Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:31]4[CH:41]=[CH:40][C:34](C(OCC)=O)=[CH:33][CH:32]=4)[O:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Mg]Br>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:31]4[CH:32]=[CH:33][C:34]([C:9]([OH:8])([CH3:18])[CH3:10])=[CH:40][CH:41]=4)[O:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc([C@H]2OC3(CCCC3)c3c2c(C(C)C)nc2c3[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2)cc1
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(C)(C)O)cc1)OC31CCCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -5 °C

Procedure:
110 mg Ethyl 4-((3′R,9′S)-9′-(tert-butyldimethylsilyloxy)-4′-isopropyl-7′,7′-dimethyl-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline]-3′-yl)benzoate are dissolved in 3 ml tetrahydrofurane, cooled to −5° C. and treated dropwise with 820 μl of a 1.4 M solution of methylmagnesium bromide in toluene/tetrahydrofurane (72:25). The mixture is warmed to room temperature during 1 hour, then recooled to 0° C. and the reaction is quenched by addition 1 ml methanol. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (petrole ether/ethylacetate 90:10 to 50:50).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Reactant: CCCCN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)NCCc1ccc(C(C)(C)NCCCn2ccnc2)cc1

Procedure:
A solution of butylisocyanate (0.17 g) in dichloromethane was added to a solution of N-{1-[4-(2-aminoethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propylamine (0.5 g) in dichloromethane (7 ml). The mixture was boiled under reflux for 30 minutes and then the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica using methanol as the mobile phase to give N-butyl-N′-[2-(4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl)ethyl]urea as an oil.
Reaction SMILES: [CH:1]12[CH2:10][C:5]3([C:11]([O:13]C)=[O:12])[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[N:2]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8]2.C1COCC1.O.[Li+].[OH-]>CO>[C:18]([O:17][C:15]([N:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][C:5]([C:11]([OH:13])=[O:12])([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C12CC3CC(C1)N(C(=O)OC(C)(C)C)C(C3)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CC3CC1CC(C(=O)O)(C3)C2
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a 0° C. cooled stirred solution of 2-tert-butyl 5-methyl 2-azatricyclo[3.3.1.13,7]decane-2,5-dicarboxylate, intermediate-9 (0.16 g, 0.5 mmol) dissolved in methanol (3 ml), THF (1 ml) and water (1 ml), LiOH (50 mg, 2 mmol) was added and the resulting reaction mass was stirred at room temperature for 6 hrs. Upon completion of the reaction (reaction monitored by TLC), the solvent present in the reaction mixture was completely removed under vacuum and the crude residue was acidified with saturated citric acid solution and extracted with ethyl acetate (3×15 ml). The organic layer was then washed with brine solution and dried over sodium sulfate and was finally concentrated under vacuum to get intermediate-10 as an oily mass, 0.16 g (95%).
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]([OH:13])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11][CH3:12].[C:16]([OH:25])(=[O:24])[C@H:17]([C@@H:19]([C:21]([OH:23])=[O:22])[OH:20])[OH:18]>CC(C)=O>[C:21]([C@H:19]([C@@H:17]([C:16]([OH:25])=[O:24])[OH:18])[OH:20])([OH:23])=[O:22].[Cl:15][C:2]([Cl:1])([Cl:14])[C@H:3]([OH:13])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11][CH3:12]
Reactant: CCc1cnccc1CC(O)C(Cl)(Cl)Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(C)=O
Product: CCc1cnccc1C[C@@H](O)C(Cl)(Cl)Cl

Procedure:
To 1.6.6 g. of 1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2-ol dissolved in 1.2 l. of hot acetone was added a solution of 65.2 g. of d-tartaric acid in 1 l. of acetone. Upon cooling, crystalline material separated (66.8 g.) which after fractional crystallization from acetone, yielded pure 1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(R)-ol d-tartrate, m.p. 176°-177.5°, [α]D25 + 30.7° (c 0.960, ethanol)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[CH:12]=[N:13][O:14][C:15]=2[CH:16]([CH3:18])[CH3:17])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[CH:1]1([CH2:6][CH:7]([C:8]2[NH:10][C:11]([C:15](=[O:14])[CH:16]([CH3:18])[CH3:17])=[CH:12][N:13]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1oncc1NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)c1cnc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution (40 mL) of 3-cyclopentyl-N-(5-isopropylisoxazol-4-yl)-2-[4-(methylsulfonyl)phenyl]propanamide (2.50 g) in ethanol was added 10% palladium carbon (containing 50% water, 0.500 g) and the mixture was stirred under hydrogen atmosphere (5 atm) for 4 hr. The reaction mixture was filtered to remove the catalyst, sodium hydroxide (0.261 g) was added to the filtrate, and the mixture was heated under reflux for 1 hr. To the reaction mixture was added ammonium chloride (0.430 g), and the mixture was cooled to room temperature, and stirred at room temperature for 16 hr. The reaction solution was concentrated, the obtained residue was suspended in acetone, and the suspension was filtered to remove insoluble materials. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0, volume ratio), and recrystallized from ethyl acetate-hexane to give the title compound (1.20 g, yield 50%) as colorless crystals. melting point 171-172° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:25][N:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[N:28]=[CH:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:25][N:26]1[CH:30]=[C:29]([C:31]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[N:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[O:17])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:32])[N:28]=[CH:27]1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)c1
Temperature: 60 °C
Yield: 26.1 %

