Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][CH3:25])(=[O:23])/[CH:21]=[CH:22]/[CH:2]=[CH:1]/[CH3:6]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Product: C/C=C/C=C/C(=O)OC
Temperature: 120 °C
Yield: 4 %

Procedure:
Quantities of 1.1 grams palladium acetate, 5.25 grams triphenyl phosphine, 42 cc alkyl bromide, 45 cc methyl acrylate and 119 cc tributyl amine are introduced into a reactor chamber and heated to 120°C for 27 hours. The resulting reaction mass is extracted with ether followed by distillation yielding 2.9 grams (4% yield) of methyl sorbate and alkyl-tributyl ammonium bromide as the major product.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:18])C(=O)C1>CC#N>[Cl:18][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccnn1CC(=O)O
Solvent: CC#N
Product: Cc1c(Cl)cnn1CC(=O)O
Temperature: 80 °C
Yield: 99.7 %

Procedure:
A mixture of 2-(5-methylpyrazol-1-yl)acetic acid (0.700 g, 5 mmol) and NCS (0.668 g, 5 mmol) in CH3CN (10 mL) was heated at 80° C. for 1.5 hrs. It was then cooled to rt, evaporated in vacuo, and purified by flash chromatography (SiO2, with a gradient elution of 0-20% MeOH/CH2Cl2) to afford 2-(4-chloro-5-methylpyrazol-1-yl)acetic acid (0.870 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH:16]O.Br>CO>[C:11]([C:7]1[CH:8]=[C:9]([OH:16])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: OO
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Br
Solvent: CO
Product: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reaction time: 0.83 h
Yield: 97 %

Procedure:
A solution of 2,6-di-tert.butyl-phenol (11 g, 53.3 mmol), hydrogen peroxide at 60% (8 ml) and hydrogen bromide (5 g, 61.7 mmol) in methanol (150 ml) is refluxed for 25 minutes. On concentrating the solution, 2,6-di-tert.butyl-1,4-benzoquinone (10.5 g, 89.4%) crystallizes. This product is hydrogenated, in methanol (110 ml), in autoclave, with Pd/C at 5% (0.12 g), under a hydrogen pressure of 10 kg/cm2, for 50 minutes, at 20° C. After the catalyst being filtered off, and solvent evaporation, 2,6-di-tert.butyl-hydroquinone is obtained with a yield of 97%.
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(C)=O>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(O)c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
There were weighed out 1-phenylethanol (122 mg, 1.00 mmol) and 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-N-oxyl compound (3.0 mg, 0.01 mmol). Then, 2 ml of acetone was added to obtain a uniform solution. Added thereto was 500 mg of silica gel (product of Merck, grade 9385) and the mixture was vigorously agitated for 5 minutes. The acetone used was distilled off under reduced pressure. Added thereto was 7% aqueous solution of sodium bicarbonate (5 ml) containing 20 wt % of sodium bromide. Then, the mixture was thoroughly stirred. Two platinum electrodes (1.5×1.0 cm2) were applied to the mixture which was then subjected to electrolytic oxidation reaction for 2 hours while being vigorously stirred at room temperature and maintaining the current at 30 mA (quantity of electricity being 2.2 F/mol). After completion of reaction, silica gel was filtered off from the reaction mixture, extraction was effected with 5 ml of acetone and acetone was distilled off. The obtained residue was passed through silica gel column to adsorb it on the column, and elution was performed with a solvent mixture of ethyl acetate/hexane=7/1, giving 116 mg of to acetophenone in a yield of 96%. 1H-NMR (200 MHz, CDCl3)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: NCCCCO
Product: O=S(=O)(NCCCCO)c1ccc(Br)cc1F

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-2-fluorophenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([N:20]([CH:34]1[CH2:36][CH2:35]1)[C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[C:6]([C:8]1[N:9]=[N:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=O)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:45]>>[CH2:1]([O:3][C:4]([C:5]1[N:20]([CH:34]2[CH2:35][CH2:36]2)[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)=[N:45][C:6]=1[C:8]1[N:9]=[N:10][N:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1)=[O:37])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C(=O)c1cn(Cc2ccccc2)nn1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1c(-c2cn(Cc3ccccc3)nn2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1

