Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CS(C)=O>O>[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:19][CH2:18]1
Reactant: COCCN1CCNCC1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: COCCN1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
4-Fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol), 1-(2-methoxyethyl)piperazine (0.94 mL, 6.5 mmol) and DMSO (3.5 mL) were added and stirred at 100° C. for 1.0 hour. The reaction mixture was added with water and was washed with hexane/ethyl acetate (4/1) to remove impurities. After removing impurities, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4-[4-(2-methoxyethyl) piperazin-1-yl]-2-nitrobenzaldehyde (0.23 g, 68%).
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[C:1]([N:9]1[CH2:16][C@@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([O:13][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline (7.074 gm, 30.1 mmole) in acetone was treated dropwise with 1,8-diazabicyclo[5.4.0]- undec-7-ene (5.4 ml, 36.1 mmole) while cooling with a water bath. After stirring under argon for 10 minutes, benzyl bromide (4.3 ml, 36.1 mmole) was added dropwise. After stirring for 3 hours at room temperature, an additional aliquot (0.25 ml) of benzyl bromide was added. The reaction was stirred overnight and the acetone removed in vacuo. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with additional HCl, sodium bicarbonate solution, brine, and dried (sodium sulfate). Filtration, followed by concentration in vacuo afforded a solid which was recrystallized from ethyl acetate. The yield of the title compound was 8.77 gm (90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([OH:22])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[CH:9][CH:8]=2)=[N:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([O:22][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]2[O:5][CH2:6][C:2]([CH3:23])([CH3:1])[N:3]=2)=[CH:12][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])(=[O:26])[CH3:25]
Reactant: COc1ccccc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccccc1C(OC(C)=O)c1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[4-(4,4-Dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methyl alcohol (100 mg) was dissolved in pyridine (0.4 ml), added with acetic anhydride (0.25 ml) with ice cooling and stirred at room temperature for 4 hours. After the reaction mixture was added with methanol (0.25 ml) with ice cooling and stirred at room temperature for 10 minutes, the solvent was evaporated under reduced pressure to obtain 1-[4-(4,4-dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:17]([CH3:16])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CNCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(Br)cc2)c1CN(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.150 g, 0.56 mmol) and N-methyl-phenethylamine (0.10 mL, 0.67 mmol) were combined in MeOH and stirred at room temperature overnight. Once no starting material was seen by analytical LCMS, sodium borohydride (0.064 g, 1.69 mmol) was added and the reaction was stirred at room temperature for 1 hour. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(C)(C)C.[ClH:27].CO>>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1.[ClH:27]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)c1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)NCc1ccc(-c2cccc(N)c2)cc1

Procedure:
A solution of [4′-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acid tert-butyl ester (5 g, 13 mmol) in HCl/MeOH (4M, 150 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was washed with ether to give the target compound N-((3′-aminobiphenyl-4-yl)methyl)methanesulfonamide as its HCl salt (3.0 g, 71%). 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.71 (m, 6 H), 7.46 (d, J=7.8 Hz, 2 H), 7.36 (d, J=7.5 Hz, 1 H), 4.19 (s, 2 H), 2.87 (s, 3 H). MS (ESI) m/e (M+H+): 277.0.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([CH3:25])=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1>C(Cl)Cl.