Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH2:19])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
A mixture of 5-bromo-2-chloro-3-nitro-pyridine (2.4 g, 10.1 mmol), benzene-1,3-diamine (2.7 g, 25 mmol) and DIPEA (5.3 ml, 30 mmol) in dry NMP (20 ml) was stirred and heated at 120° C. under N2 for 2 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→50% EtOAc/petrol) to give the title compound (2.5 g) as a red solid. 1H NMR (400 MHz, DMSO-d6): 9.78 (1H, s), 8.66 (1H, d), 8.60 (1H, d), 7.00 (1H, t), 6.83-6.71 (2H, m), 6.39 (1H, d), 5.13 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[CH2:13]([O:20][CH2:21][C:22](Cl)=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl>[CH2:13]([O:20][CH2:21][C:22]([NH:11][C:5]1[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl-2-amino-5-bromobenzoate (15 g, 62.6 mmol) in DCM (241 mL) at 0° C. was added benzyloxyacetyl chloride (12.5 mL, 75.1 mmol) followed by Et3N (20 mL, 144 mmol) dropwise. The resulting white suspension was stirred at room temperature for 3 hours. The mixture was then washed with saturated aqueous NH4Cl (200 mL) followed by water (200 mL). The organics were dried (Na2SO4), filtered and concentrated to dryness. The crude solid was triturated with MeOH (90 mL) and dried under vacuum to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
N-[3,5-Dichloro-4-(6-chlorobenzothiazol-2-yloxy)-phenyl]-4-trifluoromethoxy-benzenesulfonamide was synthesized (83%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-trifluoromethoxybenzenesulfonyl chloride (Maybridge) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.03-7.98 (m, 2H), 7.68 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.31 (s, 2H). MS (EI): m/z 567 (M−H).
Reaction SMILES: C(OC1C(C(C)C)CCC(C)C1)(=O)C1C(=CC=CC=1)[NH2:4].[C:21]([O-:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)O>>[CH:23]1[C:22]([C:21]([OH:30])=[O:29])=[CH:28][CH:27]=[C:26]([NH2:4])[CH:25]=1
Reactant: O=C([O-])c1ccccc1O
Reactant: CC1CCC(C(C)C)C(OC(=O)c2ccccc2N)C1
Product: Nc1ccc(C(=O)O)cc1

Procedure:
Menthyl Anthranilate or Salicylate
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:37][N:36]=[C:35]([CH2:38][CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[S:37][N:36]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCc1nsc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nsc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (563 mg; compound B50) is reacted with 5-(chloromethyl)-3-ethyl-1,2,4-thiadiazole (226 mg; compound D20) in the presence of potassium carbonate (364 mg) in DMF (10 ml). After 3 h and additionally after 6 h at 100° C. additional 5-(chloromethyl)-3-ethyl-1,2,4-thiadiazole (214 mg and 107 mg; compound D20) in DMF (5 ml each) is added, and the mixture is stirred at 100° C. for another 5 h. Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/1 (v/v)] as a solid.
Reaction SMILES: CC(C)([S@@]([NH:6][C@@H:7]([C:13]([CH3:17])([CH3:16])[CH2:14][F:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O)C.[ClH:19].O1CCOCC1>CO>[NH2:6][C@@H:7]([C:13]([CH3:16])([CH3:17])[CH2:14][F:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[ClH:19]
Reactant: CCOC(=O)[C@@H](N[S@@](=O)C(C)(C)C)C(C)(C)CF
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](N)C(C)(C)CF
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of (S)-ethyl 2-((S)-1,1-dimethylethylsulfinamido)-4-fluoro-3,3-dimethylbutanoate (0.38 g, 1.350 mmol) in MeOH (10 mL) was added HCl/dioxane (1.350 mL, 5.40 mmol). The reaction mixture was stirred at rt for 30 min and concentrated to afford (S)-ethyl 2-amino-4-fluoro-3,3-dimethylbutanoate/HCl as a white solid (0.29 g).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])=[O:19]
Reactant: [H][H]
Reactant: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 93.3 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 194 (0.30 g, 0.83 mml) in methanol (20 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-6-hydroxy-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 195 (0.21 g, 95%) as a colorless foam.
Reaction SMILES: [Li+].[OH-].[C:3]([C:7]1[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[N:9]([CH:17]([CH3:19])[CH3:18])[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>O.C1COCC1>[C:3]([C:7]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]([CH:17]([CH3:19])[CH3:18])[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1nc(C(C)(C)C)cc1C(=O)O
Temperature: 50 °C
Yield: 97.8 %

