Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([C:17]([NH2:19])=[O:18])=[CH:12][N:11]=1.C(N(CC)CC)C.O>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:13]([C:17]([NH2:19])=[O:18])=[CH:12][N:11]=1
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Reactant: Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2nc(Cl)ncc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A solution of p-toluidine (46.9 g) in DMF (100 ml) was added dropwise to a solution of 2,4-dichloro-5-pyrimidinecarboxamide (80 g) and triethylamine (63.9 ml) in DMF (300 ml) with ice cooling. The mixture was stirred for 2 h allowing to warm to room temperature, then added to water (1 l) and stirred for 20 min. The slurry was filtered and the solid washed with water. The solid was suspended in a mixture of methanol (500 ml) and ether (500 ml), stirred for 20 min and filtered to give 2-chloro-4-[(4-methylphenyl)amino]-5-pyrimidinecarboxamide as pale yellow solid (94.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cc(C)cc(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,3,5-trimethylphenol (10.0 g), ethyl 4-bromobutyrate (12.6 ml), potassium carbonate (12.2 g), and dimethylformamide (DMF, 100 ml) was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate (AcOEt) and water. The separated organic phase was washed with a saturated aqueous solution of sodium hydrocarbonate (sat. NaHCO3aq.), water, and brine, and was dried over magnesium sulfate (MgSO4). After evaporation, the resulting residue was purified by chromatography over silica gel (CHCl3 as eluent) to give ethyl 4-(2,3,5-trimethylphenoxy)butyrate (16.35 g) as an oil compound.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:13])[NH:4][C:3]1=O.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:13])[N:4]2[CH:16]=[N:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]12
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cn1c(=O)[nH]c2cccc(Cl)c2c1=O
Product: CCOC(=O)c1ncn2c3cccc(Cl)c3c(=O)n(C)c12

Procedure:
M.p. 248°-254° C. by reaction between 3-methyl-5-chloro-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: Cl/[C:2](=[N:8]\[OH:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C(N(CC)CC)C>CCOCC>[C:12]1([C:10]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: C#Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (3.03 g, 20 mmol) and ethynylbenzene (4.39 mL, 40 mmol) in ether (80 mL) at room temperature was added a solution of triethylamine (5.58 mL, 40.0 mmol) in ether (20 mL) dropwise over 60 minutes. The reaction mixture was stirred for 2 h at room temperature and filtered. The filtrate was concentrated to give an yellow oil which was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (0-12%) to afford ethyl 5-phenylisoxazole-3-carboxylate (3.06 g, 14.09 mmol, 70% yield) as a white solid. The compound had an HPLC retention time=2.99 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS:(M+H)=218.12. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (t, J=7.3 Hz, 3H), 4.48 (q, J=7.3, 2H), 6.93 (s, 1H), 7.45-7.53 (m, 3H), and 7.77-7.85 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=3)[NH:8][CH:7]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCc2c[nH]c3ccc(C#N)cc23)cc1

Procedure:
3-[4-(p-Toluenesulfonyloxy)butyl]-1H-indole-5-carbonitrile was prepared by reacting 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile with p-toluenesulfonyl chloride in the presence of base in dichloromethane as per the process exemplified in example 2 of Chinese Patent Application Publication No. CN 102267932 A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:50])[CH2:9][CH2:10][N:11]([CH3:49])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33]([O:35]C)=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:37]=[CH:38][C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[CH:40][C:15]=2[O:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([N:8]([CH3:50])[CH2:9][CH2:10][N:11]([CH3:49])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33]([OH:35])=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[C:17]2[C:16]2[CH:37]=[CH:38][C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[CH:40][C:15]=2[O:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)OC(C)(C)C)COc1cc(OCc2ccccn2)ccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(CCN(C)[C@H]1COc2cc(OCc3ccccn3)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To the solution of methyl (7R)-7-[{2-[(tert-butoxycarbonyl)(methyl)amino]-ethyl}(methyl)amino]-14-cyclohexyl-3-(pyridin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in dioxane (0.1 M) was added 2M KOH solution (3 eq). The mixture was warmed to 60° C. After 4 days the mixture was neutralised by addition of 1N HCl and all volatiles were evaporated in vacuo. The residual material was dried in vacuo and used without further purification. (ES+) m/z 669 (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.F[C:23]1[C:24]([N+:31]([O-:33])=[O:32])=[C:25]([CH:28]=[CH:29][CH:30]=1)[NH:26][CH3:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:8][C:23]1[C:24]([N+:31]([O-:33])=[O:32])=[C:25]([CH:28]=[CH:29][CH:30]=1)[NH:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cccc(F)c1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 100 %

