Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)(N)=O.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[CH2:14](Br)[CH:15]([CH3:17])[CH3:16].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>>[CH2:14]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: NC(N)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: CC(C)COc1ccc(C=O)cc1

Procedure:
A method of synthesizing N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-Another embodiment disclosed herein includes a) phenylmethyl)carbamide, including reacting the 4-hydroxybenzaldehyde with isobutylbromide in the presence of potassium iodide and potassium carbonate to produce 4-isobutoxybenzaldehyde, reacting the 4-isobutoxybenzaldehyde with about 1.5 equivalents of NH2OH to produce 4-isobutoxybenzoxime, reacting the 4-isobutoxybenxoxime with H2 in the presence of Raney-Ni and from about 13 to about 16 equivalents of NH3 to produce (4-isobutoxyphenyl)methanamino acetate, reacting the (4-isobutoxyphenyl)methanamino acetate with about 30% NaOH and extracting with toluene to produce (4-isobutoxyphenyl)methanamine, reacting the (4-isobutoxyphenyl)methanamine with HCl and COCl2 in the presence of toluene to produce 1-isobutoxy-4-(isocyanatomethyl)benzene, and reacting the 1-isobutoxy-4-(isocyanatomethyl)benzene with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to produce N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide. In one embodiment, the product of the method comprises than about 0.2% by weight of Impurity 1:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1.[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Brc1cncc(C2=CCNCC2)c1
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-1′,2′,3′,6′-tetrahydro-[3,4′]bipyridinyl (Intermediate 214) (1 eq, 0.523 mmol, 125 mg) in DCM (5 ml) at 0° C. is added TEA (1.1 eq, 0.575 mmol, 0.08 ml). Then acetyl chloride (1.1 eq, 0.575 mmol, 0.041 ml) is added and the resulting mixture is stirred for 20 h at r.t. Additional TEA (1.1 eq, 0.575 mmol, 0.08 ml) and acetyl chloride (1.1 eq, 0.575 mmol, 0.041 ml) are added and stirring is continued for another 1.5 h. The mixture is diluted with DCM and washed with 10% aqueous K2CO3 solution. The organic layer is dried over MgSO4, filtered, and the solvent is removed under reduced pressure giving the title compound; [M+H]+=281/283.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:23][CH2:24]1)=[O:18])[C:13](=[O:14])[N:45]1[CH2:46][CH2:47][CH:42]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:43][CH2:44]1)[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: C1CCN(C2CCNCC2)C1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 160 mg (0.99 mmol) 4-pyrrolidin-1-yl-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7].[Si](C=[N+]=[N-])(C)(C)[CH3:20]>C(Cl)Cl.CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:20])=[O:12])=[O:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)CCC(=O)Nc1ncccc1C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCC(=O)Nc1ncccc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
2-(4-Methoxy-4-oxobutanamido)nicotinic acid (ii-h-1) (1.28 g, 4.8 mmol) was dissolved in an equimolar mixture of CH2Cl2 and methanol (20 mL) and cooled to 0° C. TMS diazomethane (2M solution in diethyl ether; 5.2 mL, 10.6 mmol) was added dropwise. The mixture was stirred for 1 h and warmed to 23° C. Volatiles were removed under reduced pressure to provide ii-h as a pale yellow solid (1.37 g, 100%) MS m/z═267 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([I:11])[CH:3]=1.[CH3:12]C(C)([O-])C.[Na+].CI>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]#[N:10])=[C:4]([I:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1I
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)c1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-(4-Chloro-2-iodophenyl)acetonitrile (1.070 g, 3.9 mmol) was dissolved in THF (50 mL) and cooled to 0° C. Sodium tert-butoxide (0.74 g, 7.7 mmol) was added, and the solution was stirred for 10 minutes (the reaction color changed from colorless to orange.) MeI (0.24 mL, 3.9 mmol) was then added dropwise as a solution in THF (10 mL). The reaction was complete in ten minutes as determined by TLC. The crude residue was purified by silica flash chromatography using 0-15% EtOAc/hexanes. MS m/e=292 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OCc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: OCc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100 %