Procedure:
The title compound was prepared from 3-(1-benzyl-1H-[1,2,3]triazol-4-yl)-2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-propionic acid ethyl ester in direct analogy to intermediate 8B, by reaction with ammonium trifluoroacetate. MS: 498.1 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[Cl:12]N1C(=O)CCC1=O>C(O)(C)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][C:8]=1[NH2:11]
Reactant: COCCc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Product: COCCc1ccc(N)c(Cl)c1

Procedure:
2 g (13.2 mmol) of 4-(2-methoxy-ethyl)-phenylamine (Example 42b) and 1.85 g (13.9 mmol) of N-chlorosuccinimide (Aldrich, Buchs, Switzerland) in 26 ml of isopropanol are stirred at rt for 30 min. The reaction mixture is evaporated to dryness and the residue is taken in EtOAc. The organic layers is washed with sat. aqueous NaHCO3 (2×), dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 5:1 to 2:1) to provide the title compound as an oil. ES-MS: 186 (M+H)+; analytical HPLC: tret=2.42 minutes (Grad 1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[N:35](C2C=C(C=CC=2)N)[N:34]=[N:33][N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([N:32]3[C:31]([CH3:30])=[N:35][N:34]=[N:33]3)[CH:21]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Cc1nnnn1-c1cccc(N)c1
Product: Cc1nnnn1-c1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(5-methyl-1H-tetrazol-1-yl)aniline in step 1. MS: 409.5 (M+H).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=1)[C:43]([NH:45][CH2:46][CH3:47])=[O:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:46]([NH:45][C:43]([C:42]1[CH:41]=[C:40]([C:33]2[CH:34]=[CH:35][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=3)[CH:3]([CH3:4])[CH3:5])=[CH:31][CH:32]=2)[CH:50]=[CH:49][CH:48]=1)=[O:44])[CH3:47]
Reactant: CCNC(=O)c1cccc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 43.8 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (7.40 g, 14.7 mmol), 3-bromo-N-ethylbenzamide (2.20 g) and tetrakis(triphenylphosphine)palladium(0) (0.441 g), the title compound (2.56 g) was obtained as a yellow amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[NH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NN1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2c(NN3CCCCC3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
In DMF (N,N-dimethylformamide) was dissolved 700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then a solution of 751 mg (7.5 mmol) of 1-aminopiperidine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further one hour. After completion of the reaction, ice go water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 573 mg (yield: 59.4%) of the title compound.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:33](Cl)(=[O:36])[CH2:34][CH3:35].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]2[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][O:11][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14][N:15]([CH:30]([CH3:32])[CH3:31])[C:16]=2[CH3:29])=[CH:20][CH:21]=1)([CH3:27])[CH3:28]
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Reactant: CCC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CCC(=O)OC[C@H]1O[C@@H](Oc2nn(C(C)C)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 65.8 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.10 g) in 2,4,6-trimethylpyridine (1 mL) was added propionyl chloride (0.072 g) at 0° C., and the mixture was stirred for hours. To the reaction mixture were added citric acid monohydrate (3.3 g) and water, and the resulting mixture was purified by ODS solid phase extraction (washing solvent: distilled water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) afforded 4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methyl-3-(6-O-propionyl-β-D-glucopyranosyloxy)pyrazole (0.074 g)
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[S:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([SH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:9][CH:8]=1)(=[O:12])[CH3:11]
Reactant: Cc1ccc(C=S)cc1
Reactant: CC(=O)Cl
Product: CC(=O)[SH]=Cc1ccccc1

