Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C)(C)[O:24][CH2:25][CH2:26][CH:27]([CH:35]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([I:44])=[CH:40][CH:39]=1)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(C)C>O1CCCC1>[OH:24][CH2:25][CH2:26][CH:27]([CH:35]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([I:44])=[CH:42][CH:43]=1)[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29]
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A solution of tetra-n-butylammonium fluoride (1.0 M in THF; 7.0 mL, 7.0 mmol) was added dropwise over 15 min to a stirred solution of 1,1-dimethylethyl 2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (4.14 g, 6.33 mmol) in tetrahydrofuran (25 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature at which stirring was continued for 2 h. The volatiles were evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (100 mL), dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (25% to 50% ethyl acteate: cyclohexane) to give the title compound (2.87 g, 84%) as a yellow oil which was a mixture of diastereomers. LC/MS: 3.86 min; z/e 541, calcd (M+1) 541. 1H NMR (400 MHz: CDCl3): 7.55-7.25 (4H), 6.90-6.75 (4H), 4.55-4.35 (2H), 3.80 (3H), 3.65 (3H), 2.90-2.45 (3H), 1.90-1.60 (4H), 1.35 (9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:29]3[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:31][C:30]=3[O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[N:16][N:17]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:52]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([C:29]3[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:31][C:30]=3[O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[N:16][N:17]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:20])=[O:21])[C:18]=2[CH3:52])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)n2)cc1
Reactant: CI
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
N-Butyl lithium (1.6M in hexane; 0.25 ml, 0.4 mmol) was added dropwise to a stirred, cooled (−78° C.) solution of 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester) 240 mg, 0.33 mmol) in tetrahydrofuran (2 ml), under a nitrogen atmosphere. The mixture was stirred at −78° C. for 10 minutes, then methyl iodide (40 μL; 0.64 mmol) was added. The reaction mixture was warmed to room temperature, then partitioned between water (20 ml) and ethyl acetate (2×20 ml). The combined organic phases were dried over magnesium sulphate, then concentrated in vacuo, and purified on silica cartridge (200 mg) eluting with hexane, then hexane:diethyl ether, 1:1, then diethyl ether gave 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-5-methyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (70 mg; 29%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)[CH3:2].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:7]=1[Br:25])[CH3:2]
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)c2ccc(OC)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(OC)cc12
Reaction time: 1.5 h
Yield: 42.7 %

Procedure:
A mixture of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester (10.8 g, 32 mmol) and 6.3 g (35 mmol) of N-bromosuccinimide in 250 mL of carbon tetrachloride was stirred for 1.5 hours, washed with Na2S2O3 solution, water, brine, and dried (Na2SO4). After concentrating at reduced pressure, the residue was chromatographed on silica gel and eluted with a gradient, 25% ether/hexane→40% ether/hexane, to give 5.5 g (43% yield) of 2-bromo-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)(F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2,2,3,3,3-pentafluoropropan-1-ol (9.7 ml) and pyridine. Cool to between 0° C. and 10° C. and add portion-wise the p-toluenesulfonylchloride (6.2 g) and stir with warming to room temperature. After 3 hours at room temperature, pour the reaction mixture into ice water and stir for 30 min to give a solid. Filter the solid, wash with water, and dry to give of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28]>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][N:27]([CH3:28])[CH3:26])=[CH:11][CH:10]=1)[CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C#CCCCOS(C)(=O)=O)cc1
Solvent: CC(=O)N(C)C
Product: CN(C)CCCC#Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 1.84 g (5 mmol) of Methanesulfonic acid 5-[4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-pent-4-ynyl ester in 20 ml DMA was treated with 8.93 ml (50 mmol) of (33% in ethanol, 5.6 M) dimethylamine and stirred at RT for 18 h. The reaction was treated again with 4.46 ml (2 mmol) (25 mmol) of (33% in ethanol, 5.6 M) dimethylamine and stirred at RT for further 6 h. The solution was concentrated and the residual oil was extracted with aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to yield 1.50 g (95%) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 317 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[CH:8]=1)=[O:6]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccc(C(F)(F)F)o3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 55 mg (0.20 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 10 mg of 60% sodium hydride, 55 mg (0.24 mmol) 2-bromomethyl-5-trifluoromethyl-furan and 0.7 mL of N,N-dimethylformamide. Yield: 70 mg of a white solid: LC-MSD, m/z for C24H18F3NO3 [M+H]+=426.4; HPLC retention time: 2.7 min.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]([F:32])([F:31])[C@:6]([C:9]2[N:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]([NH2:24])=[N:22][C:21]([C:25]([F:28])([F:27])[CH3:26])=[C:20](Cl)[N:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[F:30])([CH3:8])[N:7]=1>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[O:3][CH2:4][C:5]([F:31])([F:32])[C@:6]([C:9]2[N:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]([NH2:24])=[N:22][C:21]([C:25]([F:28])([F:27])[CH3:26])=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[F:30])([CH3:8])[N:7]=1
