Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:17]([S:19]Cl)=[O:18]>>[O:18]=[C:17]1[NH:1][C:2]([C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:19]1
Reactant: CCOC(=O)C=C(N)C(F)(F)C(F)(F)F
Reactant: O=C(Cl)SCl
Product: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a stirred mixture of 65 g (0.4995 ) mole of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazole-carboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]O.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][Cl:15]
Reactant: COc1ccc(CO)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCl)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
In a nitrogen atmosphere, 5 g (29.73 mmol.) of 3,4-dimethoxybenzyl alcohol was dissolved in 25 ml of dichloromethane. The obtained solution was placed in an ice-bath, and to this was dropwise added a solution of 2.16 ml (29.74 mmol.) of thionyl chloride in 5 ml of methylene chloride. The mixture was then stirred at room temperature for 1 hour. The mixture was placed under reduced pressure at room temperature to distill off the solvent to give 5.624 g of the desired compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1S(=O)(=O)N.NC1CCN(CC2C=CC(Br)=CC=2)CC1>C(O)CCCC>[O:7]=[C:6]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:12][CH:11]=2)[C:9](=[O:10])[NH:8]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Agent: NC1CCN(Cc2ccc(Br)cc2)CC1
Solvent: CCCCCO
Product: O=C1NC(=O)c2ccccc21

Procedure:
Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide (6.48 g., 0.025 mole) and 4-amino-1-(4-bromobenzyl)piperidine (6.7 g., 0.025 mole) in n-pentanol according to the procedure of Example 1(a) afforded the 1,3-dioxoisoindole product. Purification of the crude product by triturating with n-heptane and crystallization from DMF-methanol afforded 6.9 g. (54%) of 2-[1-[(4-bromophenyl)methyl]-4-piperidinyl]-6-chloro-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 246°-247° (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C:7]2=[O:8])[O:3]1.[H-].C([NH2+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[O:3][C@@H:4]2[CH2:5][O:6][C@@H:7]([OH:8])[C@@H:9]2[O:10]1
Reactant: CC1(C)O[C@@H]2COC(=O)[C@@H]2O1
Agent: CC(C)C[NH2+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)O[C@H]2[C@H](O)OC[C@H]2O1
Reaction time: 0.5 h

Procedure:
2,3-O-isopropylidene-D-erythronolactone (1.04 g, 6.42 mmol) was dissolved in toluene (20 ml), followed by the addition of 1 M diisobutylammonium hydride (DIBAL)/THF to the solution at −78° C. The reaction mixture was stirred at the same temperature for 30 min and methanol was slowly added until the reaction terminated. The suspension was filtered through a Celite filter and the filtrate was extracted with ethyl acetate and water, followed by silica gel column chromatography using a mixture of hexane:ethylacetate (3:1, v/v) to give the object compound in syrup form (1.94 g, 96%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:5][CH:4]=1)[NH2:2].C([O-])(=O)C.[Na+].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O.C(O)C.C(OCC)(=O)C.C(Cl)Cl>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[N:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:11])=[O:12])=[CH:7][CH:8]=1
Reactant: C1=COCCC1
Reactant: CN(C)S(=O)(=O)Cc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Cc1ccc(NN=CCCCCO)cc1
Yield: 28.2 %

Procedure:
To a solution of 5.02 g (18.9 mmol, 1.0 equiv.) of 4-hydrazinyl-N,N-dimethyl-benzenemethanesulfonamide in 20 mL of water and 20 mL of ethanol was added sufficient sodium acetate to raise the pH to four. To the resulting slurry was added 1.90 mL (20.8 mmol, 1.1 equiv.) of 3,4-dihydro-2H-pyran. The reaction was stirred for sixteen hours then diluted with 200 mL of ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate, dried over anhydrous sodium sulfate and concentrated in vacuo to yield an oil. Chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide yielded 1.67 g (28%) of pure 4-[2-(5-hydroxypentylidene)hydrazinyl]N,N-dimethylbenzenemethanesulfonamide as an oil.
Reaction SMILES: Br[CH2:2][CH3:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([CH:11]=1)[NH2:10]>>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([CH:11]=1)[NH:10][CH2:2][CH3:3]
Reactant: Cc1ccc(Br)cc1N
Reactant: CCBr
Product: CCNc1cc(Br)ccc1C
Yield: 71 %

