Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:31]=[C:32]([CH:42]4[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]4)[NH:33][C:34]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:29][C:24]=2[O:23][CH2:22]1>C1COCC1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:31]=[C:32]([CH:42]4[CH2:47][CH2:46][CH:45]([NH:48][S:8]([CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:10])=[O:9])[CH2:44][CH2:43]4)[NH:33][C:34]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1cccc(-c2[nH]c(C3CCC(N)CC3)nc2-c2ccc3c(c2)OCO3)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(C3CCC(NS(=O)(=O)Cc4ccccc4)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.4 %

Procedure:
α-Toluenesulfonyl chloride (0.023 g, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 4-[4-benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl] cyclohexylamine (see Example 19; 0.038 g, 0.10 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.005 g (9%) of the title compound as a yellow solid. MS (ESP+) m/z 531.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.67 (m, 1H), 7.41 (m, 6H), 7.30 (m, 1H), 7.22 (m, 1H), 7.01 (m, 2H), 6.07 (s, 2H), 4.34 (s, 2H), 3.05 (m, 2H), 2.63 (s, 3H), 2.13 (m, 2H), 1.95 (m, 2H), 1.72 (m, 2H), 1.43 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([OH:23])[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([O:23][CH3:26])[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1CC(O)(c2cc(F)cc(OCc3ccccc3)c2)CCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC(C)C1
Reaction time: 0.75 h
Yield: 71 %

Procedure:
A mixture of (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-hydroxy-2-methyltetrahydropyran (0.45 g) and dimethylformamide (5 ml) cooled in an ice bath, sodium hydride (0.068 g of a 55% w/w dispersion in mineral oil) was added and the mixture was stirred for 45 minutes. Methyl iodide (0.11 ml) was added and the mixture was stirred for 15 minutes. The ice bath was removed and the mixture was stirred at ambient temperature for 30 minutes. The mixture was poured into water (15 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 10:1 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained as an oil, (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-methoxy-2-methyltetrahydropyran (0.33 g, 71%);
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[CH2:9][OH:10])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a suspension of trans-2-aminocyclohexylmethanol hydrochloride (4.50 g, 27.3 mmol) and triethylamine (11 mL, 81 mmol) in 200 mL dichloromethane at 0° C. was added dropwise a solution of 4-chlorobenzenesulfonyl chloride (5.69 g, 27.1 mmol) in 25 mL dichloromethane. The reaction was stirred at 0° C. for 1 h, then washed with aqueous sodium bicarbonate and water. The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 0 to 100% ethyl acetate in hexane to give 4-chloro-N-(trans-2-hydroxymethylcyclohexyl)benzenesulfonamide (6.5 g, 78%). 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (m, 2H), 7.48 (m, 2H), 5.21 (d, J=7.81 Hz, 1H), 3.76-3.95 (m, 1H), 3.37 (ddd, J=11.14, 7.11, 3.40 Hz, 1H), 2.87-3.10 (m, 1H), 2.34-2.55 (m, 1 H), 1.47-1.70 (m, 4H), 1.19-1.40 (m, 2H), 0.94-1.19 (m, 3H). LC/MS R.T.=2.73 min; [M+H]+=304. HRMS [M+H]+ calc'd 304.0774, found 304.0768.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]([Br:26])([F:25])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1)O.CCOC(C)=O>C(Cl)Cl>[Br:10][C:11]([Br:26])([F:25])[CH:12]([F:7])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: COc1ccc(C(O)C(F)(Br)Br)cc1[N+](=O)[O-]
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(F)C(F)(Br)Br)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
(DAST 730 μL (5.58 mmol; 1.8 eq) in 5 mL CH2Cl2 was added to a solution of 1.146 g (3.1 mmol) of the alcohol (7) in 7 mL CH2Cl2 at −78° C. The reaction mixture was allowed to warm up to 0° C. over a period of 2 h, quenched with 15 mL of NaHCO3 saturated solution and diluted with 20 mL of diethyl ether. The organic phase was dried over anhydrous sodium sulfate and purified by chromatography on SiO2 using Hexane/Ethyl Acetate 7:3 to give 960 mg (2.6 mmol; 84%) of a yellow oil. Rf=0.493 (Hex./AcOEt 7:3)
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:13]([O:15]CC)=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:13]([OH:15])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(Cl)nc1-c1ccccc1
Yield: 90.1 %