Reactant: CC(F)(F)c1nc(N)c(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)n2)nc1Cl
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(F)(F)c1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)n2)c(N)n1
Reaction time: 2.5 h

Procedure:
To a solution of 3-amino-6-chloro-5-(1,1-difluoro-ethyl)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide [Example 34] (54 mg, 0.113 mmol) in MeOH/THF (1:1, 10 ml) was added Pd/C 10% (BASF 4505 D/R E, 12 mg) and the mixture was set under an hydrogen atmosphere. After 2.5 h more Pd/C 10% (BASF 4505 D/R E, 11 mg) was added and the hydrogenation continued for another 2.5 h. The reaction mixture was filtered through a pad of Celite, washed with MeOH and the solvent evaporated. The residue was purified by chromatography on silica gel (DCM to DCM/MeOH 9:1) to provide the title compound as yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[C:37]#[CH:38].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:38]#[C:37][C:31]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=3[Cl:29])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: C#Cc1cc(Cl)ccc1Cl
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4cc(Cl)ccc4Cl)cc3F)[nH]c2=O)c1)C1CC1
Yield: 36 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 by using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.060 g, 0.10 mmol), 1,4-dichloro-2-ethynylbenzene (Intermediate-23, 0.026 g, 0.15 mmol), TBAF (0.064 g, 0.20 mmol), bis(triphenylphosphine)palladium(II) chloride (0.064 g, 0.20 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (m, 4H), 1.60 (m, 1H), 4.33 (d, J=5.7 Hz, 2H), 7.38 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.57-7.69 (m, 5H), 7.86-7.94 (m, 2H), 8.68 (m, 1H), 12.45 (br s, 1H); MS (m/z): 557.05 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]([CH:18]1[CH2:23][NH:22][CH:21]([CH3:24])[CH2:20][CH2:19]1)[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:22]1[CH2:23][CH:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH:21]1[CH3:24])=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: CCC1CCC(C)NC1
Product: CCC1CCC(C)N(C(=O)c2cnoc2-c2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 5-ethyl-2-methylpiperidine (7.6 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (2.8 mg). Calcd for C18H21ClN2O2: 332.1292, found 332.1293.
Reaction SMILES: C([Li])(CC)C.C1CCCCC1.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH3:28])=[O:18])([CH3:15])([CH3:14])[CH3:13].CON(C)[C:32](=[O:35])[CH2:33][CH3:34]>C1COCC1>[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH2:28][C:32](=[O:35])[CH2:33][CH3:34])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCC(=O)N(C)OC
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCC(=O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of 1.3M sec-butyl lithium/cyclohexane (81 mL, 0.105 mol) was added slowly to 11.85 g (0.05 mol) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline in 80 mL of THF while keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to -20° C. and then the bath was replaced. After the temperature had cooled to -60° C., 6.1 g (0.052 mol) of N-methoxy-N-methylpropanamide in an equal volulme of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 1 hour. It was then poured into a mixture of 200 mL of ether and 200 mL of 1N HCl. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated at reduced pressure to give 10.9 g (74% yield) of 1-(2-(tert-butoxycarbonylamino)-5-methoxyphenyl]-2-butanone, melting at 80°-81° C., after chromatography on silica eluting with 5% EtOAc/toluene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14](=[O:35])[N:15]([CH2:32][CH2:33][CH3:34])[C:16](=[O:31])[N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:18]=1[NH2:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[NH:12][C:13]3[C:14](=[O:35])[N:15]([CH2:32][CH2:33][CH3:34])[C:16](=[O:31])[N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)[C:18]=3[N:19]=2)=[CH:6][CH:7]=1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CCCn1c(=O)c2[nH]c(Cc3ccc(F)cc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 4-fluorophenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By the methods of Example 3 and Example 4, 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is alkylated with a mixture of 1,2-dichloroethane and 2-(ethylamino)ethanol, to afford 7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-fluorobenzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine, which, in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-fluorobenzyl)-1-propylxanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)=[CH:16][C:15]=2[CH2:27][NH:28][CH2:29][CH3:30])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[CH:22][C:23]([F:26])=[CH:24][N:25]=3)=[CH:16][C:15]=2[CH2:27][N:28]([C:35]([CH:32]2[CH2:34][CH2:33]2)=[O:36])[CH2:29][CH3:30])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(-c2ncc(F)cn2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ncc(F)cn3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-ethylaminomethyl-4′-(5-fluoro-pyrimidin-2-yl)-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([O:21]C)=[O:20])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: COC(=O)c1nc(-c2ccc(F)cc2)c(C(F)(F)F)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)c(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 3-amino-6-(4-fluorophenyl)-5-(trifluoromethyl)picolinate (step 1) (6.00 mmol) in EtOH (5 ml) was added 2M NaOH (3 ml, 6.00 mmol) and the solution was stirred at RT for 15 minutes. The resulting mixture was diluted with water (10 ml) and the pH was adjusted to pH 6 using 1M HCl. The mixture was extracted with DCM (2×10 ml) and the phases were separated using a phase separating cartridge. The combined organic extracts were concentrated in vacuo and used in the next step without further purification;
