Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13].C(N(CC)CC)C.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:3]([CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH:4]=[N:5]1
Reactant: Cn1ncc(CCCNC=O)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(CCCNC=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To a solution of N-[3-(5-amino-1-methylpyrazol-4-yl)propyl]formamide (3.64 g, 20 mmol) and triethylamine (2.23 g, 22 mmol) in methylene chloride (50 ml) was added triphenylmethyl chloride (6.13 g, 22 mmol). The mixture was stirred at room temperature for 90 minutes. The reaction mixture was washed with successively 10% aqueous citric acid solution, brine, and 10% aqueous sodium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give N-[3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propyl]formamide (6.8 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][CH2:7][C:8]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O1CCCC1.[N:43]1[C:50](Cl)=[N:49][C:47]([Cl:48])=[N:46][C:44]=1[Cl:45].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O>[Cl:48][C:47]1[N:46]=[C:44]([Cl:45])[N:43]=[C:50]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][C:8]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:50]4[N:49]=[C:47]([Cl:48])[N:46]=[C:44]([Cl:45])[N:43]=4)=[CH:15][CH:16]=3)([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:50]4[N:49]=[C:47]([Cl:48])[N:46]=[C:44]([Cl:45])[N:43]=4)=[CH:22][CH:21]=3)[CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:50]4[N:49]=[C:47]([Cl:48])[N:46]=[C:44]([Cl:45])[N:43]=4)=[CH:37][CH:36]=3)=[CH:34][CH:33]=2)[N:49]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(OCC(COc2ccc(N)cc2)(COc2ccc(N)cc2)COc2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccc(OCC(COc3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)(COc3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)COc3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)cc2)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 1,3-bis(4-aminophenoxy)-2,2-bis[(4-aminophenoxy)methyl]propane (5.00 grams, 10.0 mmol; prepared as described in Part C of this Example) in 120 milliliters of a mixture of dry acetone and tetrahydrofuran (1:1 (v/v)) was added dropwise to a solution of cyanuric chloride (7.75 grams, 42.0 mmol; obtained from Aldrich Chemical Co.) in 200 milliliters of dry acetone at −10° C. This mixture was stirred for 1 hour at −10° C. and was then added, with Na2CO3 (4.45 grams, 42.0 mmol), to 1.5 liters of cold water to give a precipitate. The white solid was filtered off, dried, and dissolved in dichloromethane to remove insoluble material (hydrolyzed product). The resulting solution was filtered over CELITE and dried with magnesium sulfate. Volatiles were removed under reduced pressure, and the residue was dried under vacuum to afford pure 1,3-bis(4-[N-(2,4-dichloro-1,3,5-triazin-6-yl)amino]phenoxy)-2,2-bis[(4-[N-(2,4-dichloro-1,3,5-triazin-6-yl)amino]phenoxy)methyl]propane (9.20 grams, 8.42 mmol, 84 percent yield) as a white solid: softening point 143–145° C.; mp 240–250° C.; IR (KBr) 3366, 3268, 3123, 2947, 1609, 1550, 1506, 1386, 1318, 1219, 1167, 1019, 846, 829, 794 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 4H), 7.40 (d, 8H, 3J=9.0 Hz), 6.96 (d, 8H, 3J=9.0 Hz), 4.36 (s, 8H); 13C NMR (100 MHz, CDCl3) δ 171.46, 164.44, 156.93, 129.12, 123.93, 115.39, 66.90, 45.11; MS (FAB, 3-nitrobenzyl alcohol) m/e 1092.7; Anal. Calcd for C41H28Cl8N16O4: C, 45.08; H, 2.58; N, 20.52. Found: C, 45.07; H, 2.58; N, 20.12.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21]>C1COCC1.C(OCC)(=O)C>[F:20][C:19]1[C:14]2[NH:13][C:1](=[O:2])[O:21][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1c(O)cccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c(F)cccc2o1
Temperature: 60 °C