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([CH3:25])=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: Cc1nc2c(cc1C#CCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2c(cc1CCCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1,7-dimethyl4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (0.12 g, 0.30 mmol) in CH2Cl2 (20 mL) and MeOH (3 mL) is added 10% Pd/C (21 mg). The reaction is subjected to hydrogenation at 18 psi for 30 min. The reaction is filtered over Celite and monitored to determine the extent of the reaction. Fresh catalyst is added and the reaction is placed under hydrogen at 18 psi again. After another 30 minutes, the reaction is complete. The reaction is filtered over Celite. The filter cake is rinsed thoroughly with CH2Cl2, and MeOH. The filtrate is concentrated in vacuo and the residue is then dissolved in CH2Cl2 and adsorbed onto silica. Purification by chromatography (eluent 1% MeOH/CH2Cl2 (1 L), 2% MeOH/CH2Cl2 (1 L), 4% MeOH/CH2Cl2 (1 L)) affords the desired product as a white solid (0.079 g, 0.20 mmol, 66%). Physical characteristics are as follows: m.p. 176-177° C.; 1H NMR (300 MHz, DMSO-d6) δ10.30, 8.98, 8.35, 7.41, 7.36, 4.59, 4.56, 4.01, 3.47, 2.82, 2.67, 1.75; IR (drift) 1658, 1609, 1556, 1531, 1503, 1458, 1420, 1357, 1333, 1260, 1095, 1056, 1017, 811, 701 cm−1; MS (ESI) m/z 400.1 (M+H)+, 398.1 (M-H); HRMS (FAB) calcd for C21H22ClN3O3+H1 400.1428, found 400.1434.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[NH2:17][C:18]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3](=[O:4])[CH2:2][O:24][C:23]1[C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ncccc1O
Product: Cc1onc(-c2ccccc2)c1C(=O)COc1cccn2cc(-c3c(-c4ccccc4)noc3C)nc12
Yield: 7 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-hydroxypyridine instead of 2-amino-3-methylpyridine, to the title compound (18 mg, 7%) which was obtained as a yellow foam. MS: m/e=491.3 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)N1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
N-Acetylhomopiperazine (7.2 mL, 54.6 mmol) and DIPEA (12.3 mL, 74.4 mmol) were added to a stirred solution of 4-fluoronitrobenzene (7.0 g, 49.6 mmol) acetonitrile (100 mL) and the mixture was heated to 80° C. under nitrogen with stirring for 16 h. Volatile material was removed by evaporation and the residue was dissolved in EtOAc (150 mL) and water (150 mL) was added. The organic layer was separated and the aqueous layer was extracted again with EtOAc (2×150 mL). The organic layers were combined and dried, concentrated by evaporation then the residue was triturated with isohexane to give the title compound (5.6 g, 53%) as a solid; 1H NMR δ 8.01 (2H, qd), 6.92-6.82 (2H, m), 3.80 (1H, t), 3.70-3.56 (5H, m), 3.35 (2H, dt), 1.97-1.71 (5H, m); MS m/e MH+: 264.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:26]=3)=[N:8][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: CCCn1cnc2nc(-c3cn[nH]c3)n(COCC[Si](C)(C)C)c2c1=O
Reactant: BrCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3cnn(Cc4cccnc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
A mixture of 1-Propyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (100 mg, 0.2 mmol), 3-Bromomethylpyridine (55 mg, 0.3 mmol), K2CO3 (50 mg, 0.3 mmol) and DMF were stirred at 60° C. for 2 hours. Organic volatiles were evaporated and purified to obtain pure 1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (8 mg, 6%) as an colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:8][C:6]=2[N:7]=1.[CH3:28][N:29]([CH:31](OC)OC)[CH3:30]>>[C:24]([NH:23][C:21](=[O:22])[NH:20][C:9]1[C:10]([C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([N:1]=[CH:28][N:29]([CH3:31])[CH3:30])=[N:7][C:6]=2[N:8]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1

Procedure:
1-[2-Amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-yl]-3-tert-butylurea from Example 3 was reacted with DMF dimethyl acetal for 13.5 hours as described in Example 78. Workup as described above, followed by purification on flash silica gel chromatography eluting sequentially with 100:0, 3:1, 1:1, and 0:100 dichloromethane:ethyl acetate gave a solid that was triturated in 2-propanol to afford the title compound N'-[7-(3-tert-butylureido)-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-2-yl]-N,N-dimethylformamidine, mp 190°-193° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I>O1CCCC1>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C

Procedure:
To a solution of 5-nitroindole (0.20 g) in tetrahydrofuran (2 ml) was added sodium hydride (0.06 g of 60% dispersion in oil) and evolution of gas noted. After stirring for 30 min methyl iodide (0.086 ml) was added to the dark brown reaction mixture and the reaction mixture heated to 65° C. for 2 hr before cooling to room temperature and partitioning between dichloromethane and water. Organic phase separated, washed with sodium thiosulphate solution, dried (Na2SO4) and concentrated to leave sub-title compound as a yellow solid (0.20 g). 1H NMR (DMSO-d6) δ 8.58 (1H, d), 8.04 (1H, dd), 7.65 (1H, d), 7.61 (1H, d), 6.75 (1H, dd), 3.88 (3H, s).
