Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CS(O[C@H:11]1[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+]>C(O)C.O>[C:1]([S:3][C@@H:11]1[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@H](SC(C)=O)CN1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Potassium thioacetate (677 mg) was added to a solution of methyl (2S,4R)-4-methylsulfonyloxy-1-methyl-2-pyrrolidinecarboxylate (609 mg) obtained from Reference example 4 in ethanol/water (9:1) (6 ml), and the resulting mixture was stirred at 80° C. for 3 hours, and then the mixture was allowed to stand overnight at the same temperature. Ethyl acetate (20 mL) and 10% aqueous sodium chloride solution (10 mL) were added to the reaction mixture, which was then extracted. The organic layer was separated from the aqueous layer, which was washed with water (10 mL). The solvent of the organic layer was removed by distillation under reduced pressure to give the title compound (543 mg, yield 97%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[O:6].C(N(CC)CC)C.Cl[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.[Cl-].[Na+].O>[OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:11]=1)=[O:6]
Reactant: O=C(CCCO)c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
4-Hydroxy-1-(1H-imidazol-4-yl)butan-1-one (9.23 g) was dissolved in N,N′-dimethylformamide (120 ml), and triethylamine (12.5 ml) and chlorotriphenylmethane (16.69 g) were added. The mixture was stirred at room temperature for 2 h. Brine was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=9:1) to give the title compound (25.22 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]2[O:10][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(O)c(N)c1
Reactant: O=Cc1ccc(F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: COc1ccc2oc(-c3ccc(F)cc3)nc2c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-4-methoxyphenol (3.07 g, 22.09 mmol) and 4-fluorobenzaldehyde (3.55 mL, 33.14 mmol) in 40 mL of methanol was stirred at 45° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methylene chloride (50 mL), to which was added DDQ (6.02 g, 26.51 mmol) slowly. The resulting mixture was stirred at room temperature for 45 minutes. The solvent was evaporated under reduced pressure, and to the residue was added 300 mL of ethyl acetate. The organic layer was washed sequentially with saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated under reduced pressure. Column chromatography (ethyl acetate: Hexanes=1:9) gave 2-(4-fluorophenyl)-5-methoxybenzoxazole as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].O=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCC=O
Reactant: CC(=O)OC1CCNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCC(OC(C)=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To rac-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HF)(70 mg, 0.187 mmol) in 1,2-dichloroethane (3 ml) was added ethyl 7-oxoheptanoate (97 mg, 0.562 mmol). The reaction mixture was stirred at room temperature for 20 minutes and sodium triacetoxyborohydride (119 mg, 0.562 mmol) was added. The solution was stirred at room temperature overnight. Water (5 ml) was added and the reaction mixture was stirred vigorously for 15 minutes. The resulting mixture was extracted with DCM (×3). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (20 ml). The solvent was removed in vacuo and the resulting crude was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane to afford the title compound LC-MS Rt=1.58 mins; [M+H]+ 530.4, Method 2minLC_v003.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[Si:13]([O:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1OCCC1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxydihydrofuran-2(3H)-one (5 g, 49 mmol) in anhydrous DMF (50 mL) was added imidazole (6.7 g, 98 mmol) and TBDMS chloride (8.1 g, 54 mmol). The reaction was allowed to stir under an N2 atmosphere at room temperature overnight. The reaction was diluted with diethyl ether and washed with 1 N aqueous HCl×2 then brine×1. The organic phase was dried over Na2SO4 and the solvent removed in vacuo to yield 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (11 g, 49 mmol) as a clear oil. [M+H] calc'd for C10H20O3Si, 217; found, 217.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH3:43][O:44][C:45](Cl)=[O:46]>CC1CCCO1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:45]([O:44][CH3:43])=[O:46])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC1CCCO1
