Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH2:26][CH2:27][N:28]=4)=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[O-2].[Ca+2].[H][H]>[Pd].CO>[O:25]1[CH2:26][CH2:27][N:28]=[C:24]1[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[N:4]=[N:3][CH:2]=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)=[CH:23][CH:22]=1
Reactant: Clc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: c1cnnc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)c1
Yield: 17.2 %

Procedure:
A mixture of 3.8 parts of 3-chloro-6-[4-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]-1-piperazinyl]pyridazine, 200 parts of methanol and 2 parts of calcium oxide was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried over weekend at 60° C., yielding 0.7 parts (17.2%) of 3-[4-[3-[4-(4,5-dihydro-2 -oxazolyl)phenoxy]propyl]-1-piperazinyl]pyridazine; mp. 144.7° C. (comp. 169).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=2[CH:15]=1.O>CN(C=O)C>[N:1]1[C:5]2[C:4](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:3]([CH2:13][C:14]2[CH:24]=[CH:23][C:17]3[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=3[CH:15]=2)[CH:2]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.6 %

Procedure:
To a stirred solution of 4-azabenzimidazole (613 mg, 5.15 mmol) in anhydrous DMF (20 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 216 mg, 5.41 mmol) and the mixture was stirred at 0° C. for 20 min. The mixture was allowed to warm to rt and stirred for a further 20 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.3 g, 5.66 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was stirred at rt for 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 100% DCM followed by 1% MeOH in DCM) to afford 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (670 mg, 41%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.38 (dd, J=1.3, 4.7 Hz, 1H), 8.11 (dd, J=1.2, 8.0 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.46 (dd, J=1.6, 8.4 Hz, 1H), 7.30 (dd, J=4.7, 8.1 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:18]2[O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:17]2=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:18]2[O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:17]2=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1OC[C@H]1CCCN21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCCN21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was added to a solution of methyl (R)-7-amino-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 6, 0.525 g) in pyridine (10 mL) and DCM (10 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 0.5M hydrochloric acid solution. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give a pale yellow solid which was triturated with ether and cyclohexane (1:2) to give methyl (R)-7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.820 g).
Reaction SMILES: Br[CH:2]1[CH2:4][C:3]1([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(C1(CCCCC)CC1)CCCC.CC(C)([O-])C.[K+]>CS(C)=O>[CH2:10]([C:3]1([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[CH:2]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC1(CCCCC)CC1Br
Agent: CC(C)(C)[O-]
Agent: CCCCCC1(CCCCC)CC1
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCC1(CCCCC)C=C1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 1.90 g of an equal mixture of 2-bromo-1,1-dipentyl-cyclopropane and 1,1-dipentyl-cyclopropane in 10 ml dimethylsulfoxide was added 0.818 g (0.00308 mol) of potassium t-butoxide. The resulting mixture was heated to 85° C. for 5 hours and then stirred at room temperature for 16 hours. To this was added 0.100 g of potassium t-butoxide. The resulting mixture was heated to 85° C. for 2 hours then cooled to room temperature. The reaction mixture was poured onto water and then extracted with diethyl ether. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 1.90 g of 3,3-dipentyl-cyclopropene mixed in equal parts with 1,1-dipentyl-cyclopropane as an oil.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[O:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=2[OH:35])[CH2:24][CH2:23]1>C(#N)C>[F:21][C:32]1[CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][O:22][CH2:27][CH2:26]2)[C:29]([OH:35])=[CH:30][C:31]=1[OH:34]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: Oc1ccc(C2CCOCC2)c(O)c1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: Oc1cc(O)c(C2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.2 %

Procedure:
3.65 g of N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) are added to a solution of 2 g of 4-(tetrahydropyran-4-yl)benzene-1,3-diol (Example 1) in 20 ml of acetonitrile at 0° C. The reaction mixture is stirred for 16 hours at ambient temperature. The reaction mixture is extracted with ethyl acetate, and the organic phases are washed and then dried over sodium sulphate. The residue is chromatographed on silica gel (9/1 heptane/ethyl acetate). 200 mg of 4-fluoro-6-(tetrahydropyran-4-yl)benzene-1,3-diol are obtained. Yield=10%.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].C[S+](C)(C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][C:25]4[C@@:33]5([CH2:39][C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[CH2:34][CH2:35][C:36](=[O:38])[CH2:37][C@H:32]5[CH2:31][CH2:30][CH2:29][C:26]=4[CH:27]=3)[CH:22]=[N:21]2)=[CH:16][CH:15]=1.F[C:47]1C=CC(N2C3C(=CC4[C@]5(CC6C=CC=CN=6)CCC(=O)C[C@@H]5CCCC=4C=3)C=N2)=CC=1>C1COCC1.CCOC(C)=O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[CH:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36]6([CH2:47][O:38]6)[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CC[C@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Reactant: O=C1CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2ncc3cc4c(cc32)CCCC2CC3(CCC42Cc2ccccn2)CO3)cc1
Temperature: 65 °C
Yield: 96.8 %