Procedure:
1,1′-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to a solution of 2-amino-3-fluorophenol (Step 3, 8.94 g, 0.0703 mol) in THF (200 ml) and warmed at 60° C. for 2 h. The reaction mixture is diluted with ethyl acetate (200 ml), washed with 2N HCl and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%); mp 131–3° C.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:28][C:29]1[CH:52]=[CH:51][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[C:43]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:44])=[CH:31][CH:30]=1>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)[CH2:13][CH2:14][N:48]1[CH2:49][CH2:50][CH:45]([C:43]([C:35]2[N:34]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:52][CH:51]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=2)=[O:44])[CH2:46][CH2:47]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccc2c(c1)OCO2)C(=O)c1ccccc1
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccc2c(c1)OCO2)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(benzo[1,3]dioxol-5-yl)-4-methanesulfonylbutyl)benzamide and 4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[C:13]3[C:14](=[O:28])[N:15](CC4C=CC(OC)=CC=4OC)[CH2:16][C:12]=3[C:11]([F:29])=[C:10]([NH:30][C@H:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:32]([NH2:34])=[O:33])[N:9]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)(C(F)(F)F)=O>[C:1]([C:3]1[S:7][C:6]([C:8]2[C:13]3[C:14](=[O:28])[NH:15][CH2:16][C:12]=3[C:11]([F:29])=[C:10]([NH:30][C@H:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:32]([NH2:34])=[O:33])[N:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccc(C#N)s4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](Nc1nc(-c2ccc(C#N)s2)c2c(c1F)CNC2=O)C(N)=O
Yield: 17 %

Procedure:
A solution of (R)-2-(4-(5-cyanothiophen-2-yl)-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (68 mg, 0.126 mmol) in TFA (2 mL) was heated to 65° C. for 3 h. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DCM (3.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (40%, 0.035% TFA). The collected fractions were combined and the solvent was removed via rotary evaporation to yield the title compound (8.3 mg, 17%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86-0.96 (m, 6H), 1.53-1.62 (m, 1H), 1.67-1.88 (m, 2H), 4.45 (s, 2H), 4.50-4.57 (m, 1H), 6.96-7.06 (m, 1H), 7.32-7.54 (m, 2H), 7.86-8.02 (m, 1H), 8.61 (s, 1H), 9.00-9.15 (m, 1H). [M+H] calc'd for C18H18FN5O2S, 388. found, 388.
Reaction SMILES: C([NH:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([O:19][CH3:20])[CH:6]=1)(=O)C.[OH-].[Na+].O.Cl>CCO>[NH2:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:19][CH3:20])[CH:6]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-acetamido-2-methoxy-5-nitrobenzoate (4.0 g; 14.9 mmol) and NaOH (40 mL, 1 M aq; 40 mmol) in EtOH (80 mL) was refluxed for 2 h. The mixture was cooled to rt and water (20 mL) was added. The mixture was acidified by HCl (6 M aq) and the sub-title compound was filtered off. Yield: 3.0 g (95%).
Reaction SMILES: C([O:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:7]=1)(C)C.[ClH:19]>>[ClH:19].[CH2:14]([CH:13]([C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([CH3:12])[N:9]=1)[C:5]([OH:18])=[O:4])[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)c1cc(C(=O)OC(C)C)cc(C)n1
Agent: Cl
Product: CCC(CC)c1cc(C(=O)O)cc(C)n1

Procedure:
A solution of 2-(1-ethyl-propyl)-6-methyl-isonicotinic acid isopropyl ester (1.54 g, 6.18 mmol) in 25% aq. HCl (60 mL) is stirred at 65° C. for 16 h. The solvent is removed in vacuo and the residue is dissolved in dioxane and concentrated again to give 2-(1-ethyl-propyl)-6-methyl-isonicotinic acid hydrochloride (1.70 g) as a brownish solid; LC-MS: tR=0.62 min, [M+1]+=208.52.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.CN(C)CCN(C)C.C([Li])CCC.IC.[H-].[Na+].Cl[CH2:30][CH2:31][O:32]C1CCCCO1.[I-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.CN1CCCC1=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:30][CH2:31][OH:32])[C:6](=[O:11])[CH2:5]2
Reactant: ClCCOC1CCCCO1
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: CN(C)CCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: O=C1Cc2cc(F)ccc2N1CCO
Temperature: -75 °C
Reaction time: 0.67 h

Procedure:
5-Fluoro-1,3-dihydro-2H-indol-2-one (2.4 g, 15.9 mmol) (prepared according to the method of Clark et al., Synthesis (1991) 871) was dissolved in freshly distilled tetrahydrofuran with tetramethylethylenediamine (3.7 g, 31.9 mmol) and was cooled to -75° C. under nitrogen. n-Butyllithium (2.4 equivalents) was added and the mixture was stirred at -75° C. for 40 minutes. Iodomethane (9 g, 63 mmol) was added and the mixture was allowed to warm to room temperature. After two hours' stirring at this temperature, water (5 ml) was added and the mixture was concentrated under reduced pressure, the resulting oil was taken up in dichloromethane, washed with dilute hydrochloric acid, dried (MgSO4), filtered and concentrated to dry under reduced pressure to give a yellow oil. This oil was dissolved in N-methylpyrrolidone and stirred at room temperature under nitrogen. Sodium hydride (0.625 g, 15.6 mmol) was added and the mixture was stirred until gas evolution ceased. 2-(2-Chloroethoxy)tetrahydro-2H-pyran (2.5 g, 15 mmol) and sodium iodide (0.1 g, 0.66 mmol) was added and the mixture was warmed to 75° C. for 15 hours. Water was added and the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed (×3) with water, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was taken up in methanol, para toluenesulphonic acid (0.1 g, 0.5 mmol) was added and the mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure, taken up in ethyl acetate, washed (×3) with aqueous sodium hydrogen carbonate solution dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography on silica gel, (eluent hexane/ethyl acetate) to give 5-fluoro-1-(2-hydroxy-1-ethyl)-1,3-dihydro-2H-indol-2-one as a yellow oil. MS shows 224 (MH+) base peak and 241 (M+NH4)
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([CH:35]2[CH2:37][CH2:36]2)=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[CH:35]1([C:33]([N:30]([CH2:29][C:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:38])=[O:3])[CH:7]=2)[CH2:31][CH3:32])=[O:34])[CH2:36][CH2:37]1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)C2CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(-c2ccc(-c3cc(CC(=O)O)ccc3OC)c(CN(CC)C(=O)C3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-(6-ethoxy-pyridin-3-yl)-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester (32.7 g, 63.3 mmol) in tetrahydrofuran (150 mL) and water (75 mL) was treated with lithium hydroxide (8.0 g, 190.6 mmol) and the reaction was stirred at room temperature overnight. When the reaction was complete by analytical LCMS, the mixture was acidified with 1N aqueous hydrochloric acid to pH 3 and extracted 2 times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to afford the title compound as an off-white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Product: COc1cccc(C(=O)N2CCCC3=C2CC(C)(C)CC3=O)c1

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5(6H)-one was reacted with 3-methoxybenzoyl chloride according to the procedure of Part b) of Example 1 to give 7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-(3-methoxybenzoyl)-quinolin-5(6H)-one (20) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=401.1, tR (minutes, Method G)=2.61. [α]D20=+28.13 (c=1.6 mg/mL,CHCl3)
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:41])=[C:19]([C@@:21]23[N:30]=[C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[S:28][CH2:27][C@@H:26]2[CH2:25][C@H:24]([CH2:39]O)[O:23][CH2:22]3)[CH:20]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:41])=[C:19]([C@@:21]23[N:30]=[C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])[S:28][CH2:27][C@@H:26]2[CH2:25][C@H:24]([CH2:39][F:11])[O:23][CH2:22]3)[CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CO)C[C@H]2CS1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[Bis(2-methoxyethyl)amino]sulfur trifluoride (155 μl) was added dropwise to a solution of tert-butyl [(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-hydroxymethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]carbamate (200 mg) in dichloromethane (5.0 ml) at −78° C. The mixture was stirred overnight with gradual heating to room temperature. A sodium bicarbonate solution was added to the reaction mixture to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (145 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:16][P:17]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: CCOP([O-])OCC
Reactant: COC(=O)C(C)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(C)C(=O)OC)cc1
Temperature: 110 °C