Procedure:
A mixture of Example C1 (0.15 g, 0.455 mmol), 1-methyl-1H-imidazole-4-carboxylic acid (0.172 g, 1.366 mmol), TBTU (0.439 g, 1.366 mmol) and DIEA (0.476 mL, 2.73 mmol) in DMF (5 mL) was stirred at RT for 2 h, then heated at 60° C. overnight. Additional 1-methyl-1H-imidazole-4-carboxylic acid (0.172 g, 1.366 mmol) and TBTU (0.439 g, 1.366 mmol) were added and the mixture heated at 60° C. overnight. The mixture was cooled to RT, treated with 10% K2CO3, extracted with DCM (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was further purified via preparative TLC (MeOH/DCM) to afford 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)-1H-imidazole-4-carboxamide (52 mg, 26%). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.44 (s, 1H), 9.47 (s, 1H), 8.29 (d, J=2.9 Hz, 1H), 8.22 (d, J=5.8 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.78-7.77 (m, 2H), 7.75 (d, J=2.4 Hz, 1H), 6.75 (dd, J=5.8, 2.4 Hz, 1H), 3.71 (s, 3H), 1.22 (s, 9H); MS (ESI) m/z: 438.2 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH3:13])[N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH3:13])[N+:4]=1[O-:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc2ccccc2c(CCl)n1
Solvent: ClCCl
Product: Cc1cc2ccccc2c(CCl)[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 300 mg of 1-chloromethyl-3-methyl-isoquinoline in 3 ml of methylene chloride is combined with 390 mg of 3-chloroperoxybenzoic acid and stirred overnight at ambient temperature. The reaction mixture is diluted with some methylene chloride and extracted with saturated sodium hydrogen carbonate solution. The combined organic phases are dried over magnesium sulphate and evaporated down. The solid, yellowish crude product is triturated with tert.-butylmethylether, suction filtered, washed with tert.-butylmethylether and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]2[C:6]([CH2:7][C:8]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:9]=32)=[CH:5][C:4]=1[O:31]COCC[Si](C)(C)C.Cl>CO.C(Cl)Cl>[OH:31][C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][C:3]=1[O:2][CH3:1])[C:9]1[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])[N:11]=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)[C:8]=1[CH2:7]2
Reactant: COc1cc2c(cc1OCOCC[Si](C)(C)C)Cc1c(-c3ccc(C#N)nc3)nn(COCC[Si](C)(C)C)c1-2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1O)Cc1c(-c3ccc(C#N)nc3)nn(COCC[Si](C)(C)C)c1-2
Yield: 99760.6 %