Procedure:
Two other S-protected p-thiobenzaldehydes were obtained as shown in Scheme 2 (FIG. 15). The thiocyanato-benzaldehyde 8 was prepared according to a general procedure (Suzuki and Abe (1996) Synth. Commun., 26: 3413–3419) in 20% yield. All attempts to improve the yield by replacement of DMF with 1,3-dimethyl-2-imidazolidinone, increasing the temperature, or prolonging the reaction time were unsuccessful. S-Acetylthiobenzaldehyde 9 was prepared in a two-step one-flask procedure. Cleavage of the methyl group of 4-methylthiobenzaldehyde according to a general procedure (Tiecco et al. (1982) Synthesis, 478–480) followed by trapping of the resulting anion with acetyl chloride afforded the desired S-acetylthiobenzaldehyde 9 in 55% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH3:21])(O)[C:18]#[N:19].[O-]S([O-])(=O)=O.[Mg+2]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:17]([C:18]#[N:19])([CH3:21])[CH3:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(O)C#N
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)(C#N)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
The mixture of 2a (0.83 g, 4 mmol), acetone cyanohydrin (4 ml) and MgSO4 (2 g) was heated to 80° C. and stirred over 2.5 h. After cooling down to room temperature, compound 2b was crystallized into water (30 ml). The solid was filtered and dried to yield {4-[(1-cyano-1-methylethyl)amino]phenyl}carbamic acid tert-butyl ester, 2b (1.08 g, 3.9 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[N:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].[NH4+:35].C(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[N:13]([CH3:18])[C:14]([C:15]([NH2:35])=[O:17])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1
Reactant: [NH4+]
Reactant: Cn1c(C(=O)O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1c(C(N)=O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.5 h

Procedure:
A stirred suspension of 3 g (0.0075 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid in 90 ml of methylene chloride was cooled in an ice bath and treated with 1.9 g (0.009 mole) of phosphorus pentachloride in portions. Stirring in the cold under a drying tube was continued for 30 min. Ammonia was then bubbled into the cold solution for 5 min and stirring in the cold was continued 30 min. longer. Evaporation at reduced pressure gave a tan solid. The solid was stirred with 3N ammonium hydroxide and extracted with methylene chloride. An emulsion formed but was destroyed by filtering to remove some high melting solid. The methylene chloride layer was dried over sodium sulfate and evaporated to give a yellow solid which was recrystallized from benzene to give off-white needles with mp 158°-160°. Uv λ sh 215 mμ (ε=43000) max 272 (15500) sh 330 (2500); ir (CHCl3) 3510, 3400 cm-1 (NH2) 1703 (CO) 1685 (CONH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[CH3:26])=[O:8].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:31](=[O:33])[CH3:32])[CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[CH3:26])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(N)ccc2n1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)c(C(=O)NCc1ccc(F)c(F)c1)c(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.9 %

Procedure:
To a solution of 5-amino-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 46, 50 mg, 0.12 mmol) in pyridine (3 ml) was added acetic anhydride (120 μl, 1.23 mmol). The reaction was stirred at room temperature for 72 h, diluted with EtOAc, washed successively with 1M HCl, H2O, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was crystallized from CH2Cl2-Et2O to yield 5-acetamido-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 47) as a white solid (37 mg, 68%).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].[Sn](Cl)Cl>Cl>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: O=N[O-]
Reactant: Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: NNc1ccc(F)c(F)c1F
Yield: 33.8 %

Procedure:
2,3,4-Trifluoroaniline (25 g) was added to concentrated hydrochloric acid (125 ml), and an aqueous solution (20 ml) of sodium nitrite (12.9 g) was added dropwise under ice-cooling. A solution of tin (II) chloride (114.6 g) in concentrated hydrochloric acid (50 ml) was separately prepared and it was added dropwise to the reaction solution. The precipitated solid was collected by filtration, added to an aqueous solution of sodium hydroxide and the aqueous solution was extracted with toluene to give 2,3,4-trifluorophenylhydrazine (9.3 g).
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:23])[CH:6]([C:21]#[N:22])[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[S:12][CH:13]=1)C.C([OH:27])C.O>CS(O)(=O)=O>[OH:23][C:5]1[C:4](=[O:3])[NH:22][C:21](=[O:27])[C:6]=1[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[S:12][CH:13]=1
Reactant: CCOC(=O)C(=O)C(C#N)CCc1csc(-c2ccc(Br)cc2)n1
Reactant: CCO
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C1NC(=O)C(CCc2csc(-c3ccc(Br)cc3)n2)=C1O
Reaction time: 8 h