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:16])[CH:3](OC(=O)C)[O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.C(O)(=O)C>CCCCCC>[Cl:1][C:2]([Cl:16])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OC(Oc1cccc(C)c1)C(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1cccc(OC=C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
71 g of 3-(2,2,2-trichloro-1-acetoxy-ethoxy)-toluene and 150 ml of acetic acid are stirred in a reaction vessel at 35°-45° C. 37 g of zink dust are added subsequently in the course of 2 to 3 minutes and the resultant reaction mixture is stirred for 1 hour at room temperature. The suspension is then mixed with hexane, filtered and washed. Acetic acid is removed by shaking out the organic phase with 2 N NaOH. After evaporation, 43 g 3-(2,2-dichlorovinyloxy)-toluene are obtained as a colourless oil, which can be used for processing without purification.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:38][C:39](=[O:57])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]>C(OCC)(=O)C.[Pd]>[C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:38][C:39](=[O:57])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:28]([OH:30])=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)O

Procedure:
A solution of benzyl 3-(N-FMOC-L-valyloxy )-2-stearoyloxypropionate (0.78 g, 1 mmole) in 20 ml ethyl acetate was hydrogenated with 10% palladium on charcoal (0.2 g) at normal pressure for three hours at room temperature. The catalyst was filtered and washed with ethyl acetate and 1,4-dioxane. The solution was evaporated under reduced pressure. Yield: 0.63 g=90%
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[N:9][CH:10]=1)=[O:16])(=[O:30])=[O:31]
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Reactant: O=C(O)c1cnc(-c2cccnc2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccnc3)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of 2-(3-pyridyl)-pyrimidine-5-carboxylic acid hydrochloride (237 mg 1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (15 mL) is treated with diisopropylethylamine (0.36 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc. The resulting solid is filtered, washed with ether to afford 2-(3-pyridyl)-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl-benzylamide (185 mg, 48%). MS: 384 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.43 (d, 3H), 4.65 (d, 2H), 7.45-7.55 (q, 1H), 7.60-7.75 (m, 3H), 7.80 (s, 1H), 8.72-8.80 (m, 2H), 9.35 (s, 2H), 9.55 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[CH3:17][C:18]1[O:22][N:21]=[CH:20][C:19]=1[C:23](Cl)=[O:24]>O>[CH3:17][C:18]1[O:22][N:21]=[CH:20][C:19]=1[C:23]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:9][CH:8]=1)=[O:24]
Reactant: Cc1oncc1C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C

Procedure:
4-Trifluoromethylaniline (5.75 g, 35.7 mm) was suspended in a solution of NaHCO3 (3.16 g, 37.6 mm) in water (30 ml). The suspension was warmed to 50° C. and then rapid stirring was begun. 5-Methylisoxazole-4-carboxylic acid chloride prepared by the procedure of Example 1 (5 g, 34.4 mm) was added dropwise to the rapidly stirred suspension over 20 min. After cessation of the addition, the mixture was stirred for another 2 h. The mixture was then allowed to cool to ambient temperature and leflunomide was isolated as a white powder by filtration. Drying at 60° C. gave leflunomide (8.2 g, 88%) in 96% purity by HPLC analysis.