Procedure:
To a solution of methyl 2-(4-bromophenyl)propanoate, 7-e, (500 mg, 2.06 mmol), diethylphosphite (994 mg, 7.20 mmol) and triethylamine (681 mg, 6.7 mmol) in toluene (5 mL) was added [1,1′-bis(diphenylphosphino) ferrocene]dicholoropalladium (54 mg). The resulting reaction mixture was heated at 110° C. under nitrogen overnight. The cooled reaction mixture was filtrated (washed with DCM, 3×10 mL), and the filtrate was concentrated to afford the crude product which was purified by column chromatography to give the title compound, 7-f, as yellow brown oil (500 mg, 99%). 1H NMR (300 MHz, CDCl3) δ1.30-1.39 (m, 6H), 1.51 (d, J=7.2 Hz, 3H), 3.67 (s, 3H), 3.77 (q, J=7.2 Hz, 1H), 4.05-4.20 (m, 4H), 7.37-7.41 (m, 2H), 7.72-7.79 (m, 2H). LC-MS (M+H)+ 301.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3]CC.[F:29][C:30]1[CH:31]=[C:32]([OH:42])[CH:33]=[C:34]([F:41])[C:35]=1[O:36][C:37]([F:40])([F:39])[F:38].C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC=CC=1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[C:20]3[CH:28]=[CH:27][C:23]([C:24]([O:42][C:32]4[CH:31]=[C:30]([F:29])[C:35]([O:36][C:37]([F:39])([F:40])[F:38])=[C:34]([F:41])[CH:33]=4)=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH3:3]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3ccc(C(=O)O)cc3)CC2)CC1
Reactant: Oc1cc(F)c(OC(F)(F)F)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3ccc(C(=O)Oc4cc(F)c(OC(F)(F)F)c(F)c4)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
(E)-4-(2-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)vinyl)benzoic acid in an amount of 1,3 g (3.7 mmol), 0.8 g (3.7 mmol) of 3,5-difluoro-4-trifluoromethoxyphenol, 0.1 g (1.1 mmol) of DMAP, and 30 ml of dichloromethane were mixed. To this mixture was added dropwise 5 ml of solution of 1.0 g (4.8 mmol) of DCC in dichloromethane while being cooled with ice in 5 min, and stirred as it was for 12 hours. Separated crystals were filtered off, and 80 ml of toluene was added to the filtrate, washed with 2N-NaOH five times and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (eluent: toluene) to obtain 1.7 g of a crude (E)-3,5-difluoro-4-trifluoromethoxyphenyl 4-(2-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)vinyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate (1 g; 2.99 mmol) was dissolved in 7.5 mL of a 4M solution of HCl in dioxane. The mixture was stirred at room temperature for 2 hours and was concentrated under reduced pressure to give quantitatively 5-chloro-3-(piperidin-4-yl)-1H-indole hydrochloride as a solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH:25](OCC)=[O:26]>C1COCC1>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][CH3:13])=[O:11])=[C:8]([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=[O:26])[CH:17]=1
Reactant: CCOC=O
Reactant: CNC(=O)c1ccc(OC)cc1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(OC)cc1C(C=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 2-benzyl-4-methoxy-N-methylbenzamide (125 mg) in 5 mL THF was cooled to −78 C. n-BuLi (0.400 mL, 2.5 M in hexanes) was added, and the reaction was stirred at −78 C for 20 min. A solution of ethyl formate (0.160 mL) in 1 mL THF was added via cannula. The reaction was quenched at −78 C by addition of saturated aqueous ammonium acetate. The mixture was extracted with EtOAc and concentrated to give 4-methoxy-N-methyl-2-(2-oxo-1-phenylethyl)benzamide, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].Cl[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:16]([O:15][C:13]([CH2:12][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:14])[CH3:17]
Reactant: CCOC(=O)CCl
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C(N)=O)c1
Yield: 72.5 %

Procedure:
The subject compound was prepared using the general method of Example 3, except that 10.0 g (72.9 mmol) of 3-hydroxybenzamide was reacted with 29.0 g (236.6 mmol) of ethyl chloroacetate and 19.0 g (137.5 mmole) of K2CO3 in the presence of 150 cc dry DMF. There was obtained 11.8 g (72%) of the desired product having an mp of 158°-159° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][OH:12].C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][O:12][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1COc2ccccc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Yield: 99.2 %

Procedure:
(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methanol (24.1 mmol, 4.0 g), triethylamine (24.3 mmol, 3.42 ml) and DCM (50 ml) were mixed and stirred on an ice-bath. p-Toluenesulfonyl chloride (24.3 mmol, 4.63 g) in DCM (10 ml) was added dropwise. The mixture was stirred over night at r.t and washed with water. The organic phase was evaporated to dryness. The crude product was dissolved in THF (10 ml) and treated with 1 M NaOH (2 ml) for 10 minutes. Water (100 ml) was added. The aqueous solution was extracted with EtOAc, the organic phase was dried and evaporated to dryness. Flash chromatography, using heptane/EtOAc as eluent gave 7.66 g of the desired product.
Reaction SMILES: [P:1]([O-:19])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])[O-].[Ag+2:24]>C(#N)C.O.[Al]>[P:1]([O-:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2].[Ag+:24]
Reactant: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: [Al]
Solvent: CC#N
Solvent: O
Product: [Ag+]

Procedure:
Dibenzyl phosphate (10 mmole, 2.78 g) is dissolved in a mixture of acetonitrile (20 ml) and water (10 ml). Silver carbonate (10 mmole, 2.76 g) is added, and the mixture is stirred at room temperature in the dark (wrapped in aluminum foil) for 2 hours. Excess of silver carbonate is removed by filtration. The solution is evaporated to dryness, and dried over P2O5 in the dark to constant weight (2 days). Yield of silver dibenzoyl phosphate is 3.61 g.