Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[CH3:22][OH:23].C[O-].[Na+]>CO>[CH3:22][O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(SCCCCCCBr)CC1
Agent: C[O-]
Agent: [Na+]
Product: COCCCCCCSC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 4-(6-bromohexylthio)-N-t-butyloxycarbonylpiperidine (4.95 g) in methanol (20 ml) was added 28% sodium methoxide methanol solution (26.6 ml), and the mixture was stirred under reflux for 4 hours. After cooling, the reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give 4-(6-methoxyhexylthio)-N-t-butyloxycarbonylpiperidine (3.32 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:15][C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)[CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:15][C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 66.8 %

Procedure:
A mixture of 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (1.04 g, 2.1 mmol) and 10% palladium on activated carbon (200 mg) in methanol (300 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (700 mg, 70%) as a white solid: LC/MS m/e calcd for C27H34N2O5S [M+H]+ 499.65, observed 499.7; 1H NMR (400 MHz, CD3OD) δ ppm 1.24 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.51 (m, 2H), 1.57 (s, 6H), 1.60-1.90 (m, 5H, H), 2.13 (m, 1H), 2.29 (m, 1H), 3.10 (s, 3H), 4.26 (q, J=7.2 Hz, 2H), 4.33 (t, J=7.9 Hz, 1H), 6.46 (s, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.71 (d, J=2.4 Hz, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.92 (br, 1H).
Reaction SMILES: [OH-].[Na+].S([O-])(O)(=O)=O.C([NH3+])CCC.[OH:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.Br[CH2:29][C:30]([O:32]CC)=[O:31]>C1(C)C=CC=CC=1>[C:30]([CH2:29][O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)([OH:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: CCOC(=O)CBr
Agent: CCCC[NH3+]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(COCC(=O)O)C1
Temperature: 15 °C

