Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:21][N:20]=[C:19]4[CH2:22][CH2:23][S:24][CH2:25][C:18]=34)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:29].[K+].[K+]>C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:21][N:20]=[C:19]4[CH2:22][CH2:23][S:24](=[O:29])[CH2:25][C:18]=34)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CSCC4)CC2)cc1
Agent: OO
Agent: [K+]
Solvent: O=CO
Product: O=S1CCc2n[nH]c(CCCN3CCN(c4ccc(F)cc4)CC3)c2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(3-(4-(4-Fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole (0.5 g) obtained in Example 138 was dissolved in formic acid (5 ml) and 30% hydrogen peroxide (0.27 ml) was dropwise added under ice-cooling, and the mixture was stirred for 30 minutes at not more than 5° C. The reaction mixture was poured into ice water, made alkaline with potassium carbonate and extracted with ethyl acetate. After drying over magnesium sulfate, the solution was concentrated and recrystallized from isopropyl alcohol:isopropyl ether (1:2) to give 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazole 5-oxide, m.p. 140-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][NH:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:12])[CH2:14][CH2:15][NH:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCCNC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNCCN(C)S(=O)(=O)c1ccc(F)cc1

Procedure:
A solution of 4-fluorobenzenesulphonyl chloride (6.0 g) in chloroform (30 ml) was added dropwise to a well-stirred solution of N,N'-dimethyl-ethylenediamine (25 g) in chloroform (300 ml) at room temperature. After 2 hours the chloroform solution was vigorously shaken with aqueous sodium carbonate solution, separated, dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was treated with chloroform (60 ml) and water (100 ml). The two solvents were mixed thoroughly and were then separated. The chloroform layer was dried (MgSO4) and evaporated under reduced pressure to give an oil. Final traces of N,N'-dimethyl-ethylenediamine were removed by heating the oil under low vacuum to give 4-fluoro-N-methyl-N-[2-(methylamino)ethyl]benzenesulphonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].C(Cl)Cl.[CH3:15][CH2:16][O:17]C(C)=O>>[O:11]1[CH2:15][CH2:16][O:17][CH:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2OCCO2)nc1

Procedure:
2-(1,3-Dioxolanyl)-5-nitropyridine was prepared from 5-nitropyridine-2-carboxaldehyde by the procedure employed for the synthesis of Example III. Yield: 2.0 g (84%); mp 104°-105° C.; TLC Rf 0.73 (CH2Cl2 /EtOAc, 1:1, v/v); 1H NMR (90 MHz, CDCl3) δ 4.10 (s, 4H, CH2CH2), 5.92 (s, 1H, 2-CH), 7.72 (d, 1H, 3-H, J3,4 =8 Hz), 8.50 (dd, 1H, 4-H, J3,4 =8 Hz, J4,6 =2 Hz), 9.42 (d, 1H, 6-H, J4,6 =2 Hz). Anal.(C8H8N2O4) C, H, N.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1F.CCN(CC)CC>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(Cl)c1
Yield: 63.1 %

Procedure:
To a solution of morpholine (1.1 mL, 12.6 mmol) in DMF (30 mL) were added 2-chloro-1-fluoro-4-nitrobenzene (1.76 g, 10.0 mmol) and Et3N (4.2 mL, 30.1 mmol) with stirring and the mixture was stirred at rt overnight. The mixture was then filtered and the organic phase was poured into 150 mL of DCM, washed with water (150 mL×3) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=10:1) to give the title compound as a yellow solid (1.53 g, 63%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([C:13]1[C:14](=[O:38])[NH:15][C:16](=[O:37])[N:17]([CH:36]=1)[C@@H:18]1[O:35][C@H:22]([CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:20]([OH:21])[CH2:19]1)[CH3:12]>CN(C)C=O>[CH2:1]([S:8][CH2:23][C@H:22]1[O:35][C@@H:18]([N:17]2[CH:36]=[C:13]([CH2:11][CH3:12])[C:14](=[O:38])[NH:15][C:16]2=[O:37])[CH2:19][C@@H:20]1[OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CSCc3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 100.8 %

