Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O:4][CH2:5][C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[C:7](OC)=[O:8])([O-:3])=[O:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:21]([NH:28][C:7](=[O:8])[C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[CH2:5][O:4][N+:1]([O-:3])=[O:2])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 73 %

Procedure:
1 g (3.5 mmol) of methyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate is heated with 3 ml of benzylamine and 100 ml of ammonium chloride for 3 hours at 130° C., cooled, taken up in 50 ml of chloroform and washed in sequence with water, dilute hydrochloric acid, aqueous bicarbonate solution and again with water. The crude product obtained after evaporating off the solvent is purified column chromatographically. 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid N-benzylamide is obtained as a colourless oil. Yield: 73%.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])[CH2:3][OH:4].N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.CCOCC>[C:31]([O:4][CH2:3][C:2]([CH3:1])=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC=C(C)CO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OCC(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaene-1-ol (1.6 g, 5 mmol) and pyridine (9.6 ml, 7.3 mmol) in 15 ml of anhydrous methylene chloride is stirred in an ice bath and a solution of acetyl chloride (0.37 ml, 5.25 mmol) in 5 ml of anhydrous methylene chloride is added dropwise. The mixture is stirred at 0° C. for 11/2 hours and at room temperature for 30 minutes and then taken up in 250 ml of ether. The solution is washed with ice cold 5% aqueous sodium bicarbonate and water, dried (MgSO4) and evaporated to give the crude product; recrystallization from ethanol affords the titled compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.0 g) and commercially available 5-hydroxyindole (1.19 g) were mixed and stirred at 150° C. for 1.5 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting in sequence with hexane/ethyl acetate, chloroform and chloroform/methanol, to obtain 898 mg of the title compound (yield: 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2(C3C=CN=CC=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][C:26]([S:29](N)=[O:30])([CH3:28])[CH3:27].CO.C(=O)(O)[O-].[Na+]>CCO.CCO.CCO.CCO.[Ti].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]#[N:18])=[N:10][S:29]([C:26]([CH3:28])([CH3:27])[CH3:25])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2ccccc21
Reactant: CC(C)(C)S(N)=O
Agent: [Ti]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1ccccc1C#N
Reaction time: 0.08 h
Yield: 30 %

Procedure:
A mixture of 2-(3-bromo-4-fluorobenzoyl)benzonitrile (Scheme #11, E) and tetraethyl orthotitanate (1 M solution in tetrahydrofuran, 18.3 mL, 18.3 mmol) was stirred for 5 minutes, then 2-methyl-2-propanesulfinamide (1.11 g, 9.13 mmol) was added and the resulting mixture was heated to reflux over night. When the reaction had cooled to room temperature methanol, aqueous saturated sodium bicarbonate and ethyl acetate was added. After filtering the reaction mixture through a pad of sodium sulfate, the filtrate was concentrated. Purification of the residue by column chromatography using chloroform as the eluent gave the title compound (1.22 g, 30% over 2 steps). 1H NMR (CDCl3) δ 7.90-7.69 (m, 3 H), 7.68-7.39 (m, 3 H), 7.18 (t, J=8.21 Hz, 1 H), 1.38 (br s, 9 H); MS (AP) m/z 407, 409 [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:22])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31]1[CH:39]=[CH:38][C:37]([C:40](=[O:43])[CH2:41]Br)=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].[BH4-].[Na+]>CN(C)C=O.O>[CH2:23]([O:30][C:31]1[CH:39]=[CH:38][C:37]([CH:40]([OH:43])[CH2:41][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:22])=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: CC(CCCCN(C)c1ccccc1)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCN(C)c1ccccc1)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(C(N)=O)c1
Reaction time: 20 h

Procedure:
To N-(5-benzylaminohexyl)-N-methylaniline (3.06 g= 10 mmol) and 3.48 g (10 mmol) 2-benzyloxy-5-(bromoacetyl)benzamide in 35 ml dimethylformamide, add 2.70 g (20 mmol) K2CO3. Stir 20 hrs. and pour into 150 ml water. Allow the gum to settle, decant, and dissolve the gum in ether. Extract with 1.0 N HCl, and then neutralize into NaHCO3 and extract with EtOAc. Dry, concentrate, and dissolve the oil in 50 ml ethanol. Add 0.3 g (8 mmol) NaBH4, stir 20 hrs., and concentrate. Partition between EtOAc and 1.0 N NaHCO3. Dry and concentrate to give a yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[S:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][C:23]3[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][N:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: COc1cc2c(=S)cc[nH]c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Sc3ncc([N+](=O)[O-])s3)ccnc2cc1OCc1ccccc1

