Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[H][H].FC(F)(F)C(O)=[O:28]>[Pt]=O>[OH2:28].[CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: [H][H]
Reactant: CCCCc1nc2c(N)nc3ncccc3c2n1CC(C)C
Agent: O=[Pt]
Product: CCCCc1nc2c(N)nc3c(c2n1CC(C)C)CCCN3
Product: O

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine (2.0 g, 6.2 mmole) in trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus under 50 psi (3.5 Kg/cm2) hydrogen pressure. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with water, sodium bicarbonate and 10% sodium hydroxide. An oil was recovered and purified using reverse phase high performance liquid chromatography eluting with 30:70 buffer (7.68 g potassium phosphate, monobasic; 1.69 g of sodium hydroxide, 1 L of water):methanol to provide 2-butyl-6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine hemihydrate as a solid, m.p. 81-84° C. Calculated for C17H27N5+½H2O: %C, 65.77; %H, 9.09; %N, 22.56; Found: %C, 65.57; %H, 9.15; %N, 22.53.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:25])[CH2:17][N:18]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]2)[CH2:12][CH2:11]1.[OH-].[Na+]>C1COCC1.CO>[CH3:24][C:20]1[CH:21]=[C:22]([CH3:23])[N:18]([CH2:17][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:26])=[O:2])[CH2:11][CH2:12]2)=[O:25])[N:19]=1
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)Cn2nc(C)cc2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3C(=O)O)CC2)n1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
2-{4-[2-(3,5-Dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid methyl ester (0.848 g, 2.38 mmol) is dissolved in 10 mL of 1:1 THF/MeOH and 2 mL of 15% aqueous NaOH is added. The mixture is stirred overnight and then concentrated to dryness and suspended in 50 mL of H2O. The pH is adjusted to 4 by careful addition of conc. HCl. The aqueous phase is extracted with 3×100 mL of CH2Cl2. The combined organic phase is dried (MgSO4), filtered and concentrated to give 0.730 g of 2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid in 90% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH3:9].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][CH:16]=[CH:15][N:14]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COC(=O)CCCCC(C)=O
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: COC(=O)CCCCc1ccc2cccnc2n1

Procedure:
A mixture of 1-2 (1.4 g, 9.04 mmol), 1-3, 2-amino-3-formylpyridine (552 mg, 4.52 mmol) (for preparation, see: J. Org. Chem., 1983, 48, 3401), and proline (260 mg, 2.26 mmol) in absolute ethanol (23 mL) was heated at reflux for 18 h. Following evaporative removal of the solvent, the residue was chromatog,raphed (silica gel, 80% ethyl acetate/hexane, then ethyl acetate) to give ester 1-4 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[N:30]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1>CO>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:25][CH:26]([CH3:27])[CH3:28])[NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:36][C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[CH:9][C:8]=1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N)cc1-c1cccc2ccccc12
Reactant: O=Cc1ccncc1
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(NCc2ccncc2)cc1-c1cccc2ccccc12