Procedure:
A solution of 0.5 g of benzyl mercaptan in 10 ml of dry dimethylformamide was treated with 60 mg of a 80% dispersion of sodium hydride in mineral oil. After the effervescence had ceased a solution of 1.64 g of 2'-deoxy-5-ethyl-5'-O-(p-toluenesulphonyl)uridine in 20 ml of dry dimethylformamide was added. The mixture was stirred and heated at 100° C. under a nitrogen gas atmosphere. The course of the reaction was followed by thin layer chromatography. After 4 hours the mixture was evaporated to give an oily residue. This was purified by flash column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution. The fractions containing the product were combined and evaporated to yield an oil which solidified and was recrystallized from diethyl ether to give 1.46 g of 5'-benzylthio-2',5'-dideoxy-5-ethyluridine, mp 149°-151° C.
Reaction SMILES: S(O[C@H:12]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C:21]2=[O:31])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:32][OH:33]>>[CH3:32][O:33][C@H:12]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C:21]2=[O:31])[CH2:13]1
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]43)C2)cc1
Product: CO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1

Procedure:
A solution of 3β-tosyloxyandrost-5-ene-17-one (18) (4.0 g. 9.05 mmol) in anhydrous methanol (120 mL) was refluxed for 2 h. The reaction mixture was concentrated under vacuum. On cooling, a white solid 3β-methoxyandrost-5-ene-17-one (19) was obtained. Recrystallization from methanol afforded shining crystals (2.57 g. 94%), m.p. 133-5° C. (lit m.p. 118-120° C. aq. MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16](B(O)O)[CH:17]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=1[C:21]([F:22])([F:23])[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(F)ccc1C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(F)ccc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 45.9 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 400 mg, 2.74 mmol), 5-fluoro-2-(trifluoromethyl)phenylboronic acid (Cuschem, Inc., Yonkers, N.Y.; 512 mg, 2.46 mmol), copper(II) acetate (497 mg, 2.74 mmol) and triethylamine (380 μL, 2.7 mmol) in 1,2-dichloroethane (18 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(5-fluoro-2-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (348 mg, 41%) as a colorless oil that solidified.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:11][CH2:10][N:9](C(OCCCC)=O)[CH2:8][CH2:7]1)(=[O:4])=[O:3].[ClH:19]>ClCCl.CO>[ClH:19].[NH:9]1[CH2:8][CH2:7][CH:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:11][CH2:10]1
Reactant: CCCCOC(=O)N1CCC(NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCNCC1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
In a dried reaction flask, butyl 4-(methylsulfonamido)piperidine-1-carboxylate (2.53 g, 9.1 mmol) was dissolved in a mixed solvent of dichloromethane (20 mL) and methanol (5 mL). A dried HCl gas was passed thereto at room temperature for 2 hr, and a white solid was formed. The mixture was filtered and washed with dichloromethane and anhydrous ethyl ether, and dried to obtain a white powdery solid (1.88 g) in a 96.3% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([O:23][CH2:24]Cl)=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:26].[Na+]>CC(C)=O>[I:26][CH2:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCI
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-propionate (2.05 g, 5.51 mmole) in dry acetone (50 ml) was added sodium iodide (4.12 g, 27.5 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl acetate water. The organic phase was washed with a 5% sodium thiosulfate solutions dried with sodium sulfate and evaporated under reduced pressure. Yield: 2.35 g=92%.
Reaction SMILES: C([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:17])[CH:5]=1)(=O)C.C1C=C(Cl)C=[C:20]([C:25]([O:27]O)=[O:26])C=1>ClCCl>[C:25]([O:27][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:17])[CH:5]=1)(=[O:26])[CH3:20]
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(OC(C)=O)cc1C
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of ethyl 2-(4-acetyl-2-methylphenoxy)acetate (683) (8.78 g, 37 mmol), mCPBA (2.eq.), and p-TsOH monohydrate (0.15 eq.) in dichloromethane (160 mL) was heated at 40° C. overnight. The reaction was cooled to room temperature and washed with 1M KI (2×200 mL), 5% NaHSO3 (2×150 mL), and water (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to provide ethyl 2-(4-acetoxy-2-methylphenoxy)acetate (684) (72%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CCO>[ClH:38].[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][C:18]2[N:17]([CH2:16][CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:37][CH:36]=1
Reactant: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(COc3ccc(Cl)cc3)nc12
Agent: Cl
Solvent: CCO
Product: COc1cccc2c(=O)n(CCCC3CCNCC3)c(COc3ccc(Cl)cc3)nc12
Reaction time: 2 h

