 0.27 g (0.7 mmol) of (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid, mp 170 °-190° C.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[N:17]\[S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[CH:12][CH:11]=1>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:2]([F:4])([F:3])[F:1])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
Add neat (trifluoromethyl)trimethylsilane (109 mL, 0.74 mol) at 0° C. to a stirred solution of tetrabutylammonium acetate (88 g, 0.29 mol) and (N—Z)—N-[(4-bromophenyl)methylene]-(R)-2-methyl-propane-2-sulfinamide (85 g, 0.29 mol) in DMF (1.2 L) at 0° C. Stir the mixture at 0-5° C. for 90 minutes. Add saturated aqueous ammonium chloride solution (1.2 L) and extract with EtOAc (4×400 mL). Combine the organic extracts and sequentially wash with water then brine (2×1 L); dry over magnesium sulphate; filter; and concentrate the filtrate under reduced pressure. Triturate the residue with hexane (200 mL) for 10 minutes; filter; and dry the filtrate under vacuum to afford the title compound as a yellow solid (81 g, 76% yield, >98 de). MS (m/z): 358 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([O-:19])=[O:18].[OH-].[Na+].Cl>C(OCC)(=O)C.C(N(CC)CC)C>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:23])([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 3.90 g (17.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry ethyl acetate, add 3.26 g (17.56 mmol) of 2-nitrobenzoyl chloride dissolved in 5 ml of dry ethyl acetate and 1.76 g of triethylamine. Allow the reaction mixture to stir for 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the solid has completely disappeared. Immediately acidify with concentrated HCl and extract the product with ethyl acetate. Eliminate the solvent at low pressure and recombine the crude product with dry ether, obtaining a white solid. Purify the reaction product by recrystallization (EtOH/H2O). This yields 3.34 g (51%) of 4-[2-(2-nitrobenzoylamino)benzoylamino]butanoic acid as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([Cl:24])[C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28])[CH:9]=[CH2:10].[OH:29][N:30]=[C:31](Cl)[CH3:32]>ClCCl>[Cl:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][O:26][CH2:27][CH3:28])[N:11]([CH2:8][CH:9]3[O:29][N:30]=[C:31]([CH3:32])[CH2:10]3)[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: C=CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Reactant: CC(Cl)=NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(C)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Triethylamine (1.04 mL, 7.46 mmol) was added to a 0° C. solution of 1-allyl-4-chloro-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (1.50 g, 4.97 mmol) and N-hydroxyethanimidoyl chloride (581 mg, 6.21 mmol) in dichloromethane (80 mL). The reaction solution was allowed to warm slowly to room temperature and stir overnight under a nitrogen atmosphere. After 20 hours, the solution was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, elution with 98:2 dichloromethane/methanol) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.34 g) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[H][H]>C(O)C.[Pd]>[OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 96.2 %

Procedure:
A mixture of 3β-hydroxy-5-pregnen-20-one (980 mg, 316.5 g/m, 3.1 mmol) and 50 mg of 5% Pd/C in 50 mL of absolute ethyl alcohol was stirred under 1 atmosphere of hydrogen gas for 5 hours at room temperature. The reaction was filtered through a celite pad and the filtrate evaporated under reduced pressure to give 950 mg of 3β-hydroxy-5α-pregnan-20-one (96% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccn2)C1

Procedure:
The title compound is synthesized by coupling of (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-chloromethyl-pyridine HCl salt analogously to the preparation of Intermediate 193.2 as a white solid; ES-MS: M+=279.2: AtRet=2.81.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.CO[C:21](OC)([CH3:24])[C:22]#[N:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: COC(C)(C#N)OC
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2ncc(C#N)c(-c3ccccc3Cl)c2c1
Yield: 91.8 %