Procedure:
Using the same method as in Example 22-(i), bromoethane was reacted with the 5-bromo-2-methylaniline to give 5-bromo-N-ethyl-2-methylaniline (yield: 71%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:21])[CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16])[CH3:11].N1C=CC=CC=1>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15]([CH3:16])=[N:8][N:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)[C:18]=1[CH3:19])=[O:21])[CH3:11]
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccc(C)cc2)c1C

Procedure:
Similar to Example 1, p-tolylhydrazine (10 mmol, 1.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum. The named product was purified over silica gel (m.p. 47° C.-49° C.).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:58])([CH3:57])[C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)=[O:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([C:48]([N:50]4[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]4)=[O:49])([CH3:58])[CH3:57])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN1CCN(C(=O)C(C)(C)N)CC1
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methylpropionyl)-4-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxy-ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:20]1([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][O:1][C:2]3[CH:13]=[CH:12][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=4[CH:3]=3)=[CH:32][CH:33]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To 3-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) dissolved in DMF (20 ml) were added potassium carbonate (2.76 g, 20.0 mmol) and 4-phenylbenzyl bromide (2.72 g, 11.0 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (30 ml) and THF (30 ml) were added to the residue and the resulting mixture was washed with water (10 ml, 5 ml×3) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was mixed with diisopropyl ether, and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain 3-(4-phenylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (3.00 g, 8.76 mmol, 88%).
Reaction SMILES: C1C(C(O)CCCN2CC3C4C=C(F)C=CC=4N(C4C=CC(F)=CC=4)C=3CC2)=CC=C(F)C=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1.[C:43]([N:48]1[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]1)([O:45][CH2:46][CH3:47])=[O:44]>>[F:34][C:35]1[CH:40]=[CH:39][C:38]2[NH:41][C:51]3[CH2:52][CH2:53][N:48]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:49][C:50]=3[C:37]=2[CH:36]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1
Product: CCOC(=O)N1CCc2[nH]c3ccc(F)cc3c2C1