Procedure:
To 3-[2-(4-bromobiphenyl)thiazol-4-yl]butanenitrile (3.07 g., 0.01 mole) in dimethylformamide (30 ml.) is added diethyloxalate (1.74 g., 0.012 mole) and potassium t-butoxide (2.48 g., 0.022 mole). The mixture is stirred overnight. Following evaporation under vacuum to one-half volume, chloroform (300 ml.) is added, plus water (200 ml.), and the mixture acidified with conc. HCl to pH 2-3. The chloroform is separated and washed well with water. The combined aqueous fractions are extracted a second time with chloroform. The combined chloroform extracts on evaporation provide 2-oxo-3-cyano-5-[2-(4-bromophenyl)thiazol-4-yl]-pentanoic acid ethyl ester. The ester (1.97 g., 0.005 mole) is dissolved in methanesulfonic acid (70 ml.) and stirred overnight. To the mixture is added 80% ethanol-water (200 ml.). After standing for two hours the ethanol is partially removed by evaporation to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([O:38]C)=[O:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2].[OH-].[Na+]>CO.CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([OH:38])=[O:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(=O)OC)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(=O)O)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
(2R,4S)-2-Ethyl-6-methoxy-4-{(3-methoxycarbonyl-5-trifluoromethylbenzyl)-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (86 mg) is dissolved in methanol (9 ml) and N,N-dimethylformamide (1 ml), and thereto is added 1N aqueous NaOH solution (3 ml). The mixture is stirred at room temperature for 1.5 hours, and partitioned by adding 1N HCl and ethyl acetate. The organic layer is washed with saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by thin layer silica gel chromatography (chloroform:methanol=9:1) to give (2R,4S)-4-{(3-carboxy-5-trifluoromethylbenzyl)-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (25 mg). MS (m/z): 645 [M+H]+.
Reaction SMILES: O.O.Cl[Sn]Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1>CCO>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cc(C(F)(F)F)nn1C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1-c1cc(C(F)(F)F)nn1C
Yield: 97 %

Procedure:
SnCl2.2H2O (0.15 g, 0.66 mmol, 4.0 eq.) was added to a stirred solution of 5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole, see Example 1.99, (0.05 g, 0.16 mmol) in EtOH (2.0 mL). The mixture was stirred at reflux for 4 hrs and EtOH was removed under vacuum. The resulting solid was dissolved in EtOAc and 1N NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated to give 4-methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenylamine (0.04 g, 0.15 mmol, 97% yield): LCMS m/z (%)=272 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 6.82 (dd, J=16.0, 4.0 Hz, 1H), 6.79 (dd, J=10.0, 2.0 Hz, 1H), 6.61 (d, 1H), 6.46 (s, 1H), 3.76 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:11][CH2:10][CH2:9][O:8][C:7]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>C(OCC)C>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC1=C(C(=O)O)OCCO1
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)OCCO1

Procedure:
A mixture of thionyl chloride (1.3 g, 0.011 mole) and 5,6-dihydro-3-methyl-1,4-dioxin-2-carboxylic acid (0.57 g, 0.004 mole) was refluxed on a steam bath for 3 hours and the excess thionyl chloride was evaporated at atmospheric pressure. The resulting liquid was added dropwise to a stirred solution of 1-methylethyl 5-amino-2-chlorobenzoate (1.6 g, 0.008 mole) in diethyl ether (30 ml), cooled in an ice-water bath. The mixture was worked up by diluting with diethyl ether (120 ml), washing with dilute hydrochloric acid (50 ml), and then with water (50 ml). The diethyl ether solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure, leaving a solid residue. The crude product was washed with isopropyl alcohol (30 ml), leaving a brown solid, m.p. 103°-105° C. (1.2 g, 95.8% yield).