Procedure:
200 ml of 50% sodium hydroxide solution and 1 g of butylammonium hydrogen sulphate are added to a solution of 21.5 g of tert-butyl rac 3-hydroxymethyl-piperidine-1-carboxylate [K. Hilpert et al., J. Med. Chem., 37: 3889 (1994); EP 0 468 231] in 200 ml of toluene. The 2-phase mixture is cooled to 15° C. and treated with 30 ml of ethyl bromoacetate while stirring vigorously. After stirring at room temperature for 2.5 hours the reaction mixture is poured on to ice-water and extracted twice with ether. The organic phases are washed 4 times with water. The combined aqueous phases are acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate phases are washed with sodium chloride solution, dried and evaporated. There are obtained 18.3 g of tert-butyl rac-3-carboxymethoxymethyl-piperidine-1-carboxylate as a yellow oil, MS: 273 (M)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:21])[CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[C:22]([O:26][C:27]([NH:29][C:30]([CH3:48])([CH3:47])[CH2:31][C:32]([NH:34][C@@H:35]1[CH2:41][CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[NH:37][C:36]1=[O:46])=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:18]([O:17][CH2:16][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:37]2[C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[CH2:40][CH2:41][C@@H:35]([NH:34][C:32](=[O:33])[CH2:31][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:47])[CH3:48])[C:36]2=[O:46])=[CH:4][CH:5]=1)=[O:21])(=[O:20])[CH3:19]
Reactant: CC(=O)OCC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(=O)OCC(=O)c1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from 4'-bromomethyl-2-(acetoxyacetyl)-1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.33 (s,6H), 1.39 (s,9H), 1.87 (m,1H), 2.03 (s,3H), 2.35-2.70 (m,5H), 4.36 (s,2H), 4.51 (m,1H), 4.85 (d,15 Hz,1H), 5.28 (d,15 Hz,1H), 6.66 (m,1H), 7.1-7.6 (m,12H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[CH3:2].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH2:20][CH3:21])=[CH:23][CH:24]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(=O)CC2)ccc1OC
Reactant: CCc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3ccc(CC)cc3)CC2)ccc1OC
Temperature: 85 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-one (94.8 mg, 0.36 mmol, 1.2 equiv; intermediate C1) and 4-ethyl-phenylamine (36.4 mg, 0.30 mmol, 1.0 equiv; commercially available) in ethanol (2 mL) and acetic acid (0.38 mL) was heated to 85° C. After 2 h, sodium cyanoborohydride (22.6 mg, 0.36 mmol, 1.2 equiv), dissolved in ethanol (1 mL), was added and the mixture stirred at 85° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.2 mg (16%) of the title compound. MS (ISP): 369.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[OH-].[NH4+:19]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[NH2:19])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 40.5 g. of 2,6-dinitro-4-trifluoromethyl-1-chlorobenzene in 300 ml. of benzene was mixed with 250 ml. of 14 N ammonium hydroxide. The reaction mixture was stirred at room temperature for about 1.5 hours, at which point in time another 100 ml. of 14 N ammonium hydroxide were added and the stirring was continued for an additional 2 hours. The organic layer was separated, was washed with water and was dried. Removal of the solvents in vacuo yielded 2,6-dinitro-4-trifluoromethylaniline, which melted at about 142°-144° C. after recrystallization from a hexane-benzene solvent mixture.
Reaction SMILES: CS/[C:3](=[N:9]\[C:10](=O)[CH:11]=[C:12]([CH3:14])[CH3:13])/[N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH3:13][C:12]([CH3:14])=[CH:11][C:10]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]=[C:3]([N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)[N:9]=1
Reactant: NNc1ccccc1
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Solvent: CCOC(C)=O
Product: CC(C)=Cc1nc(N2CCCC2)nn1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
A mixture of 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylideneamide (130 mg, 0.575 mmol) and phenyl hydrazine (0.6 ml, 5.75 mmol) was stirred for 3 hours at 100° C. The mixture was cooled, diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography using 50% ethyl acetate in hexane affording 5-(2-methyl-propenyl)-1-phenyl-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (60 mg, 38.87%) as colorless liquid. MS: m/z=268.8 (M+H+)
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:29])[CH2:27][CH3:28]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:29])[CH2:27][CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Reactant: CCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature had cooled to −60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH:9]=[CH2:10])[CH2:7][O:6][C:5](=[O:8])[CH2:4]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[C:26]([O:1][CH2:2][C:3]1([CH:9]=[CH2:10])[CH2:7][O:6][C:5](=[O:8])[CH2:4]1)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: C=CC1(CO)COC(=O)C1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC1(COC(=O)CCCCCCCCCCCCC)COC(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of 8b (0.2 g, 1.4 mmol) in CH2Cl2 (20 mL) was treated with pyridine (0.45 mL, 5.6 mmol), dimethylaminopyridine (0.034 g, 0.28 mmol), and tetradecanoyl chloride (0.76 mL, 2.8 mmol). After stirring for 2 h at room temperature, the reaction mixture was concentrated, and residue was purified by flash column chromatography over silica gel with hexane:EtOAc (3:1) as eluant to give 8c (0.49 g, 99%) as an oil: IR (neat) 1788 and 1741 cm-1 (C=O); 1H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.25 (m, 20 H, CH3 (CH2)10CH2CH2CO), 1.60 (m, 2 H, CH3 (CH2)10CH2CH2CO), 2.31 (t, J=7.4 Hz, 2 H, CH3 (CH2)10CH2CH2CO), 2.60 (s, 2 H, H-3), 4.12 (AB q, J=11.3 Hz, 2 H, CH2OCOC13H27), 4.20 (AB q, J=9.3 Hz, 2 H, H-5), 5.19 (d, J=17.6 Hz, 1 H, CH=CHH), 5.28 (d, J=10.9 Hz, 1 H, CH=CHH), 5.84 (dd, J=10.9, 17.6 Hz, CH=CH2), 13C NMR (CDCl3) δ 14.02, 22.58, 24.69, 28.99, 29.11, 29.24, 29.34, 29.48, 29.53, 29.56, 31.81, 33.93, 36.57, 45.76, 66.63, 73.60, 116.63, 136.81, 173.27, 175.03. Anal. Calcd for C21H36O4 : C, 71.55; H: 10.30. Found. C, 71.46; H, 10.30.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH3:18])[C:15]([C:19]([OH:21])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[C:37]([C:41]1[CH:46]=[C:45]([NH2:47])[C:44]([O:48][CH3:49])=[CH:43][N:42]=1)([CH3:40])([CH3:39])[CH3:38].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C=O>[C:37]([C:41]1[CH:46]=[C:45]([NH:47][C:19]([C:15]2[N:16]([CH3:18])[C:17]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])[C:44]([O:48][CH3:49])=[CH:43][N:42]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: Cn1c(C(=O)O)cc2cccc(OCc3ccccc3)c21
Reactant: COc1cnc(C(C)(C)C)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(C(C)(C)C)cc1NC(=O)c1cc2cccc(OCc3ccccc3)c2n1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.2 %

Procedure:
To a slurry of 7-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (163 mg, 0.58 mmol) in methylene chloride (2 mL) at 0° C. was added oxalyl chloride (72 microL, 0.84 mmol) followed by a drop of N,N-dimethylformamide. The solution immediately bubbled and became clear after a period of 0.75 h. The mixture was concentrated and redissolved in methylene chloride (1.5 mL). The acid chloride solution was added to a solution of N,N-diisopropylethylamine (202 microL, 1.16 mmol) and 2-tert-butyl-5-methoxy-pyridin-4-ylamine (95 mg, 0.52 mmol) in methylene chloride (1.5 mL). The solution was stirred at room temperature for 3 h then poured onto saturated aqueous NaHCO3. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with saturated aqueous NaHCO3, followed by saturated aqueous KH2PO4, and again with saturated aqueous NaHCO3. The organic extracts were dried over sodium sulfate, filtered through a plug of silica-gel with diethyl ether, and concentrated in vacuo to provide pure 7-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (2-tert-butyl-5-methoxy-pyridin-4-yl)-amide (231 mg, 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC(F)=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1.[CH:55]1([C:58](Cl)=[O:59])[CH2:57][CH2:56]1>>[CH:55]1([C:58]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:59])[CH2:57][CH2:56]1
Reactant: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2F)ccn1
Reactant: O=C(Cl)C1CC1
Agent: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Product: O=C(Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2F)ccn1)C1CC1
Yield: 31.7 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 50.0 mg (0.14 mmol) of 4-(2-aminopyridin-4-yl)-3-(2-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 26-5) in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 31.5 mg (0.30 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 18.5 mg of the title compound as a white powder. (Yield: 31%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][CH:43]([O:46][Si](C(C)C)(C(C)C)C(C)C)[C@@H:42]5[CH3:57])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:42][CH2:57][C@H:44]([CH2:43][OH:46])[CH2:45]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]5C)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@H](CO)C5)n4c3)c3ccccc32)cc1

Procedure:
To a solution of Intermediate 92d (240 mg, 0.300 mmol) and TBAF (1M in THF, 0.400 mL, 0.400 mmol) in THF (3 mL) was stirred at RT for 1 h. Water was added and the mixture extracted with DCM (4×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (154 mg, 81%). LCMS (Method 5): Rt 4.01 min, m/z 635.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.68-1.79 (1H, m), 1.79-1.97 (2H, m), 1.98-2.14 (3H, m), 2.36 (3H, s), 2.40-2.48 (1H, m), 3.23-3.30 (1H, m), 3.41-3.64 (5H, m), 4.71 (1H, t, J 5.3), 4.77-4.85 (1H, m), 5.51 (1H, br t, J 4.4), 6.33 (1H, s), 7.03-7.10 (2H, m), 7.25-7.40 (8H, m), 7.53 (1H, d, J 9.9), 7.82 (1H, d, J 1.8), 8.03 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1[Br:7].[C:11]1([CH3:17])[CH:16]=CC=C[CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][C:11]([CH3:17])([CH3:16])[CH3:12])=[O:9])[O:5][C:6]=1[Br:7]
Reactant: O=C(O)c1cc(Br)c(Br)o1
Reactant: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(Br)c(Br)o1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture composed of 4,5-dibromo-2-furancarboxylic acid (20.00 g), DMF di-tert-butylacetal (71.08 ml) and toluene (100 ml) was stirred for 2 hours at 90° C. The reaction solution was diluted with toluene and washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20), thereby giving 20.10 g of tert-butyl 4,5-dibromo-2-furancarboxylate.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].OP([O-])([O-])=O.[Na+].[Na+].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(Cl)Cl>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: Nc1ccccc1F
Reactant: C=CC(=O)Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.3 %