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (20.0 g), 2,2-dimethoxypropionitrile (11.5 g), p-toluenesulfonic acid hydrate (1.46 g) and toluene (200 ml) was refluxed for 3 hrs., with removal of water by a Dean-Stark apparatus. The mixture was washed with sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The resultant precipitate was collected by filtration and washed with hexane to give 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarbonitrile (20.7 g, 92.0%), which was recrystallized from ethanol to give pale yellow plates. m.p. 153°-154° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C@@H:9]1[NH:12][C:11](=[O:13])[C@H:10]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[N:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:8].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:6][C:7]([C@@H:9]1[N:12]([C:1](=[O:3])[CH3:2])[C:11](=[O:13])[C@H:10]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[N:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])=[O:8]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Yield: 32.5 %

Procedure:
Acetyl chloride (9.5 g, 0.12 mol) was added to a -10° C. methylene chloride (50 mL) solution of compound 7 (2.0 g, 4.0 mmol). Triethylamine (12.3 g, 0.12 mol) was added dropwise with vigorous stirring of the reaction mixture. After the addition was complete, the resultant suspension was stirred for an additional 2 h at room temperature and then washed with H2O. The organic phase was separated, washed with saturated aqueous NaHCO3 solution, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 :MeOH/99.5:0.5) to afford 700 mg (36%) of the title product.
Reaction SMILES: CN(C)C=O.[CH3:6][CH:7]([OH:9])[CH3:8].[H-].[Na+].[Br:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21]Cl)=[CH:15][C:14]=1[O:23][CH3:24]>O>[Br:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21][O:9][CH:7]([CH3:8])[CH3:6])=[CH:15][C:14]=1[O:23][CH3:24]
Reactant: CC(C)O
Reactant: COc1cc(CCl)cc(OC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COC(C)C)cc(OC)c1Br
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To an N,N-dimethylformamide (15 ml) solution of 2-propanol (7.81 ml, 102 mmol) was added sodium hydride (4.08 g, 102 mmol) at room temperature, and the mixture was stirred for 30 minutes. To the mixture was added an N,N-dimethylformamide (15 ml) solution of 2-bromo-5-(chloromethyl)-1,3-dimethoxybenzene (2.70 g, 10.2 mmol) and the mixture was stirred for one hour. After the reaction was completed, water was added to the reaction mixture while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 3/1) to obtain the title compound (1.85 g, 6.40 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([SH:18])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.[CH2:28](I)[CH2:29][CH3:30].C(=O)([O-])O.[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:28][CH2:29][CH3:30])[N:15]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccc(C)cc3)c2c1
Reactant: CCCI
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
1 g of 6-[[2-mercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 15 ml of N,N-dimethylformamide, mixed with 0.3 ml of propyl iodide, 0.55 g of potassium hydrogen carbonate and 97 mg of dicyclohexano-18-crown-6, and the mixture was stirred for 48 hours at 20° C. It was filtered, and the filtrate was concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 1.06 g was obtained.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:30])=[C:19]([C:21]23[CH2:28][CH:27]2[CH2:26][O:25][CH2:24][C:23](=O)[NH:22]3)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:40]2)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:30])=[C:19]([C:21]23[CH2:28][CH:27]2[CH2:26][O:25][CH2:24][C:23](=[S:40])[NH:22]3)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCC2CC2(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(N=C(c2ccccc2)c2ccccc2)cc1C12CC1COCC(=S)N2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (1SR,7RS)-1-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-oxa-2-aza-bicyclo[5.1.0]octan-3-one (intermediate B11A) (460 mg, 1.15 mmol) in dioxane (3 ml) at 23° C. was added 2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (292 mg, 0.72 mmol) and the mixture was stirred at 80° C. for 2 h. The green solution was poured on sat. NaHCO3 solution, extracted with ethyl acetate, washed the organic layer with brine and dried over sodium sulfate. Removal of the solvent in vacuum left the title compound as a green oil (600 mg, ca. 80% pure, 100%), which was used in the next step without further purification. MS (ISP): m/z=417.3 [(M+H)+].