Reaction SMILES: C([Li])CCC.[C:6]([Si](C)(C)C)#[CH:7].[O:12]1[CH:16]=[C:15]([C:17](=[O:19])[CH3:18])[N:14]=[CH:13]1>C1COCC1.O>[O:12]1[CH:16]=[C:15]([C:17]([OH:19])([C:6]#[CH:7])[CH3:18])[N:14]=[CH:13]1
Reactant: CC(=O)c1cocn1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C#CC(C)(O)c1cocn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5M in hexane, 1.03 mL, 2.57 mmol) in THF (3 mL) at −78° C. was added dropwise ethynyl(trimethyl)silane (0.34 mL, 2.38 mmol). The reaction was stirred at −78° C. for 10 minutes and then 1-(1,3-oxazol-4-yl)ethanone (220 mg, 1.98 mmol) was added in more THF (2 mL). The reaction was stirred at −78° C. to RT for 1 hr. The mixture was then diluted with water and the volatiles removed. The product was then extracted with EtOAc (2×15 mL) and the combined organics washed with water (2×5 mL) and dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography (eluted with 2-13% methanol) to give the title compound; 1H NMR (500 MHz, CDCl3) delta 1.85 (3H, s), 2.61 (1H, s), 2.92 (1H, s), 7.71 (1H, s), 7.87 (1H, s).
Reaction SMILES: [I:1]Cl.C[Sn](C)(C)[C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1.[OH-].[Na+]>ClCCl>[I:1][C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc([Sn](C)(C)C)c2)CC1
Reactant: ClI
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(I)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Iodomono chloride (588 mg, 3.6 mmol) and anhydrous dichloromethane (10 ml) was added to a mixture of 1-(5-trimethylstannyl-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine (1.45 g, 3.3 mmol) and dichloromethane (30 ml). The mixture was stirred at room temperature for 1 hours. Aqueous sodium hydroxide (25 ml, 1 M) was added. The organic phase was separated. The aqueous phase was extracted with dichloromethane (25 ml). The combined organic phases was purified by chromatography on silica gel with dichloromethane and methanol (19:1) The title compound was isolated as an oil. Yield 0.80 g, 60%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[Cl:21]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:21])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:15])=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2csc(N)n2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(N)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(2-aminothiazol-4-yl)-N-tert-butylbenzenesulfonamide (7.56 g, 24.3 mmol) in DMF (100 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione (3.30 g, 24.7 mmol). The reaction mixture was warmed to room temperature, stirred for 6 h, and poured into water (500 mL). The solid was collected by filtration, washed with water, and dried under high vacuum to give 4-(2-amino-5-chlorothiazol-4-yl)-N-tert-butylbenzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4]Br.[C-]#N.[Na+].C[N:20](C)[CH:21]=[O:22]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][N:20]=[C:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2ccccc2)cc1CBr
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(-c2ccccc2)cc1CN=C=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
3.0 g (11.6 mmol) of 2-methyl-5-phenylbenzyl bromide (produced in the same manner as in Reference Production Example 1 (5)) was dissolved in 5 ml of anhydrous N,N-dimethylformamide, and to this solution was added 1.13 g (17.3 mmol) of sodium cyanide, and the mixture was stirred for 3 hours at 100° C., to obtain a 2-methyl-5-phenylbenzyl isocyanate solution. To this solution was added 5 ml of toluene, then, the solution was cooled to 0° C., and to this was slowly dropped 550 mg (11.9 mmol) of methylhydrazine. Further, the mixture was stirred for 3 hours at room temperature, and to this reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, then, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluant: ethyl acetate/methanol=9/1 (v/v)), to obtain 1.24 g of 2-methyl-4-(2-methyl-5-phenylbenzyl) semicarbazide.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH:3]1C(OCC)=O>C(O)(=O)C.O>[O:1]=[C:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1Cn2c(cc3ccccc32)C1=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCn2c1cc1ccccc12

Procedure:
A solution of 2,3-dihydro-1-oxo-2-ethoxycarbonyl-1H-pyrrolo[1,2-a]indole in 400 mL of acetic acid and 25 mL of water was heated at reflux under N2 for 16 hr. The resulting solution was cooled and concentrated to dryness. The residue was treated with water and methylene chloride. The organic layer was washed with NaHCO3, brine, dried and concentrated to give solid which was purified by column chromatography to give the title compound. HNMR (CDCl3)δ 2.17 (t, 2H), 4.38 (t, 2H), 6.95 (s, 1H), 7.06-7.2 (m, 1H), 7.2-7.4 (m, 2H), 7.7 (d, 1H) ppm.