Procedure:
This compound was synthesized via the reductive amination of N-[4-amino-2-naphth-1-ylbenzoyl]leucine methyl ester and pyridine-4-carboxaldehyde in methanol to afford, after purification, a white solid. 1H NMR (DMSO-d6) δ 0.71 (d, J=5.45 Hz, 3H), 0.82 (d, J=5.13 Hz, 3H), 1.20-1.27 (m, 2H), 1.29-1.32 (m, 1H), 3.72 (s, 2H), 3.79 (s, 1H), 4.15 (m, 1H), 4.41 (d, 2H, CH2), 5.52 (d, 1H, NH), 6.67-6.75 (dd, 1H), 6.89 (d, 1H), 7.23 (m, 2H), 7.25-7.35 (m, 8H), 8.55 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccsc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccsc2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a mixed solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (264 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 165 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2C(=[C:9]([F:11])[CH:10]=1)NC=[C:5]2[CH2:12][C:13]([O:15][CH2:16]C)=[O:14].[OH-].[K+].I[CH3:23].[CH3:24][N:25]([CH:27]=O)[CH3:26]>>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:26](=[C:9]([F:11])[CH:10]=1)[N:25]([CH3:24])[CH:27]=[C:5]2[CH:12]([CH3:23])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CI
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1c[nH]c2c(F)cc(Br)c(OC)c12
Agent: [K+]
Agent: [OH-]
Product: COC(=O)C(C)c1cn(C)c2c(F)cc(Br)c(OC)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 9-1 (prepared according to the same procedure of ethyl 2-(5-bromo-7-fluoro-4-methoxy-1H-indol-3-yl)acetate) (2.0 g, 6.3 mmol) in anhydrous DMF (15 mL) was added KOH (1.12 g, 20 mmol), and iodomethane (1.8 g, 12.7 mmol). The mixture was stirred for 1 h at room temperature. After quenching with water, the reaction mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over anhydrous sodium sulfate. After filtration and concentration, a residue 9-2 (3.0 g, crude) was obtained as yellow oil which was used for the next step without further purification.
Reaction SMILES: ClC1C=CC(C[C:7]2[C:16]([C:17]([NH2:19])=[O:18])=[C:15]([OH:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[ClH:33].Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>CN(C=O)C>[Cl:33][C:9]1[CH:14]=[CH:13][C:12]([CH2:21][NH:19][C:17]([C:16]2[C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:7]=2)=[O:18])=[CH:11][CH:10]=1
Reactant: NC(=O)c1c(Cc2ccc(Cl)cc2)nc2ccc(C#CCO)cc2c1O
Reactant: ClCCN1CCOCC1
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 4-(2-chloroethyl)morpholine hydrochloride (0.47 g) are added. The reaction mixture is heated to 90° C. for 2 h. Water is added and a dark solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-5% MeOH/CHCl3) gave 0.183 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.13 g of the title compound as a solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:24]([OH:26])=O)=[N:7][N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[F:45][C:46]([F:53])([CH3:52])[CH2:47][NH:48][CH2:49][CH2:50][OH:51].C(OC(C)C)(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:8]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([C:24](=[O:26])[N:48]([CH2:47][C:46]([F:53])([F:45])[CH3:52])[CH2:49][CH2:50][OH:51])=[N:7]1
Reactant: CC(F)(F)CNCCO
Reactant: CC(=O)Oc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC(C)OC(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)Oc1c(C(=O)N(CCO)CC(C)(F)F)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
4-Acetoxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6d (581.0 g, 1.48 mol) was dissolved in 10 liters of methylene chloride to give a pale yellow, slightly opaque solution. The solution was filtered through Celite® to give a clear green colored solution. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (296.8 g, 1.64 mol) was added in one portion as a solid at room temperature to give an opaque suspension (addition is slightly endothermic). 4-Methylmorpholine (182.9 g, 1.80 mol) was added over 15 minutes while keeping the temperature between 18–22° C. (reaction returned to being yellow in color). Reaction stirred for 3 hours at room temperature, then 2-(2,2-difluoropropylamino)-ethanol (228.3 g, 1.64 mol) was added neat over 10 minutes while keeping the temperature between 20–25° C. The reaction was stirred for 15 hours, then washed twice with 6 liter portions of 10% citric acid and once with 5 liters of brine. The crude product solution was concentrated in vacuo to a thick orange oil, then reconstituted in 4 liters of isopropyl ether. After removing 1 liter of distillates precipitate began to form. To the crude product suspension was added 1.5 liters of isopropyl ether and then the mixture was stirred at room temperature for 1 hour. The precipitated solids were collected by filtration and the resulting filtercake was rinsed with 2 liters of room temperature isopropyl ether, followed by air-drying for 16 hours. Acetic acid 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(2,2-difluoro-propyl)-(2-hydroxyethyl)-carbamoyl]-1H-pyrazol-4-yl ester I-6e (603.0 g, 78%) was isolated as a granular off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.ClC1C=C(Cl)N=CN=1.OCCOC1C=CC(N)=CC=1.[F:38][C:39]1[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=1[NH2:41]>>[F:38][C:39]1[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=1[NH:41][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1F
Reactant: OCCOc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Clc1cc(Cl)ncn1
Agent: Nc1ccc(OCCO)cc1
Product: OCCOc1ccc(Nc2cc(Nc3ccccc3F)ncn2)cc1
Yield: 24 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 4-chloro-6-[4'-(2-hydroxyethoxy)anilino]pyrimidine (0.52 g) (prepared from the reaction of 4,6-dichloropyrimidine and 4-(2-hydroxyethoxy)aniline) was reacted with 2-fluoroaniline (1 ml). The reaction product was chromatographed on silica and recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-(2'-fluoroanilino)- 6-[4'-(2-hydroxyethoxy)anilino]pyrimidine in 24% yield, m.p. 163°-166° C.;
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][C@@H:5]2[C@H:8]([CH:9]=1)[C@@:7]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])([CH2:10][N+:11]([O-])=O)[CH2:6]2)[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:11][CH2:10][C@@:7]1([CH2:14][C:15]([OH:17])=[O:16])[CH2:6][C@H:5]2[C@@H:8]1[CH:9]=[C:3]([CH2:1][CH3:2])[CH2:4]2
Reactant: CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Reaction time: 2 h
Yield: 43.1 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.09 g, 4.71 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the solution, iron powder (1.32 g, 23.5 mmol) and ammonium chloride (249.6 mg, 4.71 mmol) were added, and the mixture was stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (425.1 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[C:10]2[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:4][CH:3]=1.[CH3:18][S:19]([Cl:22])(=[O:21])=[O:20].O.[OH-].[Na+]>C(Cl)Cl>[ClH:22].[N:12]12[CH2:13][CH2:14][CH:15]([CH2:16][CH2:17]1)[C:10](=[CH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:3][CH:4]=1)[CH2:11]2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CC=C2CN3CCC2CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(CC=C2CN3CCC2CC3)cc1
Product: Cl
Temperature: -50 °C