Procedure:
A solution comprised of LiOH (2.3 g, 9 mmol) in water (12 mL) was added to a solution of ethyl 3-tert-butyl-1-isopropyl-1H-pyrazole-5-carboxylate (2.3 g, 9 mmol) in THF (24 mL) and the reaction mixture was heated to 50° C. overnight. The reaction was concentrated under reduced pressure and diluted with water. The solution pH was adjusted to pH 5 and the solution was extracted with EtOAc. The organics were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give 3-tert-butyl-1-isopropyl-1H-pyrazole-5-carboxylic acid (1.85 g, 93% yield). 1H NMR (300 MHz, DMSO-d6): 6.62 (s, 1 H), 5.37 (m, 1 H), 1.35 (d, J=6.6 Hz, 6 H), 1.22 (s, 9 H). MS (ESI) m/z: (M+H+) 211.2
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.CO.Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: NCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 8 h

Procedure:
N-(7-Cyano-chroman-4-yl)-3-(naphthalen-2-ylsulfonylamino)-3-phenyl-propionamide (Example 1, Step F) (30 mg, 0.06 mmol) and Pd(OH)2 (6 mg) was added in MeOH (10 mL), followed by adding 1.0 mL of 3.0 M HCl-MeOH. The solution was purged with N2, then sealed with H2 (50 psi) and shaken overnight until the reduction was completed. The solution was filtered, and concentrated to near dryness in vacuo. The crude compound was purified by precipitation in EtOAc-Et2O to provide the HCl salt as a white solid mixture of diastereomer. MS (ESI) 516 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH3:11])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([Br:15])[CH3:11])=[CH:6][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(1-hydroxy-ethyl)-benzoic acid methyl ester (Step B, 2.12 g, 11.7 mmol) in CH2Cl2 (25 mL) at 0° C. were added carbon tetra bromide (5.07 g, 15.3 mmol) and triphenylphosphine (3.71 g, 14.04 mmol). The reaction mixture was stirred overnight at room temperature, after completion of the reaction, was poured into H2O (50 mL). The aqueous solution was extracted with CH2Cl2 (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography in hexanes/ethyl acetate (5%) to afford 4-(1-bromo-ethyl)-benzoic acid methyl ester as a colorless liquid. (2.45 g, 85%): 1H NMR (300 MHz, CDCl3): δ 8.0 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 5.11 (q, J=6.9 Hz, 1H), 3.91 (s, 3H), 1.83 (d, J=6.9 Hz, 3H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:59](O)=[O:60])[CH:56]([CH3:58])[CH3:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([NH:54][C@H:55]([C:59]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:60])[CH:56]([CH3:58])[CH3:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 76 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-valine. Yield 76%. [α]D =+17.8° (c=1.09, dichloromethane). m.p. 85-86°.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)O.O>C(O)C>[CH3:2][C:1]([O:4][C:12]1[CH:11]=[CH:10][CH:9]=[CH:7][C:6]=1[C:5]([OH:14])=[O:13])=[O:3]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccccc1O
Solvent: O
Solvent: CCO
Product: CC(=O)Oc1ccccc1C(=O)O

Procedure:
A dosage form of salicylic acid acetate for topical or oral use was prepared as follows: Desalted egg phosphatides (Hepar) were dissolved in absolute ethanol at a concentration of 250 mg/ml in a 1000 ml flask. To 400 mg of salicylic acid acetate, 1.6 ml of the above solution containing 400 mg of phosphatides was added and the solution adjusted with absolute ethanol to 4 ml. The final concentration of both ingredients in this pharmacological agent-lipid solution was 100 mg/ml. This procedure was performed at about 22.5° C.+/- about 2.5° C. and atmospheric pressure. Next, the topical/oral administration dosage form was prepared by adding the pharmacological agent-lipid solution, to water at about 22.5° C.+/- about 2.5° C. and briefly agitating the mixture. A cloudy suspension promptly formed. This salicylic acid acetate formulation may then be ingested or used topically.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH:17]([CH3:21])[C:18]([OH:20])=O)[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)=[O:7].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:26][CH:25]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH:17]([CH3:21])[C:18]([N:30]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:27]1[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=1)=[O:20])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:7]
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: COc1ccc(N(C(=O)c2ccco2)C(C)C(=O)O)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(=O)c1ccco1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(2-furoyl)-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(2-furoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(2-furoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 204° to 206°).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.Cl>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)N1CCC[C@H]1CN1CCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1
Temperature: 60 °C