Procedure:
Plattner et al. and Harbert et al. also describe the earliest synthesis of flutroline: p-Fluorophenylhydrazine is condensed with N-carbethoxy-4-piperidone to form 8-fluoro-2-carbethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. By the Ulmann reaction the latter is arylated to form the 5-(p-fluorophenyl) derivative and then hydrolyzed under vigorous basic conditions to yield 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The synthesis of flutroline is completed by 2-alkylation with 3-(p-fluorobenzoyl)propyl chloride and finally reduction of the ketone group to an alcohol group.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][O:12][CH3:13]>CN(C)C=O>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCn1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 5.02 g of imidazole and 50 ml of N,N-dimethylformamide is admixed at 0° C. with 3.52 g of sodium hydride dispersion (69%) and stirred at room temperature over 1 hour. The solution of 8.36 g of 1-chloro-3-methoxypropane in 10 ml of N,N-dimethylformamide is added and the reaction solution is subsequently stirred at 60° C. over 2 hours. The reaction mixture is cooled, poured onto ice-water (150 ml) and extracted with ethyl acetate (3×150 ml). The organic phases are washed with water (3×150 ml) and brine (150 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=1.55.
Reaction SMILES: Cl.Cl.[N:3]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:8][CH2:7][CH:6]([N:9]2[C@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]3[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34].[OH-].[Na+]>ClCCl>[O:18]=[C:10]1[N:9]([CH:6]2[CH2:5][CH2:4][N:3]([CH:19]3[CH2:24][CH2:23][N:22]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:20]3)[CH2:8][CH2:7]2)[C@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]2[NH:11]1
Reactant: O=C1N[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
(3aS,7aS)-1-(1,4′-bipiperidin-4-yl)hexahydro-1H-benzo[d]imidazol-2(3H)-one dihydrochloride (0.68 g, 1.79 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (0.75 mL, 5.38 mmol) was added. Isopropyl chloroformate (1.792 mL, 1.79 mmol) (solution 1M in toluene) was added drop wise at 0° C. The mixture was stirred for 2 hours then diluted in dichloromethane (60 mL) and the mixture made basic with 1N NaOH. The phases were separated and aq. phase was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with brine (5 mL) and concentrated under reduced pressure. The crude was then purified by high pH prep LCMS to provide the title compound as a white solid (560 mg, 80%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 1.22 (d, J=6.25 Hz, 6H), 1.26-1.49 (m, 6H), 1.58-1.70 (m, 2H), 1.72-1.84 (m, 7H), 1.94 (d, J=11.33 Hz, 1H), 2.14-2.32 (m, 3H), 2.33-2.47 (m, 1H), 2.69 (t, J=13.09 Hz, 2H), 2.84-2.96 (m, 2H), 2.96-3.06 (m, 1H), 3.65-3.81 (m, 1H), 4.07-4.28 (m, 2H), 4.43 (s, 1H), 4.80-4.94 (m, 1H). MS (M+1): 393.2
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:18][CH:17]3[CH2:19][O:20][CH2:21][CH2:22][N:16]3[C:15]3[N:14]=[C:13]([Cl:23])[N:12]=[CH:11][C:10]2=3)[CH:5]=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:13]1[N:12]=[CH:11][C:10]2[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:24])[N:7]=3)[CH2:18][CH:17]3[CH2:19][O:20][CH2:21][CH2:22][N:16]3[C:15]=2[N:14]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(CN2CC3COCCN3c3nc(Cl)ncc32)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a 10 mL vial was added 5-((6-bromopyridin-2-yl)methyl)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x27, 75 mg, 0.189 mmol), K2CO3 (52.3 mg, 0.378 mmol), PdCl2(dppf) (13.83 mg, 0.019 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.053 mL, 0.378 mmol) in dioxane (2 mL) and H2O (0.4 mL) to give an orange suspension. The reaction vial was sealed, heated to 100° C., and stirred overnight. The reaction mixture was then diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give crude product, which was loaded onto an ISCO® silica gel cartridge (4 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (36 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ 2.45 (s, 3H), 2.92-3.05 (m, 1H), 3.12-3.27 (m, 2H), 3.40-3.52 (m, 2H), 3.61-3.74 (m, 1H), 3.85-4.00 (m, 2H), 4.18-4.28 (m, 1H), 4.35-4.58 (m, 2H), 7.10-7.17 (m, 2H), 7.30 (s, 1H), 7.60-7.68 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C16H18ClN5O, 331.12. found 331.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-])=O.C(OCC)(=O)C.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>[Pd].CCOCC>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[NH2:1][C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(O)c(O)c1

Procedure:
A solution of 7.76 g (50.0 mmol) of 4-nitrocatechol in 350 ml of ethyl acetate containing 38.5 ml (50.0 mmol) of trifluoroacetic acid was hydrogenated in the presence of 3.4 g of palladium (10%) on charcoal for 40 minutes. The catalyst was filtered off and the filtrate was evaporated iin vacuo to leave a residue which was stirred with dry ether, collected by suction and dried in vacuo (over potassium hydroxide); yield: 11.3 g; melting point 145°-154° C., dec.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:15]([N:8]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:6]([CH2:4][OH:3])=[N:7]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1nn(Cc2ccccc2)c2c1CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nn(Cc2ccccc2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirring solution of 1.0 g (3.52 mmol) of 4,5,6,7-Tetrahydro-1-Benzyl-1H-indazole-3-carboxylic acid ethyl ester, prepared as in Part A, in 15 mL of THF at 0° C. is added dropwise over 5 min a solution of 5.3 mL (5.3 mmol, 1.5 equiv) of a 1.0M solution of LiAlH4 in THF. The resulting solution is stirred at RT for 30 min then heated to 50° C. for 1 h. The reaction mixture is cooled to 0° C. and worked up by carefully quenching first with 0.22 mL of H2O, then 0.22 mL of 15% NaOH, then 0.66 mL of H2O. The resulting slurry is filtered and the filter cake triturated with 20 mL EtOAc and refiltered. The filtrates were combined, dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by Kugelrohr distillation gave 740 mg of (4,5,6,7-Tetrahydro-1-benzyl-1H-indazol-3-yl) methanol as a pale yellow thick oil: bp 225° C. at 0.8 mm; 1H NMR (CDCl3, 300 MHz) δ7.32-7.24 (m, 3H), 7.10 (m, 2H), 5.17 (s, 2H), 4.62 (s, 2H), 2.46 (m, 4H), 1.72 (m, 4H); low resolution MS (FAB)m/e 243 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:2]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:10][CH2:9][CH2:8][N:7]2[S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc(C2CCCN2)cs1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccsc2)cc1