Procedure:
Benzyl alcohol (9.54 mL, 92.2 mmol), tetrabutyl ammonium bromide (1.49 g, 4.62 mmol), and potassium carbonate (7.64 g, 55.3 mmol) were added to a toluene solution (39 mL) of 3-fluoro-N-methyl-2-nitroaniline (7.84 g, 46.1 mmol), and the mixture was heated under reflux for 6 hours. The reaction solution was cooled, and water (39 mL) was added thereto, followed by toluene extraction. The resulting organic layer was washed with water, and the solvent was distilled off under reduced pressure, thereby obtaining 11.9 g of a red, powdery target compound (yield: 100%).
Reaction SMILES: [C:1]([C:5]1[C:14]([OH:15])=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C=O>[C:1]([C:5]1[C:14]([O:15][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Cc1nc2cc(O)c(C(C)(C)C)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1cc2nc(C)oc2cc1C(C)(C)C

Procedure:
6.9 g of the benzoxazole derivative obtained in Step (c) above was dissolved in 50 ml of dimethylformamide and the solution was stirred at 80° to 90° C. for 6 hours together with 8 g of anhydrous potassium carbonate and 11 g of hexadecyl bromide. After the completion of the reaction, the insoluble material was removed by filtration. To the filtrate was added 150 ml of methanol and the mixture was cooled with ice to precipitate crystals. The crystals were collected by filtration, thus obtained 8.8 g (62%) yield) of 6-tert-butyl-5-hexadecyloxy-2-methylbenzoxazole.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Mg].Br[CH2:28][C@H:29]1[CH2:34][CH2:33][Si@H:32]([CH2:35][CH2:36][CH3:37])[CH2:31][CH2:30]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:35]([Si@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:28][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:30][CH2:31]1)[CH2:36][CH3:37]
Reactant: CCC[Si@H]1CC[C@H](CBr)CC1
Reactant: FC(F)(F)Oc1ccc(-c2ccc([C@H]3CC[C@H](CBr)CC3)cc2)cc1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(OC(F)(F)F)cc4)cc3)CC2)CC1

Procedure:
39.7 g (0.1 mol) of 4-(trans-4-bromomethylcyclohexyl)-4'-trifluoromethoxybiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 23.5 g (0.1 mol) of trans-1-bromomethyl-4-n-propyl-4-silacyclohexane. After a conventional after treatment, purification was conducted by means of chromatography to obtain 43.0 g (yield 88.0%) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-trifluoromethoxybiphenyl was obtained.
Reaction SMILES: [C:1]([N:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:5]([C@H:7]([CH2:13][CH:14]=C)[C:8]([O:10]CC)=O)[CH3:6])([OH:3])=[O:2].O=[O+][O-].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[CH2:26]([N:33]1[CH2:14][CH2:13][C@@H:7]([C@@H:5]([N:4]([C:1]([OH:3])=[O:2])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:6])[C:8]1=[O:10])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: C=CC[C@H](C(=O)OCC)[C@H](C)N(Cc1ccccc1)C(=O)O
Agent: O=[O+][O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]([C@@H]1CCN(Cc2ccccc2)C1=O)N(Cc1ccccc1)C(=O)O
Temperature: -78 °C
Reaction time: 0.2 h