Reaction SMILES: [NH2:1][C:2]1([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23]C(=O)OC(C)(C)C)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=1[S:49](Cl)(=[O:51])=[O:50]>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][S:49]([C:42]2[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:41]=2[O:40][CH3:39])(=[O:51])=[O:50])([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:3](=[O:33])[C:4]=1[C:13]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][S:15]([CH3:16])(=[O:32])=[O:31])=[CH:22][C:16]=2[S:15](=[O:31])(=[O:32])[N:14]=1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: CC(C)CCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Product: COc1ccc(OC)c(S(=O)(=O)NC2(CCC(C)C)C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)c3ccccc32)c1

Procedure:
Follow same procedure as Example 18D treating the product of Example 18C with 2,5-dimethoxybenzenesulfonyl chloride (9.6 mg, 0.05 mmol). 1H NMR (d6-DMSO) δ 13.45 (s, 1H), 10.30 (s, 1H), 8.69 (s, 1H), 8.03, 8.01 (d, 1H), 7.73, 7.70 (d, 1H), 7.66-7.56 (m, 2H), 7.40-7.33 (t, 1H), 7.28-7.16 (m, 2H), 7.06, 7.03 (d, 1H), 6.93-6.87 (m, 1H), 6.34, 6.33 (d, 1H), 3.95 (s, 3H), 3.41 (s, 3H), 3.10 (s, 3H), 2.37-2.16 (m, 2H), 2.01-1.85 (m, 1H), 1.33-1.14 (m, 2H), 0.68-0.57 (q, 6H); MS (ESI) m/z 719 (M+H+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[C:22]=1[CH3:30])=[O:19])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:29][C:23]1[C:22]([CH3:30])=[C:21]([NH:20][C:18]([N:6]2[CH2:7][CH2:8][C@H:9]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])[C@H:5]2[CH2:3][OH:2])=[O:19])[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)N2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]2CO)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of compound 55B (300 mg, 0.66 mmol) in anhydrous THF (6.7 mL) at −25° C. was added 1 N LAH in THF (1.34 mL, 1.34 mmol) over a period of 10 min. The solution was then warmed to 0° C. and stirred for 2.0 h before quenching with H2O (0.05 mL), 15% NaOH (0.05 mL) and H2O (0.16 mL). After warming to rt, the mixture was extracted with EtOAc (2×40 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant off-white solid was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (217.2 mg, 78%) as a white solid, mp 174-176° C. HPLC: 3.23 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=7.11 min (96.1%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 424 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:21][C:22]1[S:23][C:24]([CH2:27]Cl)=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[N:14]([CH2:27][C:24]3[S:23][C:22]([Cl:21])=[CH:26][CH:25]=3)[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: ClCc1ccc(Cl)s1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cnccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3cnccc23)CC1
Yield: 59.7 %

Procedure:
This compound was prepared following the procedure described in example 24, part C, starting with 8.7 g (31.8 mmol) of 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 5.75 ml (47.7 mmol) of 2-chloro-5-chloromethylthiophen. After standard work-up and purification, 7.67 g (60% of yield) of 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].CCOCC>O1CCCC1>[Br:18][C:10]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2Br)cc1
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a cold (0° C.) solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (5.0 g, 20.2 mmol) in tetrahydrofuran (81 mL) was added N-bromosuccinimide (3.79 g, 21.2 mmol) in two portions. The solution solidified after 5 minutes and additional tetrahydrofuran was added (20 mL). The resultant solution was stirred for 15 minutes. Saturated aqueous sodium bicarbonate and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layers were extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by recrystallization from ethyl acetate-hexane-methanol provided 3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (5.7 g, 87%) as a crystalline solid. 1H NMR (CDCl3) δ 8.07 (dd, 2H), 7.53 (d, 1H), 7.23–7.16 (m, 3H), 6.98 (d, 1H); 19F NMR (CDCl3) δ −112.60; MS m/z 325 (M+1).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([NH:29][C:30]([C:32]4[O:33][CH:34]=[CH:35][C:36]=4[CH3:37])=[O:31])[CH:23]=3)[CH:18]=[CH:17][N:16]=2)[NH:12][CH:11]=1)=[O:9])C.Cl.O.[OH-].[Na+]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:13]3[NH:12][CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[CH:14]=3)[CH:20]=2)=[CH:23][C:24]=1[NH:29][C:30]([C:32]1[O:33][CH:34]=[CH:35][C:36]=1[CH3:37])=[O:31]
Reactant: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(F)c(NC(=O)c4occc4C)c3)ccn2)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)NCCC=O)c[nH]3)c2)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide (380 mg, 0.69 mmol) in 15 ml of tetrahydrofuran was added 1 ml of 2M HCl (2.0 mmol). The mixture was stirred at room temperature for 90 minutes and poured into 100 ml of water. 1M NaOH solution was added slowly until pH=7˜8. The precipitates were filtered, washed with water and dried in vacuo to give 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 270 mg, 82%.