Procedure:
To 4.57 g (0.02 mole) of 3-[2-(4-aminophenyl)ethylidene]1-azabicyclo[2.2.2]octane dissolved in 100 ml of methylene chloride, cooled to -50° C., under a nitrogen atmosphere add dropwise a solution of 2.86 g (0.025 mole) of methanesulfonyl chloride in 25 ml of methylene chloride. After the addition is complete stir the reaction for one-half hour at -50° C. then allow to warm to room temperature. Stir at room temperature for one hour. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 95:5). At the completion of the reaction add 5 ml of water to the reaction mixture then strip the methylene chloride in vacuo. Add 50 ml of 10% sodium hydroxide. Wash the mixture with three 25 ml portions of ether and one 25 ml portion of methylene chloride. Bring the aqueous base mixture to pH=8-8.5 by the addition of 5% hydrochloric acid solution. Extract the mixture with four 100 ml portions of methylene chloride. Wash the combined methylene chloride extracts with a 50 ml portion of water and then with a 50 ml portion of saturated sodium chloride solution. Dry the methylene chloride extracts over anhydrous sodium sulfate, filter and remove the solvent in vacuo to provide the title compound as the free base.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19](OC)=[O:20])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.O.[NH2:26][NH2:27]>C(O)C>[NH:26]([C:19](=[O:20])[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:24])[CH2:6][CH2:7]2)=[N:16][CH:15]=1)=[O:23])[NH2:27]
Reactant: NN
Reactant: COC(=O)CC1CCC(c2ccc(NC(=O)C(=O)OC)cn2)CC1
Solvent: CCO
Solvent: O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of methyl ({6-[4-(2-methoxy-2-oxoethyl)cyclohexyl]pyridin-3-yl}amino)(oxo)acetate, prepared as above, (865 mg, 2.59 mmol) in absolute ethanol (50 mL) was added hydrazine monohydrate (0.15 mL, 3.09 mmol). A thick white suspension formed which was then allowed to stir at ambient temperature for ˜1.5 hrs, filtered, washed with ether (2×20 mL) and then dried to give the title compound (Intermediate 78), 610 mg (1.82 mmol, 70%) as a solid; 1H NMR δ 1.09-1.21 (m, 2H), 1.47-1.56 (m, 2H), 1.71-1.87 (m, 5H), 2.25 (d, 2H), 2.54-2.63 (m, 1H), 3.60 (s, 3H), 4.62 (s, 2H), 7.24 (d, 1H), 8.07 (d, 1H), 8.85 (s, 1H), 10.27 (s, 1H) (not all NH protons seen); MS m/e MH+ 335.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN(C)C=O.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:19])=[O:11]
Reactant: O=C(O)Cc1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccccc1F
Temperature: 22.5 °C
Reaction time: 0.33 h

Procedure:
A solution of 50.0 g of o-fluorophenylacetic acid in 150 mL of toluene and 2.2 g of N,N-dimethylformamide is added to 50.2 g (31.7 mL) of thionyl chloride with efficient stirring over a period of 20 minutes while maintaining an internal temperature of 20-25° C. After addition, the mixture is stirred for 3 hours at 20-25° C., and concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.) to obtain 2-fluorobenzenacetyl chloride as an oil.
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:18]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:12]1([C:10]2[S:11][C:7]3[C:8]([N:9]=2)=[C:18]2[C:4](=[CH:5][CH:6]=3)[NH:21][C:20](=[O:22])[CH2:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1c([N+](=O)[O-])ccc2sc(-c3ccccc3)nc12
Reactant: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3sc(-c4ccccc4)nc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (5-nitro-2-phenyl-benzothiazole-4-yl)-acetonitrile (204.2 mg 0.692 mmol) (Starting Material 6) was suspended in concentrated H2SO4 /H2O (1/1, 3 mL)) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (5 mL) heated at reflux was added excess zinc dust (0.45 g, 6.92 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-thiazolo[4,5-e]indol-7-one. (Yield 20 mg, 11%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:41][CH2:40][CH2:39][CH2:38]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:38][CH:39]3[CH2:41][CH2:40]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.9 %