Procedure:
A mixture of Example 143E (9.96 g, 0.0176 mmol) and HCl (concentrated, 4.0 mL) in MeOH (200 mL) and CH2Cl2 (100 mL) was stirred at room temperature for 1.5 hours. Most of the solvents were evaporated at room temperature. The residue was extracted with EtOAc, washed with NaHCO3, dried over MgSO4, filtered, concentrated to give 7.63 g (quantitative yield) of the desired product as pale yellow solid. MS (ESI) m/z: 435.2 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[S:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[N+]=[N-]>C(O)C.[Pd]>[C:20]1([S:17]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][NH2:1])[CH:9]=3)[NH:13][N:12]=2)(=[O:18])=[O:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=NCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Agent: [Pd]
Solvent: CCO
Product: NCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
5-(3-Azido-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole (0.763 g, 1.87 mmol) was dissolved in hot ethanol (125 mL). 10% Palladium on carbon (0.16 g) was added, and the reaction mixture was shaken and hydrogenated on the Parr apparatus for 2 hours, starting pressure 51 psi. Additional 1% Palladium on carbon (0.32 g) was added, and the reaction mixture was again hydrogenated on the Parr apparatus for 2 hours. It was then filtered over Celite and concentrated. The residue was purified by flash chromatography with 0.75% ammonium hydroxide/7.5% methanol in chloroform. The product was further purified by HPLC using a gradient of chloroform/methanol in heptane/TFA. 3-[3-(Naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propylamine as a light yellow foam (0.229 g, 32.1%) resulted. Methanol and ethereal hydrochloride were added. The mixture was concentrated and dried at 83° C. in vacuo for 12 hours to yield the hydrochloride as a light buff foam (0.235 g). Mass Spectrum (−EI, [M−H]−) m/z 380. 1HNMR (500 MHz, DMSO-d6): δ14.15 (s, 1H), 8.75 (d, 1H, J=8.67 Hz), 8.50-8.52 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.86 (s, br, 3H), 7.71-7.75 (m, 1H), 7.54-7.64 (m, 3H), 7.29 (d, 1H, J=2.20 Hz), 7.08-7.11 (m, 1H), 4.09 (t, 2H, J=6.10 Hz), 2.94-2.99 (m, 2H), 2.00-2.07 ppm (m, 2H). Elemental Analysis for C20H19N3O3S.1.00 mol HCl.0.40 mol H2O: Calcd: C, 56.51; H, 4.93; N, 9.88; Found: C, 56.21; H, 5.12; N, 9.56.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:19][C@H:18]2[CH2:20][CH2:21][O:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31](O)=[O:32])=[C:25]([F:34])[CH:24]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37].C1COCC1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH3:35][N:36]([CH3:37])[C:31](=[O:32])[CH2:30][C:26]1[C:25]([F:34])=[CH:24][C:23]([O:22][CH2:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)=[C:28]([F:29])[CH:27]=1
Reactant: O=C(O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-((1S,2R)-2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}cyclopropyl)ethoxy]-2,5-difluorophenyl}acetic acid (313 mg, 0.661 mmol) in 2.5 ml anhydrous DMF at RT was added dimethylamine, 2.0 M solution in THF (0.661 ml, 1.32 mmol) and N,N-diisopropylethylamine (0.562 ml, 3.31 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (503 mg, 1.32 mmol) was added into the solution and stirred at RT overnight. The reaction mixture in 12 ml water was extracted with 12 ml ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on Biotage column (25 g silica gel) using a gradient eluent of 0-50% ethyl acetate in hexanes (800 ml) to afford the title compound. LC/MS (m/z): 501.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]3[NH:17][CH:16]=[CH:15][C:13]3=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]3[NH:17][CH2:16][CH2:15][C:13]3=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCOc2cc3cc[nH]c3cc21
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCN1CCOc2cc3c(cc21)NCC3
Reaction time: 2 h
Yield: 80.9 %

Procedure:
4-(2-Dimethylaminoethyl)-2,3,4,6-tetrahydropyrrolo[2,3-g][1,4]benzoxazine (D18, 42 mg, 0.17 mmol) was stirred in acetic acid (5 ml) as sodium cyanoborohydride (33 mg, 0.52 mmol) was added portionwise over 10 min. The mixture was stirred for 2 h, diluted with water, basified with potassium carbonate, and extracted with ethyl acetate. The extract was dried (Na2SO4) and evaporated to give the title compound (34 mg, 80%) as a green gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+:17].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[O-:12].[K+:17]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: [O-]c1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-trifluoromethylphenol (1.96 grams; 0.010 mole) is dissolved in dimethyl sulfoxide (15 ml.) and potassium carbonate (2.76 grams; 0.020 mole) is added. The reaction mixture is stirred at room temperature overnight to afford potassium 2-chloro-4-trifluoromethylphenoxide.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])=[CH:18][CH:17]=1)#[N:20]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(C#N)cc1
Temperature: 100 °C
Yield: 35 %

Procedure:
To a solution of 6-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(4-cyano-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VI-B-5) 380 mg (0.93 mmol) dissolved in toluene (10 mL) were added 0.30 mL (2.79 mmol) of 1-chloroethyl chloroformate and 0.47 mL (2.79 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 105 mg (35%) of the title compound as a light yellow oil. ES-MS m/e: 319.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21].CC(C)([O-])C.[K+].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[C:23](\[O:22][CH2:20][CH3:21])/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CCOCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)OCC
Temperature: -20 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
4-(Benzyloxy)-3-nitrobenzaldehyde (4.12 g; 14.4 mmole) and ethyl ethoxyacetate (2.29 g; 17.3 mmole) were dissolved in dry tetrahydrofuran (20 ml) and cooled to −20° C. Potassium tert-butoxide (1.94 g; 17.3 mmole) dissolved in dry tetrahydrofuran (10 ml) was slowly added and the reaction was stirred overnight at −20° C. The reaction was quenched with acetic acid (1.3 g; 21.7 mmole). The crude product was isolated, redissolved in toluene and refluxed over night with p-toluenesulfonic acid (0.25 g; 1.44 mmole) in a Dean-Stark apparatus to separate the water. The solution was cooled, washed with sodium hydrogen carbonate, dried with magnesium sulfate and evaporated. Chromatography of the crude material from methylene chloride gave 0.85 g (11% yield) of ethyl (2Z)-3-[4-(benzyloxy)-3-nitrophenyl]-2-ethoxyacrylate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([NH:21][C:22]3[N:23](C(OC(C)(C)C)=O)[N:24]=[C:25]([C:27]4[C:28]([O:34][CH3:35])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[CH:26]=3)[N:16]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:35][O:34][C:28]1[C:27]([C:25]2[CH:26]=[C:22]([NH:21][C:17]3[CH:18]=[N:19][CH:20]=[C:15]([O:14][C@@H:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[N:16]=3)[NH:23][N:24]=2)=[CH:32][CH:31]=[C:30]([CH3:33])[N:29]=1
Reactant: COc1nc(C)ccc1-c1cc(Nc2cncc(O[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)n(C(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(C)ccc1-c1cc(Nc2cncc(O[C@@H]3CCCNC3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-3-{6-[2-tert-butoxycarbonyl-5-(2-methoxy-6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylamino]-pyrazin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (13.0 g, 22.3 mmol) in dichloromethane (150 mL) is added a solution of trifluoroacetic acid (12.4 mL, 167 mmol) dichloromethane (20 mL) over a period of 5 min at 0° C. The reaction is allowed to warm to room temperature and stirred for 3 h. The reaction is diluted with dichloromethane (1000 mL), followed by addition of saturated sodium bicarbonate solution (250 mL) and then stirred for 4 h. The organic portion is separated and dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting material is crystallized from isopropanol to obtain the desired product. Yield=7.2 g (85%). 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.71 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.97 (s, 1H), 7.46)(s, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.91 (s, 1H), 4.94-4.86 (m, 1H), 3.97 (s, 3H), 3.20-3.13 (m, 1H), 2.83-2.75 (m, 1H), 2.57 (dd, J=12.0, 84 Hz, 1H), 2.53-2.45 (m obscured, 1H), 2.42 (s, 3H), 2.15-2.05 (m, 1H), 1.71-1.63 (m, 1H), 1.60-1.49 (m, 1H), 1.49-1.40 (m, 1H); ES/MS m/z 382.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19](O)=[O:20])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:37][C:38]([F:47])([F:48])[C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][CH:44]=1)[CH2:45][NH:46][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][N:24]=[C:16]([C:5]2[CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:17]=1
Reactant: O=C(O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinic acid (1 g, 3.06 mmol, 1.00 equiv) in dichloromethane (20 mL), EDC.HCl (970 mg, 5.05 mmol, 1.65 equiv), 4-dimethylaminopyridine (620 mg, 5.08 mmol, 1.66 equiv), and (3-(trifluoromethyl)phenyl)methanamine (590 mg, 3.37 mmol, 1.10 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1˜3:1). This resulted in 800 mg (51%) of N-(3-(trifluoromethyl)benzyl)-2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinamide as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:9]=[C:8]([NH:17][C@H:18]([CH2:20][CH3:21])[CH3:19])[CH:7]=1.I[CH3:24]>CN(C=O)C>[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH3:24])[N:9]=[C:8]([NH:17][C@H:18]([CH2:20][CH3:21])[CH3:19])[CH:7]=1
Reactant: CI
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(NS(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Add sodium hydride (47 mg, 1.18 mmol, 60% dispersion in mineral oil) to a solution of (S)-2-sec-butylamino-6-methanesulfonylamino-isonicotinic acid methyl ester (356 mg, 1.18 mmol) in DMF (5 mL) at 0° C. Stir for 10 min, add iodomethane (0.11 mL, 1.77 mmol) dropwise. Stir the mixture at room temperature for 2 h, cool and quench the reaction with an ammonium chloride solution. Extract the mixture with ethyl acetate (3×30 mL) and wash the combined extract with water, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound (320 mg, 86%).