Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:23])[CH2:12][O:13][C:14]1[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[O:16][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:23])[CH2:12][O:13][C:14]1[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[O:16][N:15]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](COc1cc(C(=O)O)on1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.8 %

Procedure:
2M Aqueous sodium hydroxide solution (20 mL) was added to a solution of methyl 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)isoxazole-5-carboxylate (4.0 g) in THF/methanol (20 mL/20 mL), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, and the residue was neutralized with 6M hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][C:5]=1[C:9]([OH:11])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C[N:19](C)C=O>ClCCl>[N+:1]([C:4]1[CH:8]=[N:7][NH:6][C:5]=1[C:9]([NH2:19])=[O:11])([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=C(O)c1[nH]ncc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1[nH]ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitro-2H-pyrazole-3-carboxylic acid (2.72 g, 17.4 mmol) was added to a solution of oxalyl chloride (2.42 mL, 27.7 mmol) and N,N-dimethylformamide (80 μL) in dichloromethane (45 mL) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped from dichloromethane (3×100 mL). The crude product was dissolved in tetrahydrofuran, cooled in an ice bath, and treated with 0.880 ammonia solution (20 mL). The reaction mixture was stirred at room temperature for 18 hours then concentrated in vacuo and the residue partitioned between dichloromethane (300 mL) and water (100 mL). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to yield the title product. LRMS ES+m/z 157 [MH]+
Reaction SMILES: C([O:9][CH:10]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O)(=O)C1C=CC=CC=1.[N:26]#[C:27][NH2:28].[OH-].[K+]>CCO>[NH2:26][C:27]1[O:9][C:10]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[N:28]=1
Reactant: O=C(OC(C(=O)c1ccc(F)cc1)c1ccncc1)c1ccccc1
Reactant: N#CN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(-c2ccc(F)cc2)c(-c2ccncc2)o1
Yield: 9.9 %

Procedure:
A mixture of 1-(t-butyldimethylsilyloxy)-2-(4-fluorophenyl)-1-(4-pyridyl)ethanone [See Ex. 79 (a) of Adams et al., WO93/14081] (5.16 g, 15.0 mmol), cyanamide (0.95 g, 22.5 mmol) and KOH (0.55 g, 9.8 mmol) in EtOH (20 mL) was heated at reflux for 1 h. After cooling, the precipitate was filtered and washed with EtOH. Recrystallization from CH2Cl2/MeOH afforded the title compound as a yellow solid (0.38 g): ESMS (m/z): 256 (M++H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13][CH2:14]Br>CO>[Br:11][CH2:12][CH2:13][CH2:14][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCBr)cc1
Temperature: 70 °C
Yield: 23.4 %

Procedure:
To a solution of hydroquinone (3.0 g, 27 mmol) in MeOH (30 mL), KOH (1.5 g, 27 mmol) was added. Then, 1,3-dibromopropane (3.3 mL, 32 mmol) was added dropwise over 10 minutes. After the addition was complete, the mixture was refluxed for 12 hours at 70° C. The reaction mixture was concentrated and quenched with water (100 mL), and then the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was with washed water, thetn brine, and dried over Na2SO4. The solvent was evaporated and the product was purified by column chromatography to isolate the intermediate 10a (1.46 g, 6.31 mmol, 23% yield) as a pinkish solid. 1H NMR (CDCl3, 400 MHz) δ 6.81 (m, 4H), 5.93 (broad s, 1H), 4.06 (t, 2H), 3.61 (t, 2H), 2.30 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([O:12][CH3:13])[N:3]=1.[Li+].[BH4-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:12][CH3:13])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)cc(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of methyl (2-chloro-6-methoxypyridin-4-yl)carboxylate (15-1, 2.0 g, 9.92 mmole) in dry THF (40 mL) was added LiBH4 (7.4 mL, 2 M in THF, 14.88 mmole) then the mixture was heated to reflux. After 18 hr the mixture was cooled to RT and quenched by slow addition of H2O. The layers were separated and the aqueous layer extracted with EtOAc (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the titled compound a white solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) δ6.90 (s, 1H), 6.65 (s, 1H), 4.67 (m, 2H), 3.94 (s, 3H).
Reaction SMILES: [Cl:1][CH:2]([F:16])[C:3]([S:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([F:5])[F:4].ClS([N:21]=[C:22]=O)(=O)=O.CN(C)C=O.C(OCC)(=O)C>C(#N)C>[Cl:1][CH:2]([F:16])[C:3]([S:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:22]#[N:21])=[CH:13][CH:12]=[CH:11][CH:10]=2)([F:4])[F:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: FC(Cl)C(F)(F)Sc1cc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1c(SC(F)(F)C(F)Cl)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-[(2-chloro-1,1,2-trifluoroethyl)thio]indole (0.64 g, 2.4 mmole) in acetonitrile is treated with a solution of chlorosulfonylisocyanate (CSI) (0.85 g, 6.0 mmole) in acetonitrile at ice bath temperatures, stirred at room temperature for 3 hours, treated with dimethylformamide (0.88 g, 12 mmole) at 0° C., stirred for 1 hour at ambient temperatures, poured into ice water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to give a residue. Flash chromatography (silica gel/1:4 ethyl acetate:hexanes) affords the title product as a white solid, 0 44 g (63% yield) mp 134°-136° C. identified by IR, 1HNMR and 13CNMR.
Reaction SMILES: CN(C)C=O.FC(F)(F)S(O[C:12]1[C:13]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:14][C:15]([N:18]2[CH2:22][CH2:21][C:20]3([O:26][CH2:25][CH2:24][O:23]3)[C:19]2=[O:27])=[CH:16][CH:17]=1)(=O)=O.[C:37]([C@:39]1([OH:47])[CH:44]2[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]2)[CH2:40]1)#[CH:38].N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:28]([C:13]1[C:12]([C:38]#[C:37][C@:39]2([OH:47])[CH:44]3[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]3)[CH2:40]2)=[CH:17][CH:16]=[C:15]([N:18]2[CH2:22][CH2:21][C:20]3([O:23][CH2:24][CH2:25][O:26]3)[C:19]2=[O:27])[N:14]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N(c2ccc(OS(=O)(=O)C(F)(F)F)c(Cc3ccccc3)n2)CCC12OCCO2
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)CCC12OCCO2
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 60.7 %