Procedure:
Procedure OO: 160 mg of (4′-Nitro-biphenyl-4-yl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (0.43 mmol) is put into the solution of 485 mg of SnCl2.2H2O (2.15 mmol) in 1.0 ml of EtOH. 1.0 ml of conc. HCl is added to the mixture and heated at 60° C. for 30 min. EtOH is removed in vacuo and the solution is made it to pH=12.0 by aqueous NaOH. This mixture is extracted with dichloromethane, dried over Na2SO4 and evaporated. The crude product is applied to SCX column and washed by MeOH and the desired product is eluted with 2M NH3 in MeOH. The elution is concentrated and applied to silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=20:1) to give the title compound. 77 mg (51%) Observed mass; 350 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH:10][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:17]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: Brc1ccc(CCCN2CCCC2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(Nc2ccc(CCCN3CCCC3)cc2)nc1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A mixture of 5-nitro-pyrimidin-2-ylamine (0.15 g, 1.1 mmol), intermediate 51 (Example 101) (0.30 g, 1.1 mmol), Pd2(dba)2 (75 mg, 0.082 mmol), Xantphos (96 mg, 0.17 mmol) and cesium carbonate (0.69 g, 2.1 mmol) was suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 15 h. The mixture was allowed to cool to room temperature, filtered and washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (10% MeOH/DCM to 20% MeOH and 2% TEA/DCM) to afford the title compound as a yellow solid (0.20 g, 56%).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3]1.[F:37][C:38]([F:49])([F:48])[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][N:40]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][NH:23][C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:6][CH2:5][N:4]([C:45]([C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:38]([F:49])([F:37])[F:48])[N:44]=2)=[O:46])[CH2:3]1
Reactant: O=C(O)c1ccnc(C(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CCNC[C@H]5F)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN([C@H]2CCN(C(=O)c3ccnc(C(F)(F)F)n3)C[C@H]2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of {1-[cis-3-fluoropiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (200 mg, 0.4 mmol) and 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (83 mg, 0.43 mmol) in DMF (10 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.20E2 mg, 1.17 mmol) and triethylamine (0.14 mL, 0.98 mmol). The mixture was stirred at room temperature overnight and purified with prep-LCMS to give 100 mg (36% yield) of the desired compound as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][Cl:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cc2ccccc2)c1N
Reactant: O=C(Cl)CCCCl
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCCl

Procedure:
2-benzyl-6-methylaniline and 4-chlorobutyryl choride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: N([O-])=O.[Na+].[N:5]1([CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[CH:16][C:17](N)=[CH:18][CH:19]=3)[CH:14]=[N:13]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[BrH:22]>O>[Br:22][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH2:11][CH2:10][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:13]=[CH:14]2
Reactant: Br
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
A solution of NaNO2 (0.20 g, 2.8 mmol) in H2O (5 mL) was cooled in a wet ice bath and treated with a solution of 1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-amine (0.65 g, 2.8 mmol) in 48% aqueous HBr (2 mL). The resulting mixture was added to a pre-heated solution of CuBr (0.49 g, 3.4 mmol) in 48% aqueous HBr (2 mL) at 100° C. After stirring at 100° C. for 15 min, the dark mixture was allowed to cool. The solids were isolated by filtration, washed with 1N NaOH, and dried under vacuum. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 95:5 to 90:10 gave the title compound (0.21 g, 25%) as a brown solid: ESI MS m/z 294 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:14]=1.O>CC(N(C)C)=O>[CH3:19][C:17]1[CH:18]=[C:13]([N:5]2[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]2)[N:14]=[C:15]([O:20][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[CH:16]=1
Reactant: Cc1cc(Cl)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2cc(C(F)(F)F)nn2C)nc(-n2cc(C(F)(F)F)cn2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
0.385 g of 4-trifluoromethylpyrazole is introduced under nitrogen in 10 ml of dimethylacetamide and at 0° C. 0.096 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.757 g of 2-chloro-4-methyl-6-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine is added and the mixture is heated at 140° C. for 7 h, cooled to RT and poured into water. The product is extracted twice with ethyl acetate/heptane (1:1) and twice with ethyl acetate and then washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel gives 0.332 g of 4-methyl-2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(4-trifluoromethylpyrazol-1-yl)pyridine as white crystals.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([O:23]C(C)(C)C)=[O:22])[CH2:19][CH2:18][NH:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)[C:31]([OH:33])=[O:32]>>[C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH2:18][N:17]2[C:31]([O:33][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CCNC1CCCCCCC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1CCCCCCC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
The product of Example 17 is dissolved in trifluoroacetic acid and the solution is stored at room temperature for one hour. The mixture is then concentrated to dryness in vacuo, and the residue is acylated with t-butyloxycarbonyl azide by the procedure described in Example 13 to obtain 3-carboxy-1-[(t-butyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester.