Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:32][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OC1CCCC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OC3CCCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and cyclopentanol (67.3 mg; 0.781 mmol), example 65 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3N=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30]N([C@H]1C2C(=CC=CC=2)CCC1)C(C1C=NN(C2CCN(C(=O)CN3C(C)=CC(C(F)(F)F)=N3)CC2)C=1)=O.[OH-].[Na+]>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH:30]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]3)[CH2:14][CH2:15]2)=[O:9])[N:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2cc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1

Procedure:
By a procedure analogous to that of Example 32 Step C, ethyl 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-2H-1,2,3-triazole-4-carboxylate (0.24 g, 0.58 mmol) (i.e. the product of Example 33, Step B) was hydrolyzed with 1 N aqueous sodium hydroxide (1.2 mL, 1.2 mmol) to afford 0.125 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].O>ClCCl>[C:6]([N:9]1[CH2:10][CH2:11][CH:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)(=[O:8])[CH3:7]
Reactant: CC(=O)N1CCC(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1

Procedure:
To chlorosulfonic acid (92 mL), a solution of 1-acetyl-4-benzylpiperidine (60.00 g) in dichloromethane (100 mL) was dropwise added for an hour at 0° C. under stirring, and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 1.5 hours. The reaction mixture was poured into ice-cooled water (1 L) and extracted with dichloromethane (500 mL, 250 mL). The organic phase was washed with an aqueous solution of 5% sodium carbonate (500 mL×2) and saturated brine (250 mL). The organic phase was dried over magnesium sulfate (anhydrous), and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 250 g, ethyl acetate). The objective fraction was concentrated under reduced pressure to give the title compound as a white solid (54.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[N:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.[OH:26]S(O)(=O)=O.O>C(O)(C)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:4]([C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[N:6][C:7]3[C:12]2=[N:11][CH:10]=[N:9][C:8]=3[OH:26])=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccccc1Cl
Solvent: CC(C)O
Solvent: O
Product: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a suspension of 2-chloro-N-[4-chloro-6-(4-chlorophenylamino)-pyrimidin-5-yl]-benzamide I-(4A-7)a (1.00 g, 2.54 mmol) in isopropanol (20 ml) was added neat H2SO4 (410 μl, 7.4 mmol) at room temperature. The reaction was refluxed for 8 hours followed by cooling to room temperature and stirring for 16 hr. To the heterogeneous solution was added 20 ml of water to promote further product precipitation. After stirring for 1 an additional hour at room temperature, the solid was collected on a sintered glass funnel, rinsing with water followed by hexanes. The product was further dried under reduced pressure to give I-(4A-7)b as a colorless solid (0.72 g, 80%): 1H NMR: (400 MHz, DMSO-d6): δ 12.57 (s, 1H), 8.08 (d, J=4.1 Hz, 1 H), 7.66 (dd, J=7.4, 1.2 Hz, 1H), 7.51–7.41 (m, 5H), 7.33–7.29 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15](F)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[CH:11]=[CH:10][S:9][C:5]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CN1Cc2ccsc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CN1Cc2ccsc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:20]=[CH:19][C:18]=2[O:29][CH3:30])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[C:37]2[C:38]([F:43])=[CH:39][CH:40]=[C:41]([F:42])[C:36]=2[S:35][C:34]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:44]([C:34]2[S:35][C:36]3[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:37]=3[C:33]=2[Cl:32])=[O:45])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:29][CH3:30])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccncc2)cc1CNC1CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(CNC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a 3 L 3-neck RB flask equipped with a mechanical stirrer, N2 inlet and addition funnel is added [4-(2-methoxy-5-pyridin-4-yl-benzylamino)cyclohexyl]methylcarbamic acid t-butyl ester P5 (50.3 g, 118.20 mmol) and CH2Cl2 (750 mL). The resulting mixture is cooled in an ice bath and 3-chloro-4,7-difluorobenzothiophene-2-carbonyl chloride P10 (34.7 g, 129.92 mmol) in CH2Cl2 (250 mL) is added over 4 h. The reaction mixture is diluted with CH2Cl2 and washed with 1N HCl (800 mL), 1N NaOH (800 mL), H2O (500 mL) and brine (500 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo to an orange-brown solid. The crude product is ground to a fine solid, diluted with EtOAc (450 mL) and the resulting slurry is stirred for 1 h. The mixture is filtered and the filter cake is washed with EtOAc (100 mL), and dried to give {4-[(3-chloro-4,7-difluorobenzothiophene-2-carbonyl)-(2-methoxy-5-pyridin-4-ylbenzyl)amino]cyclohexyl}methylcarbamic acid tert-butyl ester P6 (66.0 g, 85%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=2)[CH:7]=1.O.[NH2:17][NH2:18]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:17][NH2:18])=[O:13])=[CH:9][N:10]=2)[CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cnc2ccc(Br)cn12