Procedure:
To a solution of acryloyl chloride (0.70 mL, 8.63 mmol) and sodium phosphate dibasic (2.45 g, 17.26 mmol) in anhydrous methylene chloride (18.0 mL) at 0° C. was added dropwise 2-fluoroaniline (0.834 mL, 8.63 mmol). The reaction mixture was stirred at room temperature for 12 h. It was then filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated to afford N-(2-fluorophenyl)acrylamide (C-4) as a white solid (0.959 g, 68% yield). MS (M+1): m/e 166. This material was used for the next step with no additional purification.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1([CH3:52])[C:8](=[O:9])[N:7]([C@@H:10]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:11]([NH:13][CH:14]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])[C:6](=[O:31])[N:5]1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH3:49])=[O:41])=[C:35]([O:50][CH3:51])[CH:34]=1.[ClH:53]>CO>[ClH:53].[CH3:3][C:4]1([CH3:52])[C:8](=[O:9])[N:7]([C@@H:10]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:11]([NH:13][CH:14]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][C:16]([OH:18])=[O:17])=[O:12])[C:6](=[O:31])[N:5]1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH3:49])=[O:41])=[C:35]([O:50][CH3:51])[CH:34]=1
Reactant: CCOC(=O)CC(NC(=O)[C@H](CC1CC1)N1C(=O)N(Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)C(C)(C)C1=O)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)NC(CC(=O)O)c3cccnc3)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Reaction time: 8 h

Procedure:
0.82 mL (0.82 mmol) of a 1 M aqueous lithium hydroxide solution was added to a solution of 141 mg (0.206 mmol) of the compound of Example 9 in 7.25 mL of methanol and the reaction mixture was allowed to stand overnight at room temperature. The methanol was then removed in vacuo, the residue was adjusted to pH 2 using 1N hydrochloric acid and the mixture was concentrated in vacuo. The residue was chromatographed over silica gel using dichloromethane/methanol/glacial acetic acid/water (95/5/0.5/0.5). After concentrating the product fractions, the residue was treated with 1.11 equivalents of 1N hydrochloric acid and freeze dried. Yield: 120 mg (89%).
Reaction SMILES: BrC(Br)C.C[Si](Cl)(C)C.[Cl:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.[Br-].ClC1C(F)=C(C=CC=1)C[Zn+].[F:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36](=[O:57])[C:37]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:38][N:39]2[C@@H:42]([CH:49]([CH3:51])[CH3:50])[CH2:43][O:44][C:45]([O:47][CH3:48])=[O:46])=[CH:34][C:33]=1I.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[NH4+]>C1COCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:32]=1[F:31])[N:39]([C@@H:42]([CH:49]([CH3:51])[CH3:50])[CH2:43][O:44][C:45]([O:47][CH3:48])=[O:46])[CH:38]=[C:37]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[C:36]2=[O:57]
Reactant: CCOC(=O)c1cn([C@H](COC(=O)OC)C(C)C)c2cc(F)c(I)cc2c1=O
Reactant: Fc1c(Cl)cccc1CBr
Agent: [Pd]
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cn([C@H](COC(=O)OC)C(C)C)c2cc(F)c(Cc3cccc(Cl)c3F)cc2c1=O
Temperature: 65 °C

Procedure:
A solution of dibromoethane (0.01 mL, 0.11 mmol) and 1M TMSCl in THF (0.2 mL, 0.2 mmol) was added to a mixture of Zn (200 mg, 3.06 mmol) in THF (5 mL) at rt and the resulting mixture was heated at 65° C. for 0.5 h. The mixture was then cooled to rt and a solution of 3-chloro-2-fluorobenzyl bromide (700 mg, 3.13 mmol) in THF (10 mL) was added with stirring continuing until all Zn had dissolved (approximately 1.5 hr). To the resulting gray slurry of (3-chloro-2-fluorobenzyl)zinc(II) bromide 18 was added a solution of 17 (1.22 g, 2.4 mmol), Pd(dba)2 (70 mg, 0.12 mmol) and trifurylphosphine (56 mg, 0.24 mmol) in THF (5 mL), and the reaction mixture was stirred at 60° C. for approximately 0.5 h. The mixture was cooled to rt, saturated aqueous ammonium chloride (25 mL) was added to quench the reaction and the mixture was extracted with EtOAc (2×25 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified on an AnaLogix chromatography system eluting with 33-50% EtOAc/heptanes to give 680 mg (54%, greater than 98% purity) of 19 as a colorless oil.