Procedure:
A mixture of 53.4 g (0.2 mole) of ethyl 2-chloro-4-phenyl-5-thiazolecarboxylate, 8.0 g (0.2 mole) of NaOH, 200 ml. of water and 400 ml. of tetrahydrofuran was stirred for 16 hours and extracted with ether. The organic layer was discarded. The aqueous layer was made acidic and the precipitate was collected and air-dried to give 43.2 g (90%) of the desired product, m.p. 170°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30].C(Cl)Cl>>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:12][N:11]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(Cl)cc(Nc2n[nH]c(NC3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Tert-butyl 4-(3-(3,5-dichlorophenylamino)-1H-1,2,4-triazol-5-ylamino)piperidine-1-carboxylate (180 mg, 0.42 mmol) was dissolved in 30% TFA/methylene chloride (10 mL) and the mixture was stirred at rt for 30 min. Removal of solvent under reduced pressure gave a solid, which was washed with diethyl ether (10 mL) to give 178 mg (96%) of desired product as an off-white solid. MS +m/z: 327.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([CH2:17][O:12][C:3]2[C:2]([F:1])=[CH:7][C:6]([CH2:8][CH2:9][CH3:10])=[CH:5][C:4]=2[F:11])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: CCCc1cc(F)c(O)c(F)c1
Reactant: OCc1cc(F)cc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(F)c(OCc2cc(F)cc(F)c2)c(F)c1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
Into THF (85 mL), 2,6-difluoro-4-propylphenol obtained in (1-2) in Example 1 (17.2 g), 3,5-difluorobenzyl alcohol (17.2 g), triphenylphosphine (28.9 g) were dissolved, and the product was cooled to −10° C. DIAD (21.2 g) was added thereto at a rate which did not allow the internal temperature to exceed 15° C., and the product was stirred for 3 hours at room temperature. Then, 5 mL of water was added thereto, the solvent was distilled off under reduced pressure, hexane (300 mL) was added thereto, and the product was stirred. The precipitate was removed by filtration, the filtrate was washed with an aqueous solution of 50% methanol (200 mL) and a saturated salt solution in sequence, and sodium sulfate was added thereto for dehydration. The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography, thereby yielding a slightly yellow liquid that what 1,3-difluoro-5-[(2,6-difluoro-4-propylphenyloxy)methyl]benzene (19.1 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:13][C:14]3[C:19]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[N:21]=4)=[CH:18][CH:17]=[CH:16][N:15]=3)[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].Cl.N>O1CCOCC1.CO>[CH3:12][C:8]1[C:7]([O:13][C:14]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[N:21]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:31]([O:30][C:29]([F:28])([F:38])[F:39])[CH:32]=1)=[N:3][CH:4]=[CH:5]2
Reactant: CNc1nccc(-c2cccnc2Oc2c(C)ccc3c(Cl)nccc23)n1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2c(C)ccc3c(Nc4cccc(OC(F)(F)F)c4)nccc23)n1
Temperature: 170 °C

Procedure:
4-(2-(1-Chloro-6-methylisoquinolin-5-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.150 g, 0.40 mmol) was suspended in dioxane (1.00 mL) to which mixture was added 3-(trifluoromethoxy)aniline (0.12 ml, 0.79 mmol). 4N HCl in dioxane (1.00 mL) was added and the mixture was stirred. The vessel was sealed and heated to 170° C. in microwave for 15 minutes. The reaction mixture was treated with 2M ammonia in methanol and concentrated directly onto silica gel. The material was chromatographed eluting with a gradient of EtOAc/hexanes (15-100%) followed by trituration of the pure material in EtOAc to afforded 6-methyl-5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)-N-(3-(trifluoromethoxy)phenyl)isoquinolin-1-amine. MS (M+H)+ 519.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([O:13]CC)=[O:12])=[CH:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:9])([F:10])[F:8])[C:4]([C:11]([OH:13])=[O:12])=[CH:3]1
Reactant: CCOC(=O)c1cn(C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 1-methyl-4-(trifluoromethy1)pyrrole-3-carboxylate (4.4 g, 0.02 mol) and 4N sodium hydroxide (5 ml, 0.02 mol) in ethanol is stirred for 24 hours at room temperature, diluted with water and extracted with ether. The aqueous phase is acidified with 10% HCl and filtered. The filter cake is washed with water and dried in vacuo at 45° C. to afford the title compound as an off-white solid, 2.4 mp 210° to 212° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[CH:24]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[CH:24]1([C:27]2[N:32]=[C:31]([C:33]3[NH:1][C:2]4=[N:7][C:6]([N:8]5[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]6[CH2:20][CH2:19][CH2:18][CH2:17]6)=[O:15])[CH2:9]5)=[CH:5][CH:4]=[C:3]4[N:21]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Reactant: O=Cc1cccc(C2CC2)n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
To a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (250 mg, 0.711 mmol) in ethanol (15 mL) was added 6-cyclopropylpicolinaldehyde (0.137 g, 0.974 mmol), sodium dithionite (536 mg, 2.96 mmol) and water (2 mL). The reaction mixture was stirred for 16 h at 100° C. in a sealed tube. The mixture was cooled, and the solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC eluting with 4% methanol in dichloromethane to afford the title compound (55 mg, 17%). MS (ES+APCI) (M+H) 417.2; LCMS retention time 1.944 (Method F). 1H NMR (300 MHz, CDCl3) δ 1.00-1.09 (m, 2H), 1.09-1.16 (m, 2H), 1.63-1.74 (m, 1H), 1.81-2.14 (m, 7H), 2.62-2.76 (m, 1H), 2.99 (dd, 1H), 3.08-3.21 (m, 1H), 3.44-3.55 (m, 3H), 3.58-3.70 (m, 1H), 4.35 (d, 1H), 4.48 (d, 1H), 6.71 (d, 1H), 7.19 (d, 1H), 7.66 (t, 1H), 7.87 (d, 1H), 8.04 (d, 1H), 10.18 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.Cl.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH2:23][CH2:24]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCN(c2ccncc2)CC1
Yield: 23.9 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethyl)aminobenzamide (343 mg, 0.95 mmol), 4-chloropyridine hydrochloride (709 mg, 4.73 mmol), triethylamine (479 mg, 4.73 mmol), and ethanol (3 mL) yielded 100 mg (24%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[NH:13][CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2n(n1)CCN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (0.16 g, 4.0 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.7 g, 3.35 mmol) in DMF (14 mL) at 0° C. The mixture was stirred at room temperature for 1 hour and then benzyl bromide (0.48 mL, 4.0 mmol) was added. The mixture was stirred at room temperature for 16 hours, diluted with H2O and extracted with DCM. The organic layer was separated, washed with brine, dried (NaSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 4,5,6,7-tetrahydro-4-oxo-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.83 g, 83% yield) as a white oil. C16H17N3O3 LCMS: Rt 1.79, m/z 300 [M+H]+ (see LCMS Method 1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15](Cl)(=[O:17])=[O:16])=[O:4].[OH-].[NH4+:20].O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15]([NH2:20])(=[O:17])=[O:16])=[O:4]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1CS(N)(=O)=O
Temperature: 25 °C

Procedure:
The crude product from Example 3 (15.1 g) was dissolved in 150 ml tetrahydrofuran and this solution was contacted at 0° C. with concentrated aqueous ammonium hydroxide. The resulting suspension was allowed to warm to room temperature over a 15-minute period and the solvent was removed in vacuo to yield an oily solid. Addition of water to this crude material resulted in gradual crystallization. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried and concentrated in vacuo to give a yellow oil which solidified upon scratching. This material was washed with warm n-butyl chloride, filtered and dried to give the title compound as a pale yellow solid, m.p. 119°-123°; IR(nujol): 3490, 3330, 1710 cm-1 ; NMR (CDCl3): δ 4.0 (3H, s, CO2CH3), 5.4 (2H, s, --CH2 --), 6.8 (2H, s, NH2), 7.5.8.25 (3H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:12][C:13]([O:15]CC)=O)[CH2:10][C:9](=[O:11])[NH:8][CH2:7]1)=O)C.[CH3:18][NH2:19]>>[CH3:18][N:19]1[C:13](=[O:15])[CH2:12][C:6]2([CH2:10][C:9](=[O:11])[NH:8][CH2:7]2)[C:4]1=[O:3]
Reactant: CCOC(=O)CC1(C(=O)OCC)CNC(=O)C1
Reactant: CN
Product: CN1C(=O)CC2(CNC(=O)C2)C1=O
Temperature: 220 °C

Procedure:
A solution of 20.3 g (0.084 mole) 3-ethoxycarbonyl-5-oxo-3-pyrrolidineacetic acid, ethyl ester [J. Org. Chem., 46, 2757 (1981)] in 40 ml of 40% aqueous methylamine was stirred at room temperature overnight, then placed in an oil bath and gradually heated to 220° C. over 30 minutes allowing volatiles to distill from the open flask. The crude product was crystallized from ethanol to afford 12.6 g of 2-methyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione, mp 201-204° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[C:4]([CH:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[C:3]=1[OH:29].[Cr](Cl)([O-])(=O)=[O:31].[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:31])=[C:4]([CH:12]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:3]=1[OH:29]
Reactant: COC(=O)CCCCCC(c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCC2
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: Cc1c(C)c2c(c(C(CCCCCC(=O)O)c3ccc(F)cc3)c1O)CCC2=O
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of methyl 7-(6,7-dimethyl-5-hydroxyindan-4-yl)-7-(4-fluorophenyl)heptanoate (1.4 g) in benzene (40 ml) was added a mixture of pyridinium chlorochromate (3.8 g) and cerite (7 g) and the mixture was stirred for 2 hours. The reaction mixture was filtered and the filtrate was washed with water and saturated saline and dried with magnesium sulfate. Tetrahydrofuran (10 ml) and 1N sodium hydroxide (10 ml) were added to the residue and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure and the residue was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from acetonitrile to obtain 7-(6,7-dimethyl-5-hydroxy-1-oxoindan-4-yl)-7-(4-fluorophenyl)heptanoic acid (0.4 g) (Compound 37). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][N+:24]([O-])=O)=[CH:18][CH:17]=1>C(N)C1C=CC=CC=1>[CH2:22]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:23]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(F)cc1
Solvent: NCc1ccccc1
Product: Fc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Yield: 70 %

Procedure:
The title compound (706.2 mg) was prepared from 1.31 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 700 μL of benzylamine, and 1.10 g of 1-fluoro-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C20H19FN2, 306.15; found, m/z 307.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.25 (m, 5H), 7.18-7.15 (m, 2H), 7.11-7.05 (m, 3H), 5.13 (s, 2H), 4.33 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)C(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction was carried out under argon. Allyl 4-{4-cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1200 mg, 2.19 mmol) and morpholine (1.5 eq., 286 mg, 3.30 mmol) were initially charged in dry THF (60 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 127 mg, 0.110 mmol) was added, and the reaction mixture was stirred at RT for 0.5 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (100 ml). The organic phase was washed with 0.1 N hydrochloric acid (40 ml) and with saturated sodium chloride solution (3×30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. Methanol (10 ml) was added to the residue. The precipitated product was filtered off with suction and washed with a little methanol (2×5 ml). The title compound was isolated as a solid (1060 mg, 95% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27](O)=[O:28])[CH2:22]3)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:30][NH2:31]>>[CH3:1][O:2][C:3]1[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH:31][CH3:30])=[O:28])[CH2:22]3)(=[O:19])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC(C(=O)O)C2)c1
Reactant: CN
Product: CNC(=O)C1CCCN(S(=O)(=O)c2cccc(C(=O)Nc3ncccc3OC)c2)C1

Procedure:
The entitled compound was produced according to the method of Example 57 but using the compound obtained in Example 56 and methylamine as the starting materials.