Procedure:
7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione (14.8 g), 2-bromo-5-nitro-1,3-thiazole (10.4 g), potassium carbonate (10.3 g) and dimethylformamide (150 ml) were stirred together at room temperature for 50 minutes. After adding 800 ml of water to the reaction solution, the precipitated solid was filtered out and washed with ethyl acetate to obtain 13.4 g of a light ochre powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH2:21]O)=[N:13]2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].CO>ClCCCl>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH2:21][Cl:3])=[N:13]2)=[CH:8][CH:7]=1
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (3.6 ml., 49.3 mmol) was added rapidly to a stirred solution of 3-[2(E)-(7-chloroquinolin-2-yl)ethenyl]benzyl alcohol (Example 6a part (ii)) (11.7 g, 39.5 mmol) in 1,2-dichloroethane (300 ml) at 50° C. giving an immediate yellow precipitate. The mixture was stirred for 1 hour and cooled to room temperature then the mixture was shaken with saturated sodium bicarbonate solution (400 ml) and methanol (50 ml) to give two clear phases. The aqueous phase was extracted with dichloromethane and the combined solvent phase was dried and evaporated.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[C:5](=[CH:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+]>CO.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]2[CH:13]=[C:4]([C:3]([OH:30])=[O:2])[C:5](=[CH:10][C:11]=2[NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:6]([OH:8])=[O:7])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)O
Temperature: 25 °C

Procedure:
A steady stream of argon is passed through a suspension of 5.0 g (12.12 mmol) of 4,5-bis-(4-fluoroanilino)phthalic acid dimethylester in 40 ml of methanol, and a solution of 2.04 g (48.6 mmol, 2 eq) of lithium hydroxide monohydrate in 20 ml of water is added. The reaction mixture is heated to reflux for 1 hour, cooled to RT and diluted with 50 ml water. Methanol is removed by evaporation, the resulting solution is cooled to 0°, and 12 ml 4N hydrochloric acid and thereafter 100 ml of water are added. After 15 rain at 0°, the gray crystals are filtered off, washed with water and resuspended twice in 100 ml toluene with removal of the toluene by distillation to yield the title compound in the form of gray crystals, FAB-MS: 385 [M+ +H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:27]([CH3:26])[CH2:28][CH2:29][CH3:30])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCNC
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: CCCN(C)CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and N-Methylpropylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-propyl-amine, MS: 373 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:22](=[O:24])[CH3:23])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: CC(=O)N1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 56 b), the acylation of (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester [Example 56 a)] with acetic acid anhydride yielded the title compound as a white solid; MS: m/e=334 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH2:4][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[NH:6][C:7]=1[CH:8]=O)#[N:2].C(O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>N1CCCCC1.N1C=CC=CC=1>[C:1]([C:3]1[CH2:4][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[NH:6][C:7]=1[CH:8]=[CH:22][C:23]([OH:25])=[O:24])#[N:2]
Reactant: N#CC1=C(C=O)NN(c2ncc(C(F)(F)F)cc2Cl)C1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#CC1=C(C=CC(=O)O)NN(c2ncc(C(F)(F)F)cc2Cl)C1

Procedure:
A stirred solution of 0.3 grams (0.001 mole) of 4-cyano-5-formyl-2-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole, 0.2 gram (0.002 mole) of malonic acid, two drops of piperidine, and 3 mL of pyridine was heated at reflux for about 18 hours. After this time, the reaction mixture was cooled and was concentrated under reduced pressure to a residue. The residue was stirred with excess aqueous 2N hydrochloric acid and ethyl acetate. The organic layer was separated and washed with aqueous 2N hydrochloric acid and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated several times with petroleum ether, and each time the supernatent liquid was discarded. The resultant solid was dried, yielding 3-[4-cyano-2-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid. The nmr spectrum was consistent with the proposed structure and was identical to the nmr spectrum of this compound prepared by the method of Example 4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[B:10]([OH:17])[O:11][CH:12]([CH2:13][N+:14]([O-:16])=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].C1C(=O)N([Cl:25])C(=O)C1>CN(C=O)C>[Cl:25][C:7]1[C:8]2[CH:12]([CH2:13][N+:14]([O-:16])=[O:15])[O:11][B:10]([OH:17])[C:9]=2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOc1ccc(Cl)c2c1B(O)OC2C[N+](=O)[O-]