Procedure:
A mixture of 1.94 g ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate, 6 mL hydrazine monohydrate and 20 mL ethanol was heated for 1 hour under reflux. The precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure by a vacuum pump to give 1.71 g of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: CC(C)(C)OC(=O)N1CCCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 87 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with [1,4]diazepane-1-carboxylic acid tert-butyl ester as described in Example 1 to afford 4-(3-formyl-1-phenyl-1H-indole-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (87% yield) as a yellow solid. LC/MS MS 420 (M+H); RT 3.55 min; NMR (CDCl3): 10.25 (1H, s), 8.27 (1 H, d), 7.46-7.66 (3H, m), 7.37 (2H, d), 7.22-7.30 (1H, t), 7.16(1 H, t), 6.96 (1 H, d), 3.25-3.45 (8H, m), 1.56 (2H, m), 1.44(9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=[O:4].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:19])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)n1
Temperature: 25 °C
Yield: 20.2 %

Procedure:
6-Bromomethyl-pyridine-2-carboxylic acid methyl ester was prepared according to Wells, G. J. et al. (WO 94/11398): A mixture of 6-methyl-pyridine-2-carboxylic acid methyl ester (6.5 g, 43.0 mmol), benzoyl peroxide (25 mg, 0.1 mmol) and NBS (8.5 g, 47.8 mmol) in carbon tetrachloride (250 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, filtered, evaporated, and purified by chromatography on flash silica gel, eluting with 15% ethyl acetate/hexane to give 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (2.0 g, 20%) as a white solid. 1HNMR (CDCl3): δ 8.06 (d, J=8.0 Hz, 1H), 7.87 (dd, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 4.65 (s, 2H), 4.02 (s, 3H). MS (APCI+): 231 (45), 235 (42).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5](O)=[O:6].S(Cl)(Cl)=O.[NH4+:16].[OH-].[Na+].[Cl-]>C1COCC1>[F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([NH2:16])=[O:6]
Reactant: [NH4+]
Reactant: CC(C)(CC(=O)O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(CC(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of 4,4,4-trifluoro-3,3-dimethylbutanoic acid [See: US2010/0240663](0.6 g, 3.53 mmol) in thionyl chloride (6 mL, 82 mmol) was heated at 60° C. for 2 h, cooled to RT and concentrated to dryness. The residue was dissolved in DCM (2 mL), added drop-wise to a mixture of THF (8 mL) and NH4OH (˜15M, 8 mL, ˜120 mmol) and stirred at RT overnight. Solid NaCl was added until saturated, the mixture extracted with 4:1 DCM/THF (3×) and the combined organics were washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford 4,4,4-trifluoro-3,3-dimethylbutanamide (240 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 6.93 (s, 1H), 2.20 (s, 2H), 1.18 (s, 6H).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[N:16]1(C(N)=O)[CH2:20]CC[CH2:17]1>>[CH3:17][N:16]([CH3:20])[C:13](=[O:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:7][CH:8]=1
Reactant: NC(=O)N1CCCC1
Reactant: O=C(O)Cc1ccc(C(=O)C2CC2)cc1
Product: CN(C)C(=O)Cc1ccc(C(=O)C2CC2)cc1