Procedure:
7 ml of N,N-dimethylformamide was added to a mixture of 1.1 g of 2-benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl trifluoromethanesulfonate, 437 mg of (3R)-3-ethynyl-3-quinuclidinol, 168 mg of tetrakis(triphenylphosphine)palladium(0), 24 mg of cuprous iodide and 1.1 ml of triethylamine, followed by heating under stirring at 60° C. in an oil bath for 1.3 hours in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 66% ethyl acetate/hexane and 2% methanol/ethyl acetate as eluents for separation and purification, to give 669 mg of the target compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:33]1(S(N2CCNCC2)(=O)=O)C[CH2:34]1>>[CH:32]1([S:29]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:11])=[CH:20][CH:19]=4)=[O:22])[CH2:28][CH2:27]2)(=[O:30])=[O:31])[CH2:34][CH2:33]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: O=S(=O)(C1CC1)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)cc3c2)CC1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and cyclopropylsulfonyl-piperazine to afford the desired product as light brown foam (93%). MS (ISP): 488.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:13]1C=CC=CC=1C(C)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C(=O)O)c1ccccc1Cl
Product: CC(C(=O)O)c1ccc(Cl)cc1
Yield: 73 %

Procedure:
The titled compound was prepared from p-chlorophenylacetic acid in 73% yield in the same manner as the preparation of 2-(2-Chlorophenyl)propionic acid in Example 184a. MS (ESI) 185 (MH+).
Reaction SMILES: Cl.[CH2:2]([C@H:9]([NH:23][C:24](=[O:33])[O:25]CC1C=CC=CC=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:34](OC(ONC(=O)CCC(N)=O)=O)[C:35]1[CH:40]=CC=C[CH:36]=1>C1COCC1>[CH2:2]([C@H:9]([NH:23][C:24](=[O:33])[O:25][C:35]([CH3:40])([CH3:36])[CH3:34])[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)CCC(=O)NOC(=O)OCc1ccccc1
Reactant: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Reaction time: 8 h

Procedure:
tert-Butyl (1S, 2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate (VII, PREPARATION 8, 19.2 g, 48 mmole) in THF (100 ml). The reaction mixture is cooled to 0° and treated with N-benzyloxy carbonyloxysuccinamide (11.9 g, 48 mmole) while maintaining temperature <5°. The reaction mixture is stirred overnight and in the morning is concentrated under reduced pressure. The residue is partitioned between ethyl acetate and saturated aqueous bicarbonate. The organic phase is separated and washed with citric acid (5%), saline, dried over sodium sulfate and concentrated. The crude product is purified by preparatory HPLC eluting with a gradient of from 20/80–50/50 ethyl acetate. To give the title compound, M+H=534.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[CH2:20]([C:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:20]([C:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:1][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:9][CH:8]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)NOCCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CC(OCCONC(=O)c2ccc(C(=O)C(C)(C)C)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2.8 grams (10.6 mmol) of N-(2-hydroxy-ethoxy)-4-pivaloylbenzamide in 5 ml of methylene chloride and 3 ml of pyridine at 0° C. are added 3.92 grams (12.7 mmol) of ρ-anisylchlorodiphenylmethane. The mixture is warmed to room temperature over two hours and then diluted with 40 ml of methylene chloride. This solution is washed with 50 ml of 10% sodium bicarbonate and 30 ml of brine, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatography using 5:1 hexane/ethyl acetate as the eluent to obtain the protected product, N-(2-[ρ-anisyldiphenylmethyloxy]ethoxy)-4-pivaloylbenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:16][N:15](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]2=[N:13][CH:14]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: COc1ccccc1-c1cnc2c(n1)c(-c1ccccc1OC)cn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1cnc2[nH]cc(-c3ccccc3OC)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
To a solution of 2,7-Bis-(2-methoxy-phenyl)-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.412 mmol) in MeOH (5 mL) was added a solution of NaOH (66 mg, 1.65 mmol) in water (200 μL). The mixture was stirred at room temperature for 3.5 hours before the solvents were removed. The resulting yellow residue was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 2,7-Bis-(2-methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (43 mg, 32% yield) as a pale yellow solid. 1H-NMR (500 MHz, CD3OD) δ 12.21 (s br, 1H), 8.80 (dd, 6.0 Hz, 1.75 Hz, 1H), 8.69 (s, 1H), 7.76 (dd, 6.0 Hz, 1.75 Hz, 1H), 7.43 (dt, 7.5 Hz, 1.75 Hz, 1H), 7.20 (m, 2H), 7.13 (m, 2H), 7.04 (t, 7.3 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H). MS: m/z 332.1 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([C@@H: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])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)=[O:29])[CH:5]=[CH:6][CH:7]=1.C[CH2:39][N:40](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN>CN(C)C=O>[CH3:39][NH:40][C:34]([CH2:33][CH2:32][CH2:31][NH:30][C:28]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:37])=[O:29])=[O:36]
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCCCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)CCCNC(=O)N1CC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 94.6 %

Procedure:
To a mixture 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}-butyric acid (24.0 mg, 0.043 mmol, Example 58) in N,N-dimethyl formamide (2.5 mL) was added DIPEA (48.2 mg, 0.373 mmol), HoBt (12.2 mg, 0.090 mmol), HBTU (30.7 mg, 0.081 mmol) and methylamine hydrochloride (9.6 mg, 0.142 mmol). After it was stirred at rt for 5.5 hrs, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with 1N sodium hydroxide (2×), water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (3-methylcarbamoyl-propyl)-amide (23.0 mg, 93.7%). HRMS (ES+) m/z Calcd for C28H32Cl2F2N4O2+H [(M+H)+]: 565.1943; Found: 565.1944.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:14]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH:13]=[CH2:12]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc([N+](=O)[O-])cc1F
Yield: 99.6 %

Procedure:
A solution of compound 1 (20 g, 127.3 mmol), allyl bromide (16.19 mL, 190.96 mmol) and potassium carbonate (44 g, 318.25 mmol) in acetone (300 mL) was refluxed overnight. The solvent was removed in vacuo. The residue obtained was suspended in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The filtrate was concentrated to yield the desired compound 2 (25 g, yield 99.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[CH:14][C:15]=2[Br:17])[NH:10][CH:9]=1)[NH2:6])[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[CH:14][C:15]=2[Br:17])[NH:10][CH:9]=1)[NH:6][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2cc(Br)cc(Br)c12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1c[nH]c2cc(Br)cc(Br)c12)NC(=O)OCc1ccccc1

Procedure:
Mix DL-4,6-dibromotryptophan ethyl ester (1.20 g, 3.07 mmol), triethylamine (341 mg, 3.38 mmol) and methylene chloride (50 mL). Add benzyl chloroformate (692 mg, 4.06 mmol) and stir for 12 hours. Dilute with methylene chloride, wash with 1M hydrochloric acid (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]#[N:9])#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].N.[N-:17]=[N+:18]=[N-:19].[NH4+]>CN(C)C=O>[NH:2]1[C:1]([CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]2[NH:19][N:18]=[N:17][N:9]=2)=[N:12][N:11]=[N:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCOCCC#N
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C(Cc1nnn[nH]1)OCCc1nnn[nH]1
Temperature: 5 °C