Procedure:
To a solution of [4-(4-Benzyl-piperazin-1-yl)-phenyl]-methanol in EtOH (50 ml) under a blanket of argon was added a suspension of 10% palladium on charcoal (1.5 g) in EtOH (150 ml). Hydrogen was bubbled through the suspension for 1 h and then the reaction mixture was stirred under a blanket of hydrogen for 60 h at RT. The catalyst was filtered off and the solvent removed in vacuo to yield the title compound as a white solid (4.8 g, 100%). 1H-NMR δ (CDCl3) 7.30-7.21 (2H, m, ArH), 6.94-6.88 (2H, m, ArH), 4.59 (2H, s), 3.18-2.98 (8H, m). HPLC: 0.5 min (37% @ 214 nm), 0.7 min (55% @ 214 nm), multiple peaks due to salt formation from TFA buffer; LRMS +ve: 193 (M+1, 70).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:14]3[NH:15][C:16]([C:18]([O:20]CC)=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:14]3[NH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(CCCc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c([nH]1)C(CCCc1ccccc1)CC2
Yield: 52.9 %

Procedure:
The title compound was synthesized from ethyl 6-(3-phenylpropyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (42.1 mg, 0.17 mmol, 1 equiv) and sodium hydroxide (0.42 mL, 10 M, 25 equiv), according to General Procedure 7. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 minutes) afforded the title compound (24.2 mg, 63%) with purity by HPLC of 93.1% (UV) and 97.4% (ELSD). LCMS m/z 268 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.21-7.27 (m, 2H), 7.11-7.19 (m, 3H), 6.56 (s, 1H), 2.98-3.07 (m, 1H), 2.47-2.66 (m, 5H), 1.95-2.05 (m, 1H), 1.64-1.82 (m, 3H), 1.40-1.51 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[CH2:17]([S:19]([NH-:22])(=[O:21])=[O:20])[CH3:18].Cl>CS(C)=O>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:22][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: CCS([NH-])(=O)=O
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(C)cc1
Reaction time: 14 h
Yield: 39.6 %

Procedure:
4,6-dichloro-5-(p-tolyl)-pyrimidine (717 mg) was dissolved in DMSO (5 ml) and ethanesulfonamide potassium salt (927 mg) was added and stirring continued for 14 h at rt. The solution was poured onto ice/water and acidified by 2 N HCl to pH 3-4. The precipitate was filtered off and washed with water and diethylether to give ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (370 mg) as a white powder. LC-MS: tR: 4.09, [M+H]+: 312.10.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19]2.IC.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18]([CH3:1])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19]2
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1Cc2cccc(OC)c2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(C)Cc2cccc(OC)c2C1
Temperature: -10 °C

Procedure:
At −78° C., 2.7 ml of a 2.5 M solution of n-butyllithium in hexane were added to a solution of 0.95 ml of diisopropylamine (6.75 mmol) in 30 ml of THF, and the mixture was then briefly warmed to −10° C. The mixture was once more cooled to −78° C., 1.24 g (5.63 mmol) of ethyl 4-methoxy-2,3-dihydro-1H-indene-2-carboxylate [Beilstein Reg. No. 8980172], dissolved in 10 ml of THF, were added dropwise, and the solution was stirred for another hour. 0.46 ml (7.32 mmol) of iodomethane was then added dropwise to the reaction solution, and the reaction mixture was stirred at −78° C. for a further 2 hours. After the reaction had gone to completion, saturated aqueous ammonium chloride solution was added quickly to the reaction mixture. After phase separation, the aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate. After filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 1.19 g (5.08 mmol, 90% of theory) of a colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:4][CH:5]=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:28][CH:27]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCCCCCO)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCCCCCO)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31c, using 5-Bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(5-hydroxy-pentyloxy)-nicotinamide and 4-chlorophenyl-boronic acid as starting materials to give the product as white solid, MS (ISP): 433.4, 435.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[N:8]=[CH:9][C:10]=1[N+:11]([O-])=O)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[N:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c([N+](=O)[O-])cnn1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(N)cnn1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.4 %

