Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([CH3:15])[CH:7]=2)[CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:11]1[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=1
Reactant: CC(=O)c1ccc(OCC2CC2)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Br)c(OCC2CC2)cc1C
Temperature: 50 °C

Procedure:
A suspension of 1-(4-cyclopropylmethoxy-2-methyl-phenyl)-ethanone from example A24 (6.4 g, 31.3 mmol) and N-bromosuccinimide (6.20 g, 34.5 mmol) in dry dimethylformamide (50 mL) is heated for 3 h at 50° C. After cooling to ambient temperature, water (200 mL) is added and the mixture is extracted with ethyl acetate (3×60 mL). The combined organic extracts are dried over sodium sulfate. The solvent is removed under reduced pressure. The crude is purified by column chromatography on silica gel using dichloromethane as eluent to give the title compound as a off-white solid. Yield: 4.80 g.
Reaction SMILES: C([Li])CCC.[CH:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:8][CH2:7]1.[C:24](=[O:26])=[O:25]>C1COCC1>[CH:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:24]([OH:26])=[O:25])=[C:18]([F:22])[C:17]=2[F:23])[CH2:8][CH2:7]1
Reactant: O=C=O
Reactant: Fc1cccc(OCCCCCCC2CC2)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCCCCCC2CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
30 ml of butyllithium (1.6M in hexane) were added dropwise at -60° C. to a solution of 11.7 g of 6-cyclopropylhexyloxy-2,3-difluorobenzene in 70 ml of THF. After 5 hours at -60° C., CO2 was passed in until saturation was complete. The solution was warmed to RT, the solvent was removed by distillation, 400 ml of H2O were added, and the mixture was acidified to pH 3 using acetic acid. The precipitate was filtered off with suction. 12.3 g of 4-(6-cyclopropylhexyloxy)-2,3-difluorobenzoic acid were obtained. Melting point 100°-108° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([N:18]=[C:19]=[O:20])([CH3:17])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:30][OH:31]>>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([NH:18][C:19]([O:31][CH3:30])=[O:20])([CH3:17])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC1(N=C=O)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reactant: CO
Product: COC(=O)NC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1

Procedure:
A solution of 20 g (47 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-isocyanato-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 1d) in 200 ml of methanol was refluxed for 2 hours, concentrated in vacuo and recrystallized from ethyl acetate/hexanes yielding 19.8 g (92%) of a white solid, mp 179°-181° C.
Reaction SMILES: COC1C=CC(C([O:9][CH2:10][C@H:11]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=O)=CC=1.CC(C[AlH]CC(C)C)C.CO.[K].[Na]>C(Cl)Cl>[Si:22]([O:21][C@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:10][OH:9])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: COc1ccc(C(=O)OC[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [K]
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a 1.0 L RB flask containing (S)-2,3-bis(tert-butyldimethylsilyloxy)propyl 4-methoxybenzoate (9.200 g, 20 mmol) was added DCM (100 mL) and the mixture was allowed to stir at −78° C. for 5 minutes. At this time, DIBAL-H (1.0 M, hexanes) (61 ml, 61 mmol) was added via a syringe. The reaction was allowed to stir for 30 min and then quenched with MeOH (4.1 ml, 101 mmol). Sodium potassium tartate (sat, 200 mL) and DCM (100 mL) was added and the solution was allowed to warm to 23° C. and stirred for 3 h. The aq. layer was extracted with DCM (3 100 mL). The combined organics were washed with brine and dried with sodium sulfate and concentrated to give a residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])(=[O:20])=[O:19])[CH2:9][CH2:8]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28](=[O:30])[CH3:29])(=[O:20])=[O:19])[CH2:11][CH2:12]1
Reactant: Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazin- yl)butyl)-2-aminobenzenesulphonamide and 0.5 mol of acetic anhydride are stirred at room temperature for 2 hours. The mixture is evaporated to dryness, concentrated aqueous ammonia solution is poured onto the residue and the base is extracted by shaking with methylene chloride. Purification is carried out by chromatography on silica gel; the eluting agent is CH2Cl2 /CH3OH (9:1). The substance is recrystallised from isopropanol.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.CN(C)C=[O:23].[N-]=[N+]=[N-].[Na+]>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([OH:23])=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
127 parts of 1-nitroanthraquinone are suspended at room temperature in 1000 parts of dimethyl formamide. To this suspension are then added 35 parts of sodium azide. The reaction mixture is then stirred for 8 hours at room temperature and, after addition of 1000 parts of a mixture of ice and water, filtered. The filter cake is washed with water and the moist product (28% paste) is added in the course of 2 hours to 1000 parts of conc. sulfuric acid, taking care that the temperature does not rise above 85° C. The suspension is then heated to 95° C., stirred for 3 hours at 95°-100° C. and, after the dropwise addition of 400 parts of ice-water, filtered hot. The filtrate is then poured into 4000 parts of ice-water and filtered. The filter cake is washed neutral with water, affording 100 parts of 1-amino-4-hydroxyanthraquinone.
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]3[C:20](=[O:23])[NH:21][N:22]=[C:12]3[C:11]3[CH:24]=[CH:25][CH:26]=[N:27][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[N:30]1([CH2:35][CH2:36]Cl)[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[N:30]1([CH2:35][CH2:36][N:21]2[C:20](=[O:23])[N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:9]([C:7](=[O:8])[CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[C:10]4[N:27]=[CH:26][CH:25]=[CH:24][C:11]=4[C:12]3=[N:22]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(CN1CCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: O=C(CN1CCCC1)N1c2ccccc2-n2c(nn(CCN3CCCC3)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-[(pyrrolidino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (2-pyrrolidinoethyl)chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-(2-pyrrolidinoethyl)-9-(pyrrolidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([CH:26]=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[C:36]([O:40][C:41](=[O:55])[NH:42][S:43]([CH2:46][CH2:47][CH2:48][N:49]([CH3:54])[CH2:50][CH2:51][NH:52][CH3:53])(=[O:45])=[O:44])([CH3:39])([CH3:38])[CH3:37].[BH3-]C#N.[Na+]>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:18]=[CH:24][CH:23]=[CH:22][C:21]=2[N:17]([CH3:25])[CH:16]([CH2:26][N:52]([CH3:53])[CH2:51][CH2:50][N:49]([CH3:54])[CH2:48][CH2:47][CH2:46][S:43](=[O:44])(=[O:45])[NH:42][C:41](=[O:55])[O:40][C:36]([CH3:39])([CH3:37])[CH3:38])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)N(C)c1ccccc1-3
Reactant: CNCCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)N(C)c1ccccc1-3
Reaction time: 0.08 h

Procedure:
Methyl 13-cyclohexyl-6-formyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in MeOH (0.08 M) and HOAc was added. Tert-butyl[(3-{methyl[2(methylamino)ethyl]amino}propyl)sulfonyl]carbamate (1.5 eq. prepared as described in Example 15, Steps 1-3) was added and the mixture was stirred for 5 min. NaCNBH3 (1.5 eq.) was added and the mixture was stirred for 6 h. All volatiles were evaporated and the residual material was dissolved in EtOAc. The solution was extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. A yellow amorphous solid was obtained which was used without further purification in the next reaction (60%). (ES+) m/z 711 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2)c(C)c1

Procedure:
99 mg (68%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 1-(2,4-dimethylphenyl)piperazine (59 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19][S:20][CH3:21])=[N+:17]([O-:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[C:1]([C:9]1[C:18]([CH2:19][S:20]([CH3:21])=[O:32])=[N+:17]([O-:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
A solution of 3.26 g. (0.01 mol) of 2-benzoyl-3-methylthiomethylquinoxaline 1,4-dioxide and 2.20 g. (0.01 mol.) of 85% pure 3-chloroperbenzoic acid in 150 ml. of chloroform is stirred at room temperature overnight. The reaction mixture is washed with 5% sodium bicarbonate solution, dried, and evaporated in vacuo to afford crude 2-benzoyl-3-methylsulfinylmethylquinoxaline 1,4-dioxide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.CO.[H][H]>[Pd]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:9])=[CH:15][CH:14]=1
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Yield: 99.7 %

Procedure:
(4-Methyl-piperazin-1-yl)-(4-nitro-phenyl)-methanone (2.12 g, 8.51 mmol) was dissolved in Methanol (35 mL, 860 mmol) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (0.650 g, 48.7 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 1.86 g of (4-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone without further purification. (M+H)=220.6. 1H NMR (400 MHz, DMSO, d6) δ 7.09 (d, 2H, J=8.41 Hz), 6.53 (d, 2H J=8.41 Hz), 5.48 (s, 2H), 3.46 (m, 4H), 2.28 (m, 4H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16](=[O:26])[CH2:17]P(OCC)(OCC)=O)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2].[H-].[Na+].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH:34]=O>O1CCCC1>[C:1]([NH:4][CH:5]([C:16](=[O:26])[CH:17]=[CH:34][C:33]1[CH:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:38]=[C:31]([C:30]([F:29])([F:43])[F:44])[CH:32]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOP(=O)(CC(=O)C(Cc1csc2ccccc12)NC(C)=O)OCC
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NC(Cc1csc2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of the product of step (a) (10.6 g) in dry tetrahydrofuran (200 ml) was cooled to 0° C., treated with 60% sodium hydride in oil (1.07 g) and stirred for 1 hour. 3,5-Bistrifluoromethyl benzaldehyde (6.5 g) in dry tetrahydrofuran (50 ml) was added dropwise to the reaction mixture which was stirred for 1 hour before quenching with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (100 ml), dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica using ethyl acetate/petroleum ether (bp 60-80) (2:3) to yield the title compound as a pale yellow solid (10.3 g), mp=172°-173° C.; found: C, 56.15; H, 3:54; N, 2.79; C23H17F6NO2S.0.25H2O requires C, 56.38; H, 3.60; N, 2.86%.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C1C=CC=CC=1.C1CCCCC=1>C(O)C>[OH:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(COCCOCc1ccccc1)OCC
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOP(=O)(COCCO)OCC

Procedure:
Paladium on carbon (10%, 100 mg) was added to a solution of diethyl 2-(benzyloxy)ethoxymethylphosphonate prepared in accordance with the process of Example II above (0.9 g,2.8 mmol) and cyclohexene (2.0 ml, 20 mmol) in 20 ml ethanol under a nitrogen atmosphere. The resulting slurry was heated to reflux overnight. The catalyst was filtered off and the solution concentrated under vacuum to yield 0.5 g of diethyl 2-hydroxyethoxymethylphosphonate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[CH2:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:21][CH3:22]>ClCCl>[Cl:12][C:3]1[C:2]([NH:1][S:23]([CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:10][CH:9]=[C:8]([Cl:11])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1Cl
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
3-Amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol) was dissolved in dry dichloromethane (66.7 mL). Triethylamine (4.09 mL, 29.4 mmol) was added, and the mixture was chilled to 0° C. Propane-1-sulfonyl chloride (2.48 mL, 22 mmol) was then added via syringe. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The mixture was concentrated in vacuo and diluted with diethyl ether. The mixture was washed with 0.25M NaOH (80 mL), and the aqueous layer was acidified to a pH of 1 using 1.0M HCl. The aqueous layer was extracted with 15% 2-propanol:DCM (2×300 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to afford 2,6-dichloro-3-(propylsulfonamido)benzoic acid (1.55 g, 4.96 mmol, 74.4% yield). 1H NMR (400 MHz, d6-DMSO) δ 9.77-9.75 (s, 1H), 7.84-7.80 (d, 1H), 7.71-7.68 (d, 1H), 3.82-3.72 (m, 2H), 1.89-1.70 (m, 2H), 1.05-1.03 (m, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:4].[N+:13]([CH3:16])([O-:15])=[O:14]>CO>[CH2:3]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:16]/[N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
An aq. 6M NaOH solution (1.05 eq) was added to a methonolic solution of 4-ethylbenzaldehyde (1 eq) and nitromethane (1 eq) stirred at 0° C. During the slow addition of base, maintain the temperature between 10-15° C. The reaction generates a thick white precipitate. To allow smooth stirring, an additional amount of MeOH was added. After stirring for an additional 15 min., the ice bath was removed. Upon reaching RT, water was added to the reaction, which subsequently turned clear. The clear solution was added to a flask containing a stirred 6M aq. HCl solution. A yellow crystalline precipitate formed. After 10 min., the crystalline product was filtered, washed thoroughly with water, suction dried and recrystallized from abs. EtOH. 4-ethyl trans-beta-nitrostyrene (2) was afforded as a yellow crystalline product in 52% yield and >99% purity (LC/MS m/z 178.2 MH.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:28])[C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: CI
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
479 Milligrams of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate prepared in Example 3 and 70 mg of 50% sodium hydride (in oil) were admixed in 5 ml of dimethylformamide, and the mixture was stirred at a room temperature for 1 hour. Then a solution containing 0.23 g of methyl iodide in 3 ml of dimethylformamide was added dropwise gradually to the mixture, and the whole reaction mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into a large volume of water, and the organic material was extracted with chloroform, then the chloroform layer was washed with water and dried. Chloroform was removed by evaporation to yield 125 mg of 2-(4-chlorobenzoylamino)-3-(1-methyloxindol-3-yl)propionic acid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13].OS(O)(=O)=O>CCOCC>[CH2:1]([O:8][CH2:13][CH:12]([CH3:14])[C:11]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=C(C)C#N
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C#N)COCc1ccccc1

Procedure:
Benzyl alcohol (108 g.; 1 mole) was stirred and treated with 0.3 g. of 50% by weight sodium hydride in a mineral oil dispersion. To the resulting solution was added dropwise 415 ml. (335 g.; 5moles) of methacrylonitrile over a 40 minute period, at room temperature. The reaction mixture was heated at 60°-65° C. for 5 hours then cooled, acidified with 1 N aqueous H2SO4 and diluted with ether. The ether solution was washed twice with saturated brine then dried, filtered and concentrated in vacuo. Distillation of the residue gave, after removal of low boiling materials, 149.3 g. (85%) of rac. 3-benzyloxy-2-methylpropionitrile as a colorless liquid, b.p. 90°-93° C. (0.02 mm Hg.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:20]=[C:19]([NH2:21])[N:18]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[N:27]3)[N:17]=1.ClCCl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][C:19]2[N:18]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)[N:17]=[C:16]([CH3:15])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 5.7 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.59 g, 2.5 mmol) and crude 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.47 g, 2.1 mmol) in pyridine (0.6 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 1-10% methanol containing 10% ammonium hydroxide in dichloromethane) to give the title compound as a white solid (0.18 g, 0.12 mmol, 6%). 1H NMR (400 MHz, CDCl3) δ 8.87 (dd, J=1.2, 4.0 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.58-7.53 (m, 4H), 7.42 (s, 1H), 7.40 (s, 1H), 7.29-7.23 (m, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.28 (s, 1H), 2.34 (s, 3H), 1.36 (s, 9H); MS: (ES) m/z calculated for C23H25N4O2S [M+H]+ 421.2. found 421.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>CCCCC.ClCCl>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:26]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Solvent: CCCCC
Solvent: ClCCl
Product: CC1(C)OC[C@H](NC(=S)Nc2ccc(Cl)cc2Cl)[C@H](c2ccccc2)O1
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To a solution of 130 mg (0.62 mmol) of (4S,5S)-amine 1 in pentane (2.0 mL) was added dropwise a solution of 116 mg (0.62 mmol) of 2,4-dichlorophenyl isothiocyanate in dichloromethane (0.15 mL). After stirring for ˜24 h, a white precipitate was collected, rinsed with pentane, and dried under reduced pressure to yield 172 mg (67%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1.[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[OH:10][N:9]=[C:8]([Cl:15])[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:5][CH:6]=1
Reactant: ON=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(OC(F)(F)F)cc1
Yield: 90.3 %

Procedure:
In a similar manner as described in Preparation Example 9, by using dimethylformamide (240 mL), 4-(trifluoromethoxy)benzaldehydeoxime (20.0 g, 97.51 mmol) and N-chlorosuccinimide (14.31 g, 107.26 mmol), a pale yellow solid required compound (21.10 g, 88.04 mmol, 90%) was obtained.