Procedure:
A flask with stir bar and nitrogen line was charged with DMSO (2 mL) and sodium hydride (60 wt % in oil, 0.021 g, 0.523 mmol). The mixture was warmed in an oil bath heated to about 65° C. for about 30 min then cooled to rt. THF (1 mL) was added and the mixture was cooled to about 0° C. Trimethylsulfoxonium iodide (0.115 g, 0.523 mmol) was added and the mixture was stirred for about 15 min. (4aS,12bS)-9-(4-Fluorophenyl)-12b-pyridin-2-ylmethyl-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one; compound with (4aR,12bR)-9-(4-fluoro-phenyl)-12b-pyridin-2-ylmethyl-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (10, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.115 g, 0.262 mmol) in THF (3 mL) was added and the mixture was allowed to warm to rt for about 18 h. The mixture was diluted with EtOAc (25 mL) and washed with water (25 mL). The aqueous layer was extracted with EtOAc (25 mL) then the combined organic layers were washed with water (2×25 mL) and brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield rac-(2′R,4aS,12bS)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane] (R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.115 g, 97%); LC/MS, method 3, Rt=2.63 min, MS m/z 454 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.37-8.35 (m, 1H), 8.14 (d, J=0.7 Hz, 1H), 7.85-7.77 (m, 2H), 7.65 (s, 1H), 7.44-7.32 (m, 4H), 7.08-7.04 (m, 1H), 6.48 (d, J=7.8 Hz, 1H), 3.61 (d, J=12.7 Hz, 1H), 3.34-3.26 (m, 1H), 3.13-3.06 (m, 1H), 3.01 (d, J=12.8 Hz, 1H), 2.60-2.43 (m, 1H), 2.39-2.25 (m, 2H), 2.21-2.12 (m, 1H), 1.87-1.78 (m, 2H), 1.75-1.56 (m, 3H), 1.54-1.50 (m, 1H), 1.28-1.19 (m, 1H), 1.17-1.09 (m, 1H), 0.88-0.74 (m, 1H).
Reaction SMILES: [CH2:1]([P:6](=S)([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC(S(O)(=O)=[O:26])=CC=1>ClC1C=CC=CC=1>[CH2:1]([P:6](=[O:26])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Reactant: CC(C)CCP(=S)(CCC(C)C)CCC(C)C
Solvent: Clc1ccccc1
Product: CC(C)CCP(=O)(CCC(C)C)CCC(C)C
Temperature: 25 °C

Procedure:
4.1 g (15 mmol) of triisoamylphosphine sulfide in 70 ml of chlorobenzene (b.p.=132° C.) are combined with 34.7 g (0.18 mol) of p-chlorobenzenesulfonic acid and then heated for 8 hours at reflux. After cooling to room temperature, the reaction mixture is extracted several times with 80 ml portions of ice water and then the chlorobenzene solution is washed with sodium bicarbonate solution. The solution is dried over sodium sulfate and the chlorobenzene is removed in vacuum. Yield: 3 g of solid identified by mass spectroscopy as triisoamylphosphine oxide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH:14]([F:16])[F:15])[C:10]#[N:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH:14]([F:16])[F:15])[C:10]#[N:11]
Reactant: Cc1ccc(C)c(O)c1
Reactant: N#CC(=NOC(F)F)c1ccccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NOC(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7.0 g of 2-(2-bromomethylphenyl)-2-difluoromethoxyimino-acetonitrile, 5.4 g of 2,5-dimethylphenol, 16.1 g of pulverized potash and 0.38 g of 18-crown-6 in 35 ml of acetonitrile is stirred at room temperature for 24 hours. For working up, water is added and exhaustive extraction with ethyl acetate is carried out. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (9:1) yields 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-difluoromethoxyiminoacetonitrile in the form of a sticky crystalline mass which, when treated with hexane, yields a fine crystal powder of m.p. 104°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[C:22]([CH:26]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:23]=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[C:22]([CH:26]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[NH:27][S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CCCC1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
A mixture of 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (205 mg, 0.77 mmol), N-((5-bromopyridin-3-yl)(cyclopentyl)methyl)ethane-sulfonamide (270 mg, 0.77 mmol), PdCl2(PPh3)2 (45 mg, 0.06 mmol) and Na2CO3 (2 M in water, 0.97 mL, 1.94 mmol) in DMF (4 mL) was heated at 100° C. for 2 h. The solvent was removed in vacuo. The residue was dissolved in DCM and filtered. The DCM layer was concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-50%) to give the title compound (104 mg, 33%); ESI-MS m/z: 404 [M+1]+; 1HNMR (MeOD, 400 MHz) δ 8.80 (1H, d, J=2.0 Hz), 8.61 (1H, d, J=2.0 Hz), 8.15 (1H, t, J=2.0 Hz), 8.01 (1H, d, J=1.6 Hz), 7.94 (1H, d, J=8.0 Hz), 7.82 (1H, dd, J=8.0, 1.6 Hz), 4.29 (1H, d, J=10 Hz), 2.92-2.72 (2H, m), 2.34-2.27 (1H, m), 2.03-1.97 (1H, m), 1.77-1.53 (6H, m), 1.38-1.28 (1H, m), 1.15 (1H, t, J=7.2 Hz).
Reaction SMILES: Cl[C:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][C:11]=3[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)=[O:3].[CH2:26]([OH:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[N:4]1([C:2]([O:34][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:3])[C:13]2[C:8](=[CH:9][C:10]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][C:11]=3[CH:12]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C(=O)Cl)CCC3
Reactant: OCCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C(=O)OCCc1ccccc1)CCC3
Temperature: 100 °C
Reaction time: 5.5 h

Procedure:
To a solution of 200 mg of t-butyl 1-(chlorocarbonyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2 ml of pyridine was added 140 μl of phenethyl alcohol, followed by stirring at 100° C. for 5.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 68 mg of 8-t-butyl 1-(2-phenylethyl) 3,4,6,7,9,10-hexahydro-1H-azepino[4,5-g]quinoline-1,8(2H)-dicarboxylate as a yellow viscous substance.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.C1COCC1.[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Reaction time: 2 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet and thermocouple, is added tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, Step 2, 4.4 g, 0.0132 moles, 1 equivalent) followed by THF (20 mL) and ethanol (30 mL) then cooled to −78°. Once the mixture is cooled, sodium borohydride (2.0 g, 0.0527 moles, 4 equivalents) is added as a solid portion wise over 30 min keeping the internal temperature below −70°. Once this addition is complete, the contents are stirred for 2 hr at −78° then warmed to 0° and stirred an additional 1 hr. The mixture is quenched by the addition of saturated potassium bisulfate (15 mL) and water (15 mL). This slurry is stirred for 30 min at 20-25° then concentrated under reduced pressure to half its volume. The mixture is then cooled to 0° and stirred for 30 min. After this time, the resultant solids are collected by filtration and washed with water (2×50 mL) then dried under reduced pressure at 50° to give crude product. A syn/anti ratio of 4-9:1 has been observed. The desired product is recrystallized from hexanes/ethanol (25/1) to give the title compound, NMR (DMSO-d6) δ 6.89-7.16, 5.61, 3.64-3.83, 3.19, 2.69 and 1.41; CMR (DMSO-d6) δ 163.67, 161.24, 155.44, 112.70, 101.55, 78.04, 72.99, 54.29, 48.24, 35.97 and 28.37.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:34][C:35]([NH:37][CH:38]([CH3:40])[CH3:39])=[O:36].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:26][C:27]3[C:28]([CH2:34][C:35]([NH:37][CH:38]([CH3:39])[CH3:40])=[O:36])=[CH:29][CH:30]=[CH:31][C:32]=3[CH3:33])=[O:15])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cccc(CC(=O)NC(C)C)c1N
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CC(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.25 h