Procedure:
(4-cyclopropanecarbonyl-phenyl)-acetic acid, pyrrolidineamide;
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH:13]=[CH2:14]>ClCCl>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:12][CH:13]2[CH2:14][O:6]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CC2CO2)cc1
Yield: 70.8 %

Procedure:
Add allyl tri-n-butylstannane (30.10 mmol, 9.33 ml) dropwise to a stirred solution of 4-iodo-nitrobenzene (5 g, 20.07 mmol), tetrakis-(triphenylphosphine) palladium(0) (1.16 g, 1 mmol) and copper (I) iodide (306 mg, 1.6 mmol) in 50 ml of dry 1,4-dioxane under argon atmosphere. Reflux the mixture for 24 hours and then cool to room temperature. Dilute the solution with 40 ml of diethyl ether and add 20 ml of saturated solution of KF and stir for 2 hours. Filter the mixture and wash the organic layer with water (20 ml), brine (20 ml) and dry over sodium sulfate. Evaporate the solution under reduced pressure and purify the residue by flash chromatography on silica gel using hexane-ethyl acetate as eluent (20:1) to afford 1.80 g (55%) of 1-allyl-4-nitrobenzene. Add a solution of 3-chloro-peroxybenzoic acid (5.98 g, 24.28 mmol), in 20 ml of dichloromethane to a solution of 1-allyl-4-nitro-benzene (1.8 g, 11.04 mmol) in 50 ml of dichloromethane and stir the mixture at room temperature overnight. Quench with saturated NaHCO3 (15 ml), and wash the organic layer three times with saturated NaHCO3 and dry over magnesium sulfate. Evaporate under reduced pressure to afford 1.4 g (71%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[Br:20][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(O)C(Br)c1ccc([N+](=O)[O-])cc1

Procedure:
To a mixture of 4-nitrophenylacetic acid (2.0 g), benzene (40 ml) and N-bromosuccinimide (3.3 g), 2,2′-azobis(2-methylpropionitrile)(0.16 g) was added and heated under reflux for 22 h. The reaction mixture was diluted with ethyl acetate and washed successively with 2 N HCl and water; the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate:acetic acid=75:25:1) to give 2-bromo-2-(4-nitrophenyl)acetic acid. The resulting bromo compound was mixed with 28% aqueous ammonia solution (5 ml) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure; to the resulting residue, 1 N aqueous sodium hydroxide solution (20 ml), 1,4-dioxane (10 ml) and di-t-butyl dicarbonate (7.2 g) were added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in a mixture of methanol (20 ml) and diethyl ether (10 ml); a solution of trimethylsilyldiazomethane (2.0 M) in n-hexane was added until the reaction mixture no longer foamed; the reaction mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 2-t-butoxycarbonylamino-2-(4-nitrophenyl)acetic acid methyl ester. The resulting methyl ester compound was worked up as in Example 2 to give 0.77 g of the titled compound (yield, 25%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[C:17]([F:23])=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:6]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:20][C:18]1[C:17]([F:23])=[CH:16][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:6]=2)=[C:2]([F:1])[CH:19]=1
Reactant: CCC(=O)Nc1cc(Oc2cc(F)c([N+](=O)[O-])cc2F)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 80 °C
Yield: 70.5 %