Procedure:
To a solution of 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid ethyl ester (1.97 g, 9.89 mmol; prepared from 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid according to WO 2009/026241) in EtOH (20 ml) under argon atmosphere was added 10% Pd/C (200 mg). The black suspension was stirred at r.t. under a hydrogen atmosphere for 20 h. The catalyst was filtered off and washed with EtOH. The product was obtained upon evaporation as light brown oil (1.63 g, 97%) and used without further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[ClH:32].O1CCOCC1>C(Cl)Cl>[ClH:32].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cc3)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1

Procedure:
tert-Butyl 4-(3-(4-(trifluoromethyl)phenoxy)benzylidene)piperidine-1-carboxylate (1.75 g, 4.0 mmol) from Step 4 was dissolved in CH2Cl2 (15 mL) and treated with HCl in dioxane (7.0 mL, 4.0 M, 28 mmol). After 16 h the reaction was concentrated in vacuo to provide the title compound as a white solid (1.49 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[H-].[Na+].FC(F)(F)S(O[CH2:31][CH2:32][O:33][N:34]=[C:35]([CH3:37])[CH3:36])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:31][CH2:32][O:33][N:34]=[C:35]([CH3:37])[CH3:36])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1
Reactant: CC(C)=NOCCOS(=O)(=O)C(F)(F)F
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(OCCON=C(C)C)c(Cl)cc1F
Reaction time: 1 h

Procedure:
1.70 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone are added at room temperature while stirring to a suspension of 0.22 g of a 55% sodium hydride dispersion in 25 ml of dimethylformamide and the mixture is stirred for 1 hour. Subsequently, the previously prepared solution of 2-[(isopropylideneamino)oxy]-ethyl trifluoromethanesulphonate is added at 0° C. and the mixture is stirred for 30 minutes. The reaction mixture is washed twice with 100 ml of water each time and the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using n-hexane/diethyl ether (2:1) as the eluent. The product is recrystallized from n-hexane/diethyl ether. There is obtained 1-[4-chloro-2-fluoro-5-{2-[(isopropylideneamino)oxy] -ethoxy} -phenyl]-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 136°-138° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]1[CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:30]1[CH2:31][CH2:32][CH2:33][CH:28]([N:3]2[C:4]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:5]([C:7]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)=[O:8])[NH:6][C:2]2=[O:1])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2[nH]c(=O)n(C3CCCNC3)c2-c2ccccc2)CC1
Solvent: ClCCl
Product: CC(=O)N1CCCC(n2c(-c3ccccc3)c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c2=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
16G (0.39 g, 0.85 mmol) prepared in the previous step was dissolved in 3 mL of anhydrous DCM. TEA (0.36 mL, 2.54 mmol) was added and the mixture was chilled to 0° C. To this chilled mixture, acetic anhydride (0.08 mL, 0.85 mmol) was added slowly. After about 30 minutes, TLC and LC/MS showed no signs of 16G. At this point, the mixture was concentrated to give tert-butyl 4-(1-(1-acetylpiperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate (16H) as an oil (0.42 g, quantitative yield). ESI-MS: m/z 498.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=C[C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=CC(C)=C[N:28]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:1])=[CH:24][N:28]=2)[CH:10]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: Cc1ccc(CCl)nc1
Product: COCOc1cc(SCc2ccc(C)cn2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-chloromethyl-5-methylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14]#[N:15])(=[O:3])[CH3:2].[CH2:16]([OH:18])[CH3:17].[ClH:19].C(OCC)C>>[ClH:19].[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14](=[NH:15])[O:18][CH2:16][CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(F)cc2CC1C#N
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)C1Cc2cc(F)ccc2N1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of intermediate (19) (0.004 mole) and HCl/diethylether (60 mL) was cooled in an ice bath under argon. Ethanol (0.0075 mole) was added. HCl was bubbled into the solution for 50 minutes until the mixture became homogeneous. The mixture was allowed to slowly warm to room temperature and stir for 4 hours. The ether was decanted off and dissolved in methanol. The methanol solution was concentrated in vacuum and the residue was used as is for the next step, yielding ethyl 1-acetyl-5-fluoro-2,3-dihydro-1H-indole-2-carboximidate monohydrochloride (intermediate 20).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([OH:15])[C@H:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C@@H:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[N:20]=[CH:19][N:18]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl.O>[C:39]([O:15][C@@H:13]1[CH2:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:11][C@H:12]1[NH:16][C:17]1[CH:22]=[C:21]([NH:23][C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[N:20]=[CH:19][N:18]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](O)[C@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1Nc1cc(N[C@H]2CCc3ccccc32)ncn1
Reaction time: 8 h