Procedure:
The title compound, white solid, m.p. 114° C. and MS: m/e=308.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-3-yl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[NH:22][CH2:23][C@H:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([CH3:46])([CH3:45])[C:36]([N:38]3[CH:42]4[CH2:43][CH2:44][CH:39]3[CH2:40][CH2:41]4)=[O:37])[CH:33]=2)[NH:28][C:27]=1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)[CH3:25])(C)(C)C>>[NH2:22][CH2:23][C@H:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([CH3:46])([CH3:45])[C:36]([N:38]3[CH:42]4[CH2:43][CH2:44][CH:39]3[CH2:40][CH2:41]4)=[O:37])[CH:33]=2)[NH:28][C:27]=1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)[CH3:25]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (S)-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-carbamic acid tert-butyl ester (2.6 g in 90 mL methylene chloride) at 0° C. was added 5.2 mL anisole followed by 37 mL trifluoroacetic acid and the mixture stirred at 0° C. After 2 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purification by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (2.1 g).
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(#N)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][CH:2]=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(=CO)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(=COS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
19.2 g (0.1 mol) of ethyl α-hydroxymethylene-phenylacetate are dissolved in 100 ml of acetonitrile, and first 11.2 g (0.1 mol) of potassium tert.-butylate are added, after which 19 g (0.1 mol) of p-toluenesulphonyl chloride are added in portions at 20° to 25° C. The mixture is stirred for 4 hours at room temperature and left to stand overnight. The precipitated salt is filtered off under suction, and the filtrate is evaporated down in vacuo. The residue is dissolved in toluene, and the solution is washed with water, dried over sodium sulphate and evaporated down in vacuo. 23 g (73% of theory) of ethyl α-(4-methyl-phenylsulphonyloxymethylene)-phenylacetate are obtained. The oil is dissolved in 150 ml of ethanol, and then 7.7 g (0.07 mol) of 2-hydrazino-pyrimidine are added. The mixture is stirred for 10 hours at room temperature, and then 13.5 g of concentrated sodium hydroxide solution are added dropwise in the course of 4 hours. After stirring has been continued for a further 5 hours at room temperature, dilute hydrochloric acid is added dropwise until the neutral point is reached, and the mixture is diluted with 750 ml of water. The oily product which separates out is taken up in a small amount of ether, 3.6 g (22% of theory) of 1-pyrimid-2-yl-4-phenylpyrazolin-5-one being precipitated. Melting point 159° to 160° C. (from ethanol).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][O:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][N:6]=1.[OH-].[NH4+]>C(O)C.C(OCC)(=O)C.[Ni]>[F:14][C:2]([F:1])([CH3:13])[CH2:3][O:4][C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: CC(F)(F)COc1ncncc1C#N
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(F)(F)COc1ncncc1CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
4-(2,2-difluoropropoxyl)pyrimidine-5-carbonitrile (1.0 equiv.) was dissolved in a 1:1 mixture of ethanol and ethyl acetate (0.2 M). Sponge nickel catalyst (50% aqueous slurry) (19 equiv.) and ammonium hydroxide (12 equiv.) were added to the reaction vessel, which was purged thoroughly with hydrogen gas and allowed to stir at room temperature for 16 h. The reaction mixture was filtered through a microfiber filter containing celite, washed with ethanol, and volatile solvents were removed under reduced pressure. The residue was purified using silica gel chromatography (60-100% ethyl acetate in hexanes followed by 1-20% MeOH in ethyl acetate). The desired fractions were combined and volatile solvents were removed under reduced pressure to afford (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (82% yield). MS(ESI) m/z 204.1 [M+1]+.