Procedure:
Bis-(2-cyanoethyl)ether 186 g (1.5 mole), 215 g of sodium azide and 177 g of ammonium chloride were slurried in 1070 ml of dimethylformamide. The mixture was heated at 118°-122° C. with stirring and under reflux for 24 hr. (since ammonia and some ammonium azide are evolved, the heating should be done in a hood). After the bulk of the solvent had been removed at 80°-90° C. and 25 mm pressure, the residue was first heated to boiling with 500 ml of water and 40 ml of concentrated hydrochloric acid, then cooled to 5° C. (Caution: some hydrazoic acid is liberated). The product was filtered, washed twice with cold water and dried; 287 g (91%). Recrystallization of 5 g from 85 ml of water furnished coarse blades, m.p. 199°-200° C. (dec.).
Reaction SMILES: C([O-])(=O)C.[Na+].[SH:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>O.C(#N)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:6][C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=2)=[CH:18][CH:19]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: Fc1ccc(CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Oc1cc(O)nc(SCc2ccc(F)cc2)n1
Reaction time: 20 h
Yield: 89.3 %

Procedure:
Sodium acetate (113 g) was added to a suspension of 2-mercaptopyrimidine-4,6-diol (80 g) in water (900 mL) at room temperature. A solution of 1-(bromomethyl)-4-fluorobenzene (105 g) in acetonitrile (90 mL) was added dropwise over 2 hours. The reaction was allowed to stir for 20 hours before the suspension was filtered and washed with water (3×) and isohexane (3×). The solid was dried in vacuo for 2 hours and azeotroped with toluene (3×) to afford the sub-title product (125 g) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[CH2:25][CH2:24][C@@H:23]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:22]2)[CH:20]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][O:27][CH2:26][C@@H:23]2[CH2:24][CH2:25][N:21]([C:19]3[CH:18]=[N:17][CH:16]=[C:15]([O:14][CH2:13][C@@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)[CH:20]=3)[CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@@H](COCCCc3ccccc3)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1ccc(CCCOC[C@@H]2CCN(c3cncc(OC[C@@H]4CCCN4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[3(R)-[(3-phenylpropoxy)methyl]-1-pyrrolidinyl]pyridine (280 mg, 0.56 mmol) in CH2Cl2 (5 mL) was added a mixture of CF3COOH (1 mL) and water (0.1 mL) under N2. The solution was stirred overnight at room temperature. After concentration under vacuum, the crude product was purified by preparative HPLC (column: SunFire Prep C18, 150×19 mm, 5 μm particle size; UV detection at 270 nm; flow 20 mL/min; mobile phase: A, water with 0.05% TFA; B, MeOH; 0-6 min, 40% to 50% B in A; 6-7 min, 50%; 7-8 min, 100%). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried. After concentration in vacuo, the free base (150 mg, 67%) was obtained as a yellowish oil. 1H NMR (CDCl3, 300 MHz) δ 7.67 (d, 1H, J=2.1 Hz), 7.64 (d, 1H, J=2.1 Hz), 7.32-7.19 (m, 5H), 6.37 (t, 1H, J=2.1 Hz), 4.03-3.96 (m, 2H), 3.64-3.60 (m, 1H), 3.49-3.29 (m, 7H), 3.13-3.01 (m, 3H), 2.90 (br s, 1H), 2.74-2.63 (m, 3H), 2.19-2.13 (m, 1H), 2.04-1.88 (m, 6H), 1.69-1.57(m, 1H). LC-MS (ESI) m/z 396 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH2:27][O:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=2[C:39]([O:41][CH3:42])=[O:40])=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)c(C(=O)OC)c1
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 4-[N′-(2-methylphenyl)ureido]phenylacetic acid (2.32 g, 5.15 mmol), dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate (1.51 g, 5.15 mmol) in DMF (20 mL) was added Et3 N (1.0 mL, 6.65 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc. The solution was washed with brine, dried over MgSO4, and evaporated off in vacuo. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (10:1, v/v) as eluent to give 1.58 g (55%) dimethyl 4-[1-[4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate as a yellow crystalline solid. 1H-NMR (CDCl3) δ 1.87–2.25 (m, total 7 H), 3.50–3.65 (m, 4 H), 3.85 (s, 3 H), 3.89 (s, 3 H), 4.18–4.31 (m, 2 H), 4.44 (m, 1 H), 6.95–8.45 (m, total 13 H).