Procedure:
Ethyl (S,S)-2-[1'-(carboxybenzylamino)ethyl]-4-pentenoate (2.19 g, 7.18 mmol) is dissolved in MeOH (50 ml) and the resulting solution cooled to -78° C. O3, from a Welsbach ozonator set at the standard settings, is bubbled through the reaction mixture until starting material can no longer be detected by thin-layer chromatography (2:1 hexane: EtOAc). Dimethyl sulfide (5 ml) is added to the reaction mixture which is allowed to warm to room temperature and is then concentrated by rotary evaporation. The crude aldehyde is dissolved in methanol (25 ml) and tetrahydrofuran (25 ml) and the resulting solution is cooled to 0° C. under a nitrogen atmosphere. Benzyl amine (4.06 ml, 37.15 mmol) followed by acetic acid (4.68 ml, 81.73 mmol) is added to the reaction mixture which is then stirred at 0° C. for 12 min. NaCNBH3 (0.95 g, 14.86 mmol) is added to the reaction mixture which is allowed to warm to room temperature and continuously stirred for a 24 hour period. The reaction mixture is adjusted to pH 9 with 1N NaOH and the resulting mixture is partitioned between EtOAc and water. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered and then concentrated by rotary evaporation. The crude product is purified by chromatography (1:1 hexane: EtOAc) to give (S,S)-1-benzyl-2-oxo-3-[1'(carboxybenzylamino)ethyl]pyrrolidine: 1H NMR (300 MHz, CDCl3) δ 1.30 (d, J is 7 Hz, 3H), 1.77 (ddd, J is 16, 12, 9 Hz, 1H), 2.04 (m, 1H), 2.59 (ddd, J is 9, 9, 4 Hz, 1H), 3.04-3.09 (m, 2H), 3.95 (m, 1H), 4.34 (s, 2H), 5.01 (s, 2H), 5.11 (broad s, 1H), 7.10-7.28 (m, 10H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Br[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2.0 g of dimethyl malonate, 3.36 g of 1-bromo-4-nitrobenzene, 9.64 g of potassium phosphate, 85 mg of palladium(II) acetate and 394 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene were dissolved under an argon atmosphere in 25 ml of dry dioxane and stirred at 90° C. for 8 h. For workup, the reaction mixture was filtered through a cartridge and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; n-heptane/15-35% ethyl acetate). Dimethyl 2-(4-nitrophenyl)malonate (229.1) was obtained. Molecular weight 253.05 (C11H11NO6); retention time Rt=1.88 min. [B]; MS (ESI): 254.03 (MH+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.[NH3:31]>CN(C=O)C>[F:30][C:2]([F:1])([F:29])[CH2:3][N:4]=[C:5]([NH2:31])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CN(C)C=O
Product: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-[(3-phthalimido)propylthio]pyrimidine (0.4 g.), N,N,-dimethylformamide (5 ml.), saturated ethanolic ammonia (10 ml.) and yellow mercuric oxide (280 mg.) was stirred at room temperature for 3 hours and then filtered and the filtrate evaporated to dryness. A solution of the residue in ethanol (10 ml.) was treated with hydrazine hydrate (1 ml.), the mixture heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with 1N hydrochloric acid and then filtered and the filtrate basified with 17N NaOH. The mixture was extracted with ether and the combined ether extracts dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(3-amino)propylthio]pyrimidine which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)(=[O:19])=[O:18])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1C=CC=[CH:4][CH:3]=1.[O:30]1CCCC1>[OH-].[OH-].[Pd+2]>[OH:30][CH2:4][CH2:3][CH2:2][CH2:1][N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)(=[O:19])=[O:18])[CH2:14][CH2:15][C@H:10]2[CH2:9]1
Reactant: O=S(=O)(N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)c1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: [Pd+2]
Agent: [OH-]
Product: O=S(=O)(N[C@H]1CC[C@H]2CN(CCCCO)C[C@H]21)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
N-((3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl)-3-(trifluoromethyl)benzenesulfonamide (0.4237 g, 0.998 mmol) from Step A in tetrahydrofuran (10 mL) was added to 20% palladium hydroxide on carbon (wet, 0.085 g, 0.603 mmol) in a 50 mL pressure bottle under nitrogen. The reaction mixture was then placed under a hydrogen atmosphere (30 psi) and shaken at 50° C. for 18 hours. The mixture was filtered through a nylon membrane and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane supplied the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50 (s, 1H), 8.38 (d, J=7.9, 1H), 7.85 (d, J=7.8, 1H), 7.68 (t, J=7.8, 1H), 3.89 (dd, J=8.4, 14.2, 1H), 3.82 (t, J=6.2, 2H), 2.82 (dd, J=3.3, 9.7, 1H), 2.62 (qd, J=3.4, 7.9, 1H), 2.42-2.36 (m, 1H), 2.32 (d, J=4.5, 2H), 2.26 (dd, J=6.8, 11.7, 2H), 2.10 (t, J=8.7, 1H), 1.91-1.82 (m, 1H), 1.74-1.67 (m, 2H), 1.64-1.49 (m, 5H), 1.32 (dd, J=6.1, 9.6, 1H); MS (ESI+) m/z 407 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C@@H:3]1[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:24]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][C:2](=[O:1])[C@H:3]1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C[C@H]1Nc2ccccc2NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1C(=O)Nc2ccccc2N1Cc1ccccc1
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 299 mg, 1.36 mmol) in DMF (5 mL), Cs2CO3 (885 mg, 2.72 mmol) and then (bromomethyl)benzene (0.48 mL, 4.07 mmol) were added. After overnight stirring, the crude reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were then washed with water (2×50 mL) and brine (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was subjected to silica gel chromatography eluting with 15%-25% EtOAc in Hexanes to give 131 mg (31%) methyl [(2R)-1-benzyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate. LCMS (ES) 311.3 m/z (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][S:14]([NH2:17])(=[O:16])=[O:15])[CH2:8][CH2:7]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46]([NH:17][S:14]([CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1)(=[O:15])=[O:16])=[O:47]
Reactant: NS(=O)(=O)CCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NS(=O)(=O)CCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccccc1Cl
Reaction time: 17 h
Yield: 28.7 %

Procedure:
4-(3,4-Dichlorophenoxy)-1-piperidineethanesulfonamide (0.1 g), EDCI (0.108 g), HOBT (40 mg), DMAP (40 mg) and 2-chlorobenzoic acid (88 mg) were dissolved in dichloromethane (5 mL) and triethyalamine (0.5 mL) was added. The reaction mixture was stirred for 17 h. The solvents were evaporated. The residue was purified by HPLC (gradient Ammonium acetate/Acetonitrile 95% to 25%; Xterra column) to give the subtitle compound (40 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>Cl>[NH:1]([C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1)[NH2:15]
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: NNc1ccc(C[C@H]2COC(=O)N2)cc1

Procedure:
In an embodiment, (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one of formula (II), which was prepared using prior art methods was treated with an aqueous solution of sodium nitrite in concentrated hydrochloric acid at −5 to 10° C. After completion of reaction based on HPLC, the resulting diazonium salt was treated with stannous chloride in hydrochloric acid at −15 to 10° C. to give (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one of formula (III).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(O[C:21]([CH:23]([CH3:25])[CH3:24])=[CH2:22])C>C(=O)([O-])[O-].[Na+].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]([CH:23]([CH3:25])[CH3:24])=[CH:22][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10]1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1Cl
Reactant: C=C(OCC)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(C(C)C)n(-c2ccc(Cl)cc2Cl)n1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
1550 g of ethyl 2-chloroglyoxalate 2,4-dichlorophenylhydrazone are dissolved in 600 g of 2-ethoxy-3-methylbut-1-ene and 325 g of sodium carbonate, dissolved in 300 ml of water, are added such that a pH of greater than 8.0 is always maintained. After a reaction time of 4 hours (60°-80° C.), the aqueous phase is separated off and 200 ml of hydrochloric acid (pH~1) are added to the organic phase and the mixture is heated to reflux for 1 hour. After cooling to 70° C., the organic phase is separated off and crystallized using methanol/water. 1694 g of product having a purity of 96.3% are obtained, which corresponds to a yield of 94.7% of theory. The melting point is 95°-96° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:17]=3I)[C:9]2=[O:26])[C:6]=1[CH3:7].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:17]=3[CH:31]3[CH2:33][CH2:32]3)[C:9]2=[O:26])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2I)C1=O
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C2CC2)C1=O
Temperature: 100 °C
Yield: 3.3 %

Procedure:
A solution containing 3-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-iodo-pyrazol-4-yl]pyrrolidin-2-one (34 mg, 0.061 mmol), cyclopropylboronic acid (7 mg, 0.08 mmol), palladium acetate (1.0 mg, 0.003 mmol), tricyclohexylphosphine (2.0 mg, 0.006 mmol) and potassium phosphate (45 mg, 0.21 mmol) in toluene (1.5 mL) and water (100 μL) was heated to 100° C. for 1 d. After cooling to room temperature, the reaction mixture was diluted with water and extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to afford the titled compound (1.0 mg, 0.002 mmol, 3%) as a colorless residue. 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.54 (dd, J=9.0, 4.8 Hz, 2H), 7.16 (dd, J=9.0, 8.2 Hz, 2H), 5.06 (dd, J=9.2, 6.3 Hz, 1H), 4.11 (ddd, J=9.6, 8.4, 4.8 Hz, 1H), 3.91 (ddd, J=9.6, 8.0, 4.8 Hz, 1H), 2.98 (dddd, J=12.0, 9.6, 8.4, 6.4, 6.0 Hz, 1H), 2.74 (dddd, J=13.2, 9.2, 8.0, 4.8 Hz, 1H), 2.45 (s, 3H), 1.77 (dddd, J=8.4, 8.4, 5.6, 5.6 Hz, 1H), 0.78-0.64 (m, 2H), 0.43-0.30 (m, 2H); MS: (ES) m/z calculated for C21H18ClF4N5O [M+H]+ 468.1. found 468.1.