Procedure:
The product obtained in step A was dissolved in a solution of conc HCl/EtOH (1:3 mixture, 20 mL). The reaction mixture was stirred for 2 h, concentrated under vacuum and azeotroped with ethanol and heptane to give the desired product as a white solid. API-MS: 442 (M+1). 1H NMR (300 MHz, d4-MeOH): d 7.81 (d, 1 H), 7.63 (t, 1 H), 7.55 (d, 1 H), 7.35 (d, 2 H), 7.1 (d, 2 H), 5.4 (s, 2 H), 4.15 (dd, 2 H), 4.05 (s, 3 H), 3.3 (m, 2 H), 2.9 (t, 2 H), 1.9 (m), 1.4 (m).
Reaction SMILES: [Na].CO.[S:4]1[CH:8]=[CH:7][S:6][C:5]1=[C:9]([C:15](=[O:30])[N:16]([CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:10](OCC)=[O:11]>C1C=CC=CC=1>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:16]2[C:15](=[O:30])[C:9](=[C:5]3[S:4][CH:8]=[CH:7][S:6]3)[C:10](=[O:11])[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:17]2)[CH:25]=1
Reactant: CCOC(=O)C(C(=O)N(CCC(=O)OC)Cc1cccnc1)=C1SC=CS1
Agent: [Na]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C1CN(Cc2cccnc2)C(=O)C(=C2SC=CS2)C1=O
Yield: 51 %

Procedure:
Sodium (156 mg) is added to methanol (5ml) and thereto is added a solution of ethyl 2-(1,3-dithiol-2-ylidene)-2-[N-(3-pyridylmethyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (2.21 g) in benzene (35 ml). The mixture is refluxed for 3 hours, and distilled to remove the solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and then distilled to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane to give methyl 1-(3-pyridylmethyl)-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-3-carboxylate (1.0 g, 51%) as pale yellow needles, m.p. 111°-114° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[O:36])[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccccn4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
Triethylamine (0.7 g, 7.4 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and picolinoyl chloride hydrchloride (0.5 g, 2.5 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with H2O (30 mL). The mixture was filtered, and the solid was slurried with hot methanol (15 mL) to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.6 g, 78%): mp 254-256° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.32-2.66 (m, 2H), 2.86-3.01 (m, 1H), 4.43-4.65 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.7 and 13.0 Hz, 1H, CH), 7.45-7.64 (m, 4H, Ar), 7.97-8.07 (m, 2H, Ar), 8.65 (d, J=4.2 Hz, 1H, Ar), 9.51 (t, J=5.8 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.17, 46.30, 51.57, 121.63, 122.02, 126.60, 128.28, 130.77, 131.58, 134.73, 137.79, 140.08, 148.44, 149.80, 164.16, 168.06, 170.99, 172.82; Anal. calcd. for C20H18N4O4: C, 63.49; H, 4.79; N, 14.81. Found: C, 63.32; H, 4.66; N, 14.80.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:33])[N:15]([CH3:32])[C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[N:19]=[CH:18][N:17]=1>C1COCC1.CO.[Ni]>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]([N:15]([CH3:32])[C:14]([NH:13][C:3]2[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[Cl:12])=[O:33])[CH:21]=1
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3[N+](=O)[O-])ncn2)c1Cl
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-[6-(2-nitro-phenylamino)-pyrimidin-4-yl]-urea (50 g, 0.1 mmol) in THF (10 mL) and MeOH (10 mL) was added Raney-Ni (suspension in water) at room temperature, the resulting mixture was stirred for 2 hours under hydrogen atmosphere. The reaction was filtered and concentrated to obtain the title compound (38 mg, yield: 82%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 3.28 (s, 3H), 3.85 (s, 2H), 3.94 (s, 6H), 5.86 (s, 1H), 6.52 (s, 1H), 6.78-6.87 (m, 3H), 7.16-7.20 (m, 2H), 8.39 (s, 1H), 12.62 (s, 1H); MS (ESI): 463 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]3[CH2:22][NH:23][CH2:24][CH:17]23)=[O:15])=[CH:4][CH:3]=1.Cl[C:26]1[O:27][C:28]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:29]2[N:30]=[C:26]([N:23]3[CH2:22][CH:18]4[CH:17]([N:16]([C:14]([C:9]5[N:10]=[C:11]([CH3:13])[S:12][C:8]=5[C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[O:15])[CH2:21][CH2:20][CH2:19]4)[CH2:24]3)[O:27][C:28]=2[CH:34]=1
Reactant: Cc1nc(C(=O)N2CCCC3CNCC32)c(-c2ccc(F)cc2)s1
Reactant: Clc1ccc2nc(Cl)oc2c1
Product: Cc1nc(C(=O)N2CCCC3CN(c4nc5ccc(Cl)cc5o4)CC32)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(octahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methanone and 2,6-dichlorobenzoxazole. MS (ESI) 497 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:19])[CH3:18]>CC(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cccc(O)c1C
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(OC(C)C)c1C