Product: COC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (0.99 mL, 7.02 mmol) in 2-methyltetrahydrofuran (33 mL) at −5° C. was added n-BuLi (2.67 mL, 2.5 M in hexanes, 6.69 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and aripiprazole (1.50 g, 3.34 mmol) was added. After a further 10 minutes, methylchloroformate (0.65 mL, 8.36 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature. After 2 hours the reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 1:1 ethyl acetate to dichloromethane to 10% methanol in 1:1 ethyl acetate to dichloromethane to give the product. The product was triturated in heptane to remove aliphatic impurities and then filtered to afford Compound-74 (0.824 g) as a colorless solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([CH:8]1[C:12](=O)[CH2:11][O:10][CH2:9]1)=[O:7].OS(O)(=O)=O>O.CCOCC>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([C:1]#[N:2])[CH2:11][O:10][CH2:9]1)=[O:7]
Reactant: [C-]#N
Reactant: COC(=O)C1COCC1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1COCC1C#N
Reaction time: 16 h

Procedure:
To a stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4° C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:14]([O:35]CC3C=CC=CC=3)=[CH:15][C:16]([O:27]CC3C=CC=CC=3)=[C:17]([CH:26]=2)[C:18]([N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[N:11][N:10]=[C:9]1[OH:43].[H][H]>C1COCC1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:14]([OH:35])=[CH:15][C:16]([OH:27])=[C:17]([CH:26]=2)[C:18]([N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[N:11][N:10]=[C:9]1[OH:43]
Reactant: CCCCN(C)C(=O)c1cc(-c2nnc(O)n2-c2ccccc2C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cc(-c2nnc(O)n2-c2ccccc2C)c(O)cc1O
Yield: 97.6 %

Procedure:
A solution of 1.1 kg of 5-[4-(2-methylphenyl)-3-hydroxy-4H-1,2,4-triazol-5-yl]-2,4-bisbenzyloxy-N-methyl-N-butylbenzamide, 5% Pd/C (50.5% of water) and 85 l of hydrogen in 10 l of THF is treated at 23° C. for 7 h in an autoclave. The resultant solution is subsequently evaporated and crystallised from ethanol, giving 738 g (95%) of 5-[4-(2-methylphenyl)-3-hydroxy-4H-1,2,4-triazol-5-yl]-2,4-dihydroxy-N-methyl-N-butylbenzamide (“C1”); MW 396.5.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][NH:19][CH2:20][CH:21]=[O:22]>C(O)C.O>[Cl:16][CH2:17][CH2:18][N:19]([CH2:20][CH:21]=[O:22])[C:8]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:9]
Reactant: O=CCNCCCl
Reactant: O=C=Nc1ncc(Br)s1
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: O=CCN(CCCl)C(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-β-chloroethylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about 1 hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-β-chloroethyl-3-(5-bromothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][CH2:36][CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1.C(Cl)CCl.CO>C(Cl)(Cl)Cl>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][CH2:36][NH:35][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:39]1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccccc12)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