Procedure:
To a solution of 7-ethoxy-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (42 g, 0.18 mol) in DMF (200 mL) at 80° C. was added a solution of NCS (11.8 g, 0.18 mol) in DMF (50 mL) in 30 min. The reaction was quenched with an aqueous solution of LiCl solution (500 mL) and the resulting mixture was extracted by EtOAc (3×250 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the compound as white solid. (39.7 g, contaminated with 18% C6-C1 regioisomer). The mixture was then re-crystallized from Ether/PE (1/5) to give the pure compound (28 g, yield 46.3%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.50-7.48 (d, 1H), 6.98-6.96 (d, 1H), 5.77-5.74 (d, 1H), 5.35-5.31 (d, 1H), 4.73-4.67 (m, 1H), 4.12-4.07 (m, 2H), 1.34-1.28 (t, 3H).
Reaction SMILES: ClC1C=[C:4]([N:8]2[C:16]3[C:11](=CC=CC=3)[CH2:10][C:9]2=O)C=CC=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:34])[N:25]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:20]=1.CN1CCCC1=O>>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[C:9]3[CH2:10][CH2:11][CH2:16][N:8]3[CH3:4])[C:24](=[O:34])[N:25]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:20]=1
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1c1ccccc1
Solvent: CN1CCCC1=O
Product: CN1CCCC1=C1C(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
By the procedure of Example B1 a mixture of 1-(3-chlorophenyl)-2(1H,3H)-indolone and 6-chloro-1-phenyl-2(1H,3H)-indolone (1.36 g, 5.56 mmoles) and N-methyl-2-pyrrolidone (0.9 ml, 9.34 mmoles) were converted to a crude mixture of title products, as an oil. The isomers were separated, purified and isolated as solid products by silica gel chromatography, using the same eluant. The 3-chlorophenyl isomer was the faster moving, yield 0.72 g, m.p. 134°-137°.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[C:13]([Cl:28])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>C(OCC)(=O)C>[C:38]1([O:37][C:35](=[O:36])[NH:10][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si:18]([CH:19]([CH3:20])[CH3:21])([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26])=[C:13]([Cl:28])[CH:12]=3)[N:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:9]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2N)cc1Cl)(C(C)C)C(C)C
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1Cl)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of aminopyrazole of Example 2 (325 g, 0.707 moles) in ethyl acetate (1625 ml) under nitrogen, was added sodium bicarbonate aqueous solution (8% w/v, 1625 ml, 1.54 moles). Phenyl chloroformate (145 ml, 1.155 moles) was added over 15 minutes and stirred at 20° C. for 16 hours. The organic phase was separated and washed with water (1625 ml). Solvent was distilled under reduced pressure and replaced by n-heptane (1625 ml). The solution was cooled to 5° C. and granulated for 3 hours. The solid was collected by filtration to give the title compound as a white solid (368 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2SC)=[O:4]>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(SC)C(=O)N2
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 mL of dichloromethane was cooled with stirring to −70° C. and 2.7 g (20.0 mmol) of sulfuryl chloride was added. The reaction was stirred for 30 min. at −70° C., and a solution of 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.3g (20 mmol) of Proton Sponge® in 250 mL of dichloromethane was added dropwise over 1 h. The resulting pink slurry was treated with 2.3 g (23 mmol) of TEA in one portion, and the solution was allowed to warm to rt. The solution was washed with three 250-mL portions of water, dried over MgSO4, and concentrated to give an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester: 1H NMR (DMSO-d6): δ1.97 (s, 3H), 3.35 (s, 3H), 4.67 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 10.97 (s, 1H). A solution of 2.0 g (8.4 mmol) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester in 20 mL of acetic acid was treated with 10 g of zinc powder. The reaction mixture was stirred for 2 h at rt, filtered through celite and concentrated to dryness. The residue was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 1.6 g (99% yield) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a pink solid: 1H NMR (DMSO-d6): δ3.52 (s, 2H), 3.77 (s, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.74 (s, J=1H), 7.80 (d, J=8.2 Hz, 1H), 10.72 (br s, 1H). Conversion to the 3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (mixture of E and Z isomers) was carried out via Procedure G in 49% yield: 1H NMR (DMSO-d6): δ3.29 Z (s, 6H), 3.31 E (s, 6H), 3.76 Z (s, 3H), 3.76 E (s, 3H), 6.74 Z (d, J=8.1 Hz, 1H), 6.81 E (d, J=8.2 Hz, 1H), 7.47-7.50 Z(m, 1H), 7.50-7.52 E (m, 1H), 7.57 E (dd, J=1.3, 8.2 Hz, 1H), 7.74 Z (s, 1H), 7.89 Z (s, 1H), 7.94 E (s, 1H), 10.33 Z (bs, 1H), 10.43 E (bs, 1H). The title compound was prepared in 41% yield from 3-[(dimethylamino)methylene]oxindole-5-carboxylic acid methyl ester and 4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ3.81 (s, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 8.29 (s 1H), 8.86 (d, J=12.4 Hz, 1H), 10.80 (d, J=12.4 Hz, 1H), 10.94 (s, 1H); APCI−MS m/z372 (M−1)−. Anal. Calcd for C17H15N3O5S: C, 54.68, H, 4.05; N, 11.25; S 8.59. Found C, 54.65, H, 4.12; N, 11.17; S. 8.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]([CH2:26][C:27]([O:29]C)=[O:28])[C:22](=[O:31])[CH:21]=3)=[CH:18][N:17]=[C:16]([CH3:32])[N:15]=2)=[N:7][CH:8]=1.[Li+].[OH-].Cl>O1CCCC1.CO.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22](=[O:31])[CH:21]=3)=[CH:18][N:17]=[C:16]([CH3:32])[N:15]=2)=[N:7][CH:8]=1
Reactant: COC(=O)Cn1ccc(-c2cnc(C)nc2OC[C@H]2C[C@@H]2c2ccc(OC)cn2)cc1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2ccn(CC(=O)O)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetate (Example 56, 30 mg, 0.069 mmol) in tetrahydrofuran (1 ml), methanol (1 ml) and H2O (1 ml) was added LiOH (8.3 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. To the reaction mixture was added 5 ml of brine and the pH was adjusted to 3 with 1N HCl to provide a white precipitate which was filtered and dried to provide the title compound as a white solid. LC/MS: m/z=423.1 [M+H]+; 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1 H), 8.05 (s, 1 H), 7.62 (d, 1 H), 7.56 (dd, 1 H), 7.32 (dd, 1 H), 6.83 (d, 1 H), 6.68 (dd, 1 H), 4.74 (d, 2 H), 4.59-4.63 (m, 1 H), 4.44-4.49 (m, 1H), 3.84 (s, 3 H), 2.63 (s, 3 H), 2.15-2.19 (m, 1 H), 1.81-1.83 (m, 1 H), 1.24-1.29 (m, 1 H), 1.09-1.14 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]([N:15]1C(=O)C2C(=CC=CC=2)C1=O)[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]([NH2:15])[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(c1ccsc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(N)c1ccsc1
Temperature: 60 °C

Procedure:
To a stirred solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-thiophen-3-yl-ethyl]-carbamic acid tert-butyl ester (23 g, crude) in THF (100 mL) and methanol (100 mL) was added hydrazine hydrate (63 g, 1.26 mol). The mixture was heated at 60° C. for 2 hours and then cooled to 20° C. The reaction mixture was filtered and the filtration was concentrated to dryness. The residue was purified by column chromatography (methanol:dichloromethane, 1:50) to afford (2-amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester. (Yield 8.6 g, 57% for the two steps).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:13][C:10]1[CH:9]=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH2:11][CH3:12])=[N:5][C:6]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cc(Cl)n2nccc2n1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Cl)n2ncc(Cl)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.5 g (30 mmol) of the chloro compound (Example 1, Step B) and 4.0 g (30 mmol) of N-chlorosuccinimide were dissolved in 150 ml chloroform, stirred for 4 h at room temperature, and finally heated for some minutes on a steam bath. The mixture was poured on to ice water, the aqueous layer extracted with dichloromethane, the combined organic layers washed twice with saturated sodium carbonate solution, dried over sodium sulfate, and evaporated in in vacuo. The title compound was obtained as an oil after chromatography on silica gel with dichloromethane.