Procedure:
To a stirred solution/suspension of 2,3-dimethylphenol (10 g) and potassium carbonate (6.8 g) in acetone (150 ml) at reflux was added 2-bromopropane (46 ml) drop-wise over 30 min. The solution was heated at reflux for 4 days. After cooling, the solvent was evaporated and the residue was dissolved in ether and water. The ether phase was separated and was worked up according to the general procedure. Column chromatography on silica gel (eluent:ethyl acetate/heptane 1:19) afforded pure 2,3-dimethyl-1-(2-propyl)oxybenzene (13.2 g) as a mobile, slightly brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>CC#N>[CH:27]([O:26][C:24]([N:13]1[CH2:14][CH2:15][CH:10]([S:9][C:6]2[C:7]([CH3:8])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)[CH2:11][CH2:12]1)=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1c(Cl)ncnc1SC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Cl)ncnc1SC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A mixture of 4-chloro-5-methyl-6-(piperidin-4-ylsulfanyl)-pyrimidine (HCl salt, 1.8985 g, 6.77 mmol) and triethylamine (2.825 mL, 0.02 mol) in 50 mL of CH3CN was stirred under room temperature. After 15 min, isopropyl chloroformate (1M in toluene, 8.13 mL, 8.13 mmol) were added slowly under 0° C. Mixture was stirred under room temperature. After 3 h, mixture was concentrated and residue was extracted with EtOAc and saturated NaHCO3. Organic phase was dried over MgSO4, filtered and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid isopropyl ester as yellowish oil (1.9143 g, 85%). Exact mass calculated for C14H20ClN3O2S 329.1, found 330.3 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccn1
Temperature: 25 °C
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.4 g, 0.027 mole) was added dropwise (slowly) to a stirred and chilled (10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.4 g, 0.025 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10° C.) solution of 2-aminopyridine (2.6 g, 0.028 mole) and triethylamine (5.4 g, 0.0053 mole) in anhydrous dimethyl formamide (100 ml). The reaction was stirred at room temperature overnight. Dimethylformamide (100 ml) was distilled off at 100 mm Hg. The residue was cooled, triturated in potassium bicarbonate solution (2×50 ml), and filtered. The filter cake was rinsed with water (2×50 ml) and recrystallized from ethanolisopropyl ether to give 4.8 g (47%) of white solid, mp. 191.5°-195° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:18](OC)=[O:19])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:18][OH:19])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2cnn(-c3ccc(F)cc3)c2cc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1CO
Reaction time: 12 h
Yield: 75.1 %

Procedure:
Methyl 1-(4-fluorophenyl)-6-methyl-1H-indazole-5-carboxylate (151 g, 0.53 mmol) was dissolved in 5 mL THF and 2M LiBH4 in THF (1 mmol) was added. Heated at reflux. After 12 h, the reaction was quenched with MeOH, poured into brine and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC using a 1:3 to 1:1 EtOAc/hexane gradient. Obtained 102 mg (75% yield) of (1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)methanol. MS found: (M+H)+=257.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:9]3[CH2:10][C@H:11]([OH:13])[CH2:12][C@@H:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:15][C:16]=12)=[O:25])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Product: CC(C)(C)NC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Yield: 100 %

Procedure:
Prepared by the method described in Example 1 using 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and tert-butyl amine to provide the final product as a white solid (24 mg, 100% yield). MS (apci) m/z=398.1 (M+H).