2d was synthesized the condensation of 3, 4, 5-tris(benzyloxy)benzoic acid (480 mg, 1.09 mmol) and tryptamine hydrochloride (256 mg, 1.308 mmol) using standard EDC coupling method. 2d was isolated as white solid (482 mg, 76%) by elution with 0.5% methanol in chloroform. Rf: 0.538 (1.5% methanol in chloroform); mp: 105-107° C.; IR (neat) νmax 3413.77, 1637.45, 1579.59, 1496.66; 1H NMR (300 MHz, CDCl3) δ 2.96 (t, J=6.14 Hz, 2H), 3.63 (t, J=6.2 Hz, 2H), 4.89 (s, 4H), 4.96 (s, 2H), 6.08 (bs, 1H), 6.85 (S, 3H), 6.87-7.25 (m 18H), 7.54 (d, J=7.5 Hz, 1H), 8.21 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 24.90, 40.65, 71.01 (2C), 75.05, 106.44 (2C), 111.39, 118.48, 119.36, 121.98, 122.30, 126.86, 127.44 (6C), 127.88, 128.09, 128.40 (6C), 128.48, 129.97, 136.33, 136.56 (2C), 137.31, 140.69, 140.92, 152.54 (2C), 167.12; MS (ESI) m/z calcd. for C38H34N2O4: 582.25. found: 605.07 [M+Na]+.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]=3[Cl:29])[CH3:21])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:30][CH2:31][CH2:32]O>>[N:1]1([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:32][CH2:31][Br:30])[C:23]=3[Cl:29])[CH3:21])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCCBr
Reactant: COC(=O)c1sc(-n2cnc3ccccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Product: COC(=O)c1sc(-n2cnc3ccccc32)cc1O[C@H](C)c1cccc(OCCBr)c1Cl
Yield: 70.5 %

Procedure:
Methyl 5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 11A, 600 mg, 1.4 mmol) and 2-bromoethanol (120 μL, 1.7 mmol) were coupled using a procedure analogous to Example 4, Step A to give 529 mg of the title compound (71%), 1H NMR (400 MHz, d6-DMSO) δ 8.85 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.39-7.31 (m, 5H), 7.10 (dd, J=8.0 and 1.6 Hz, 1H), 5.98 (m, 1H), 4.40-4.37 (m, 2H), 3.81-3.79 (m, 5H), 1.81 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][S:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)(=[O:43])=[O:42])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH2:40][S:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)(=[O:43])=[O:42])=[CH:38][CH:39]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)(=O)c4ccccn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)(=O)c4ccccn4)cc2)CCN3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
In ethanol (4.9 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfonyl)methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (49 mg), and sodium borohydride (13 mg) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. Sodium borohydride (13 mg) was further added to the mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfonyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 204) (23 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:19].[NH2:20][C:21]1[C:26]2[S:27][C:28]([Si](C)(C)C)=[CH:29][C:25]=2[CH2:24][CH:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:22]=1>C1COCC1>[ClH:19].[NH2:20][C:21]1[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[CH2:24][CH:23]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:22]=1
Reactant: C[Si](C)(C)c1cc2c(s1)C(N)=NC(c1ccccc1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: NC1=NC(c2ccccc2)Cc2ccsc21
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
Tetra-n-butylammonium fluoride (1.0M in THF, 1.12 ml), was added dropwise to a solution of 7-amino-5-phenyl-2-trimethylsilyl-4,5-dihydrothieno[2,3-c]pyridine hydrochloride (0.13 g, 0.37 mmol) in THF (2.5 ml) and the mixture stirred for 30 min., evaporated and the residue purified by flash chromatography on untreated neutral alumina, eluting with 4% methanol in dichloromethane, increasing the gradient by increments to 20% methanol in dichloromethane to afford a colourless glass. Recrystallisation from dichloromethane gave the title compound as white crystals (51 mg), m.p. 234-236° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C:13]#[N:14].[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:15][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C:13]#[N:14]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2ccccc2c(O)c1C#N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C#N)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