Procedure:
To a solution of (1R,2R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)cyclopentanol (0.193 g, 0.424 mmol), N,N-dimethylaminopyridine (4.7 mg, 0.039 mmol) and pyridine (0.281 mL, 3.48 mmol) in DCM (2.1 mL) was added acetic anhydride (0.044 mL, 0.46 mmol) and the mixture stirred overnight. The reaction was diluted with CH2CL2 (10 mL) and H2O (20 mL) then stirred for 10 m. The organic layer was separated and the aqueous layer was extracted with CH2CL2 and combined organics were washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to obtain the title compound. LC/MS: Rt=1.74 min, ES+ 498 (FA Standard).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH:23]3[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:27]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][CH:9]1[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH:23]3[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1

Procedure:
tert-Butyl 1-benzyl-7-(cyclobutanesulfonamidomethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.732 g, 1.51 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred overnight at room temperature. The solution was evaporated and partitioned between saturated aqueous NaHCO3 and ethyl acetate. Water was extracted with ethyl acetate (2×30 mL). The collected organic extracts were dried on MgSO4 and evaporated under reduced pressure to give a brown oil. Product was obtained as a brown oil (0.487 g, 1.31, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](N2C=CN=C2)=[O:40])=[CH:34][C:33]=1[O:46][CH3:47]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:40])=[CH:34][C:33]=1[O:46][CH3:47]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(NC(=O)n2ccnc2)cc1OC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Yield: 64.6 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (50.5 mg, 0.119 mmol) and 4-[(imidazole-1-carbonyl)-amino]-2-methoxy-benzoic acid methyl ester (325.2 mg, 1.181 mmol) in CH2Cl2 (8 mL) was stirred at reflux for 16 hrs. The reaction mixture was then purified by flash column to give rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester (48.5 mg, 64.6%). HRMS (ES+) m/z Calcd for C32H31Cl2F2N3O4+H [(M+H)+]: 630.1733; Found: 630.1738.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH:10]12[O:22][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([OH:5])=[O:7])[CH2:9]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(O)N1CCC2OC2C1
Reaction time: 8 h

Procedure:
To a stirred solution of 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Aldrich, 15.99 g, 87.28 mmol) in methylene chloride (600 mL) at 0° C., mCPBA (Aldrich, 29.4 g, 77%, 131 mmol) was added and the mixture was stirred overnight. The reaction was quenched with 10% Na2S2O3 and the organic layer was separated and washed with 5% sodium carbonate, brine and water and dried over sodium sulfate and concentrated to give a light yellow oil, which was chromatographied (10% EtOAc/Hexane) to yield a colorless oil. 14.93 g. The compound was used directly for the next step.