Procedure:
Into a 10-mL round-bottom flask, was placed 3-[(2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (150 mg, 0.32 mmol, 1.00 equiv), piperidine (27 mg, 0.32 mmol, 1.00 equiv), cyclopropanecarbaldehyde (44.5 mg, 0.63 mmol, 2.00 equiv), methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 48.5 mg (29%) of the title compound as a off-white solid. LC-MS: (ES, m/z): MS (ESI, pos. ion) m/z: 524 (M+1). 1H-NMR: (CDCl3, ppm): 1HNMR (300 MHz, CD3OD, ppm), 8.253 (1H, s), 7.686˜7.749 (2H, t), 7.363˜7.440 (1H, t), 7.185˜7.232 (2H, t), 6.833˜6.941 (3H, m), 6.450˜6.600 (1H, d), 4.301-4.555 (3H, m), 3.604˜3.638 (2H, m), 1.868˜2.005 (5H, m), 1.200˜1.294 (3H, m), 0.798˜0.810 (2H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([CH3:26])([CH3:25])[CH2:21][N:22]([CH3:24])[CH3:23])[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C>C(Cl)Cl.CO>[CH3:24][N:22]([CH3:23])[CH2:21][C:20]([C:16]1[CH:15]=[C:14]([C:10]2[S:9][C:8]([NH2:7])=[N:12][C:11]=2[CH3:13])[CH:19]=[CH:18][N:17]=1)([CH3:26])[CH3:25]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C(C)(C)CN(C)C)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)CN(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 19.1 but using {5-[2-(2-dimethylamino-1,1-dimethyl-ethyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 21.2) and stirring the reaction mixture for 2 h at rt. Title compound: ESI-MS: 291.1 [M+H]+; tR=2.48 min (System 1); TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: C(O[C:4](=[O:13])[C:5]([C:11]#[N:12])=[C:6]1[O:10][CH2:9][CH2:8][O:7]1)C.NC1[N:19]([C:20]2[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[N:18]=CC=1C(=O)C1C=CC=C(I)C=1.C(N(CC)CC)C.[CH2:49]([OH:51])[CH3:50]>>[CH2:49]([O:51][C:4]([C:5]1[C:6]([O:10][CH2:9][CH2:8][OH:7])=[N:18][N:19]([C:20]2[CH:21]=[C:22]([C:23](=[O:24])[NH:25][CH:26]3[CH2:28][CH2:27]3)[CH:29]=[CH:30][C:31]=2[CH3:32])[C:11]=1[NH2:12])=[O:13])[CH3:50]
Reactant: CCO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Reactant: CCOC(=O)C(C#N)=C1OCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(OCCO)nn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Temperature: 25 °C
Yield: 62 %

Procedure:
A stirred solution of cyano-[1,3]dioxolan-2-ylidene-acetic acid ethyl ester (prepared as described by Neidlein and Kikelj, Synthesis, 1988, 981, 266 mg, 1.45 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (Example 6 C, 463 mg, 1.45 mmol, 1.0 eq), and triethylamine (405 μL, 2.9 mmol, 2.0 eq) in 20 mL of ethanol was heated to 65° C. overnight. After cooling to room temperature, the mixture was concentrated and the residue purified by flash chromatography on silica gel (eluted with 1/1 hexanes/EtOAc followed by 100% EtOAc) to provide the desired compound as a tan solid (350 mg, 62%). HPLC (4 minute 10-95 gradient) tR 1.59 min; MS ink 389.06 [M+H]+; 1H NMR (CD3OD), δ 7.87 (d, J=7.9 Hz, 1 H), 7.78 (s, 1 H), 7.49 (d, J=7.8 Hz, 1 H), 4.29 (dd, J=14.9, 6.9 Hz, 2 H), 4.19 (d, J=4.3 Hz, 2 H), 3.84 (d, J=4.4 Hz, 2 H), 2.84 (m, 1 H), 2.22 (s, 3 H), 1.35 (t, J=7.3 Hz, 3 H), 0.81 (d, J=5.3 Hz, 2 H), 0.63 (s, 2 H) ppm.