Procedure:
To a suspension of N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)propionamide (27.2 g, 84.2 mmol) in EtOH (750 mL) was added a solution of NH4Cl (18 g, 337 mmol) in water (188 mL) and Fe powder (97%, 325 mesh, 18.8 g, 337 mmol) in one portion at RT. The mixture was then heated at 80° C. for 1 h, cooled to ambient temp, filtered through a bed of diatomaceous earth, and washed with MeOH (1 L). The combined filtrates were concentrated to dryness and purified by silica gel chromatography (EtOAc/hexanes) to give N-(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)propionamide (17.4 g, 70.5% yield). 1H-NMR (400 MHz, CDCl3): δ 8.07 (d, J=5.6 Hz, 1H), 8.00 (br s, 1H), 7.77 (d, J=2 Hz, 1H), 6.85 (dd, J=10.4, 7.2 Hz, 1H), 6.63-6.58 (m, 2H), 3.79 (s, 2H), 2.38 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); MS (ESI): m/z 294.1 (M+H+).
Reaction SMILES: C1(N[C:8]2([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[OH-].[NH4+:33]>[Pd].CO>[C:16]1([NH:33][CH:10]2[CH2:9][CH:8]([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [NH4+]
Reactant: O=C(OCc1ccccc1)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(CCc2ccccc2)C(Nc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 60 parts of phenylmethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate and 320 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. Upon the addition of a concentrated ammonium hydroxide solution, the precipitate, which is formed during the hydrogenation, is dissolved. The catalyst is filtered off and the filtrate is concentrated. Methanol is added and the whole is concentrated again. After cooling to room temperature the product is filtered off and dried in vacuo at 120° C, yielding 43.7 parts of 4-(phenylamino-1-(2-phenylethyl)-4-piperidinecarboxylic acid; mp. 268° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([F:38])[CH:37]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[N+:31]([O-:33])=[O:32])=O.[BH4-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[F:38][C:36]1[CH:35]=[C:4]([CH:3]=[C:2]([F:1])[CH:37]=1)[CH2:5][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)=[CH:20][C:19]=1[N+:31]([O-:33])=[O:32]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(C(=O)c5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Yield: 91.7 %

Procedure:
N-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide (3.61 g, 6.93 mmol) was dissolved in DCM (150 mL) in argon atmosphere and trifluoroacetic acid (150 mL) is added under stirring. Sodium borohydride pellets (2.62 gr, 69.3 mmol) is gradually added over a period of 72 hours. The reaction mixture was evaporated, taken up with a mixture MeOH/acetone and stirred for 1 hour. The resulting mixture was evaporated to dryness, redissolved in MeOH and NaOH 8N was added till basic pH was reached. Crude was evaporated and ice/water was added, the solid thus formed was filtered, washed with water and dried under vacuum at 80° C. affording 3.22 g of title compound (92% yield).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(OCC)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2([NH2:8])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccc(C(F)(F)F)cc2)CC1
Yield: 180 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-12 by using of 4-(trifluoromethyl)benzonitrile (1.0 g, 0.58 mmol), diethyl ether (20 mL), titanium isopropoxide (2.0 g, 0.70 mmol), ethyl magnesium bromide (4.30 mL, 12.86 mmol) and boron trifluoride solution (1.5 mL) to afford 0.210 g of desired product. 1HNMR (CDCl3): δ 1.05 (s, 2H), 1.60 (s, 2H), 1.78 (s, 2H), 7.36 (d, J=7.8 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:10][CH:9]=[N:8]1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:33])C(=O)C1>C(#N)C>[I:33][C:10]1[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[C:11]=1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)CCOCn1nccc1-c1nccs1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ncc(I)c1-c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)thiazole (Compound 2-BA-1) in 50 mL of acetonitrile at rt under nitrogen were added TFA (1 mL) and NIS (10.8 g). The reaction mixture was stirred at rt overnight and an additional amount of NIS (0.5 eq to 1.0 eq) was added as needed. The crude reaction mixture was slowly quenched with ˜30 mL of a saturated aqueous Na2S2O3 solution, and ˜30 mL of a saturated aqueous NaHCO3 solution. The reaction mixture was diluted with 50 mL of EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layer was purified by MPLC (eluted with 0-50% EtOAc/hex) to give 2-(4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)thiazole (Compound 4-BA-1). LCMS: 408.0 m/z (M+H)+.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[CH:8]1([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH:17]1([NH:16][C:15]([NH:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Oc1ccccc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A solution of the alcohol or phenol (1.0 eq.), of the carboxylic acid (1.1 eq.), of N,N′-dicyclohexylcarbodiimide (Aldrich, purity 99%; about 1.1-1.7 eq.) and catalytic amounts of 4-pyrrolidinopyridine (Aldrich, purity 98%; about 0.01 eq.) is stirred in anhydrous dichloromethane until the reaction is complete. The N,N′-dicyclohexylurea formed is filtered off, the solvent is removed under reduced pressure, and the residue is purified as described.