Procedure:
To a slurry of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (for preparation see WO 02/48115, 0.19 g, 0.66 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.087 mL, 1.0 mmol) and two drops of N,N-dimethylformamide. The reaction mixture was stirred for 15 minutes, resulting in a solution. The volatiles were removed with a rotary evaporator. The residue was dissolved in 10 mL of tetrahydrofuran, and the solution was added dropwise at 0° C. to 2-amino-3-methyl-N-(1-methylethyl)-benzeneacetamide (i.e. the title product of Step B) (0.14 g, 0.66 mmol), N,N-diisopropyl-ethylamine, (0.23 mL, 1.3 mmol) and 4-(dimethylamino)pyridine (5 mg) in 5 mL of tetrahydrofuran. The reaction mixture was stirred overnight at room temperature. Dichloromethane was added and the mixture was washed with water and dried (sodium sulfate). The solvent was removed with a rotary evaporator. The residue was purified by MPLC (40→60% ethyl acetate in hexanes as eluant) to afford the title compound plus an impurity. The material was purified further by MPLC (20→30% ethyl acetate in 1-chlorobutane as eluant) to afford the title product, a compound of the present invention, as a white solid (0.12 g), m.p. 206-207° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN(CC)CC.[C:31]([O:35][C:36](=[O:43])[N:37]([CH2:39][CH2:40][CH2:41][NH2:42])[CH3:38])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:42][CH2:41][CH2:40][CH2:39][N:37]([CH3:38])[C:36](=[O:43])[O:35][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.65 mmol) HATU (372 mg, 0.98 mmol), and Et3N (198 mg, 1.96 mmol) in DMF (3.0 mL). The mixture was stirred at room temperature for 0.5 hour, then tert-butyl(3-aminopropyl)(methyl)carbamate (147.39 mg, 0.79 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was purified by preparative HPLC to give tert-butyl (3-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinamido)propyl)(methyl)carbamate (150 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2.FC1C=CC(N)=C2C=1C=CC(C)=N2.[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH3:39])[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:27]([O:31][C:32](=[O:33])[NH:34][C@H:35]([C:36](=[O:37])[NH:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]2[C:8]=1[NH:7][CH:6]([CH3:13])[CH2:5][CH2:4]2)[CH3:39])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC1CCc2c(F)ccc(N)c2N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc2c(F)ccc(N)c2n1
Agent: Cl
Solvent: ClCCl
Product: CC1CCc2c(F)ccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c2N1
Temperature: 0 °C
Yield: 49 %

Procedure:
To the mixture of 5-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-8-ylamine and 5-fluoro-2-methylquinolin-8-ylamine from the previous step (0.369 mmol) in DCM (10 mL) was added (S)-2-tert-butoxycarbonylaminopropionic acid (76.8 mg, 0.405 mmol) and HOAt (56 mg, 0.41 mmol). The mixture was cooled in an ice bath, then EDCI HCl (85 mg, 0.44 mmol) was added. The reaction mixture was stirred in the ice bath for 2 h, then diluted with DCM, washed with aqueous Na2CO3 and then water. The organic layer was dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 20-50% EtOAc in cyclohexane) affording the title compound as a colourless solid (63.6 mg, 49%, 2 steps). LCMS (Method J): RT 3.40 min [M+H]+ 352
Reaction SMILES: [F:1][C:2]([C:5]([C:8]([F:11])([F:10])[F:9])=[N+:6]=[N-:7])([F:4])[F:3].[C:12]([C:14]#[CH:15])#[N:13]>>[F:1][C:2]([F:4])([F:3])[C:5]1([C:8]([F:9])([F:10])[F:11])[CH:15]=[C:14]([C:12]#[N:13])[N:7]=[N:6]1
Reactant: [N-]=[N+]=C(C(F)(F)F)C(F)(F)F
Reactant: C#CC#N
Product: N#CC1=CC(C(F)(F)F)(C(F)(F)F)N=N1
Temperature: 50 °C
Yield: 87.6 %

Procedure:
A sealed glass tube containing 36.2 g of bis(trifluoromethyl)diazomethane and 10.2 g of cyanoacetylene was heated at 50°C for 24 hours. The product was distilled to give 40.1 g of 3,3-bis(trifluoromethyl)-5-cyano-3H-pyrazole, bp 38°C/12 mm. The ultraviolet, infrared, and mass spectra as well as the proton and fluorine nuclear magnetic resonance spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[C:15](C(O)=O)[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2].O.[OH-].[Na+]>O1CCOCC1>[CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: O=Cc1c(OCCCCC(=O)O)ccc(C(=O)O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c(O)cccc1OCCCCC(=O)O

Procedure:
5-(2-Formyl-3-hydroxy-4-carboxyphenoxy)pentanoic acid (0.2 g, 0.0007 M), acidic alumina (0.1 g), water (10 ml) and dioxane (3 ml) were left at reflux for 4 days. The reaction mixture was cooled, and made alkaline by the addition of sodium hydroxide. The reaction mixture was filtered and the filtrate acidified with concentrated hydrochloric acid. The resulting precipitate was filtered and washed with a little water, then dried in a desiccator over phosphorus pentoxide to give the title compound as a pale-yellow solid, homogeneous on thin layer chromatography.