The suspension of 1-hydroxy-3-methyl-2-naphthonitrile (47.23 g), potassium carbonate (71.3 g), iodomethane (100 ml), and DMF (250 ml) was-stirred overnight at ambient temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from water/methanol to give the titled compound (50 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:38])([CH3:37])[O:11][Si:12]([O:29][Si:30]([CH3:36])([CH3:35])[CH2:31][CH2:32][CH2:33][OH:34])([O:21][Si:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][OH:26])[O:13][Si:14]([CH3:20])([CH3:19])[CH2:15][CH2:16][CH2:17][OH:18]>N1C=CC=CC=1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:37])([CH3:38])[O:11][Si:12]([O:29][Si:30]([CH3:35])([CH3:36])[CH2:31][CH2:32][CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])([O:13][Si:14]([CH3:19])([CH3:20])[CH2:15][CH2:16][CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[O:21][Si:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: C[Si](C)(CCCO)O[Si](O[Si](C)(C)CCCO)(O[Si](C)(C)CCCO)O[Si](C)(C)CCCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[Si](C)(CCCOS(C)(=O)=O)O[Si](O[Si](C)(C)CCCOS(C)(=O)=O)(O[Si](C)(C)CCCOS(C)(=O)=O)O[Si](C)(C)CCCOS(C)(=O)=O

Procedure:
Tetrakis(bromopropyldimethylsiloxy)silane was synthesized by the following reactions starting from tetrakis(dimethylsiloxy)silane. Thus, allyloxytrimethylsilane was reacted with tetrakis(dimethylsiloxy)silane in the presence of a platinum 1,1,3,3-tetramethyl-1,3-divinyldisiloxane complex as catalyst to produce tetrakis(trimethylsiloxypropyldimethylsiloxy)silane, from which the trimethylsiloxy group was subsequently eliminated by the action of excess methanol to give tetrakis(hydroxypropyldimethylsiloxy)silane. Methanesulfonyl chloride was then reacted in pyridine with the tetrakis(hydroxypropyldimethylsiloxy)silane to give tetrakis(methanesulfonyloxypropyldimethylsiloxy)silane, which was subsequently reacted with sodium bromide in DMF to give tetrakis(bromopropyldimethylsiloxy)silane:
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:5]
Reactant: C1CCNC1
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCC1

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and pyrrolidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][N:10]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[CH:11]1.CC(C)([O-])C.[K+].Cl>CC(O)(C)C>[CH3:9][N:10]1[C:18]2[CH:17]=[CH:16][C:15]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:14]([OH:19])[C:13]=2[CH:12]=[CH:11]1
Reactant: Cn1ccc2c1CCCC2=O
Reactant: O=Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cn1ccc2c(O)c(Cc3cccnc3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
500 cm3 of 2-methyl-2-propanol, 75 g of pyridine-3-carboxaldehyde and 100 g of 1-methyl-1,5,6,7-tetrahydroindol4-one were introduced into a 1-litre reactor equipped with a mechanical stirrer and surmounted by a condenser and a thermometer. After 10 minutes of stirring, 157 g of potassium tert-butoxide were added in small portions over 15 minutes. Following addition, the temperature was held at 75° C. for 1 hour. The reaction mixture was allowed to return to room temperature and then was neutralized (pH=6) with 20% hydrochloric acid. It was poured into 2 kg of ice-water. The precipitate obtained was filtered off with suction and washed with diisopropyl ether and with petroleum ether. It was dried over potash under vacuum at 30° C. This gave 120 g of 1-methyl-5-pyridin-3-ylmethyl-1H-indol4-ol with a yield of 74%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(=O)C)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH3:24])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:22][O:23][CH3:24])=[CH:4][CH:3]=1
Reactant: COCc1nc(C2CCN(C(C)=O)CC2)oc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Reaction time: 16 h
Yield: 79.6 %

Procedure:
A solution of 1-{4-[5-(4-fluoro-phenyl)-4-methoxymethyl-oxazol-2-yl]-piperidin-1-yl}-ethanone (0.79 g; 2.38 mmol) in ethanol (8 ml) is treated with a solution of sodium hydroxide (1.9 g; 47.59 mmol) in water (4 ml) and heated to 75 C. for 16 hours. Ethanol is removed in a rotary evaporator and the residue partitioned between ethyl acetate (100 ml) and water (20 ml). The aqueous phase is washed with ethyl acetate (2×30 ml) and chloroform (2×30 ml). The organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness to afford the product as a yellow oil (0.55 g; 80%) which was used without further purification. HNMR (CDCl3): 7.53 (m, 2H), 7.02 (t, 2H, J=8.6 Hz), 4.36 (s, 2H), 3.36 (s, 3H), 3.06 (m, 2H), 2.85 (ttt, 1H, J=11.3; 3.9 Hz), 2.63 (m, 2H), 1.98 (m, 2H), 1.71 (m, 2H).