Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22](O)=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:41](=[O:48])[C@@H:42]1[CH2:46][C@H:45]([F:47])[CH2:44][NH:43]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:21]([OH:25])[C:22]([N:43]1[CH2:44][C@@H:45]([F:47])[CH2:46][C@H:42]1[C:41]([NH:40][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@H](F)CN1)C(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](F)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 39.1 %

Procedure:
Following a procedure similar to that described in Example 1, but using 222 mg (0,5 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid and 144 mg (0.5 mmol) of (4S)-N-t-butoxycarbonyl-4-fluoro-N-t-butyl-L-prolinamide, 120 mg of the title compound were obtained as a colorless powder, melting at 95°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=O)[CH3:19]>CC(C)=O.ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH:17]=[C:18]([CH3:19])[C:7]=2[CH:8]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc2scc(C)c2c1
Yield: 26.9 %

Procedure:
A mixture of 4-methoxythiophenol (2.8 g, 20 mmol), K2CO3 (5.5 g, 40 mmol) and chloroacetone (6.6 mL, 82 mmol) in acetone (50 mL) was heated at reflux over night. The reaction mixture was filtered and the solvent was evaporated giving 5.0 g crude product. The intermediate thioether was dissolved in chlorobenzene (50 mL) and polyphosphoric acid (PPA, 0.5 g) was added (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The reaction mixture was refluxed over night. The solvent was decanted and the PPA residue was treated with CH2Cl2. The combined organic extracts were washed with water and dried before the solvents were evaporated. The crude product was purified on silica using heptane as eluent to give the title compound (0.96 g, 27% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.44 (d, J=1.20 Hz, 3 H) 3.93 (s, 3 H) 7.03 (ddd, J=8.78, 2.51, 0.50 Hz, 1 H) 7.11 (dq, J=1.20, 0.50 Hz, 1 H) 7.17 (d, J=2.51 Hz, 1 H) 7.73 (dd, J=8.78, 0.50 Hz, 1 H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[C:14]([OH:17])(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([O:17][CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:16])[CH3:15]
Reactant: O=C(CCl)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
In a round-bottomed flask, 1-chloro-3-(3,4-dichlorophenyl)propan-2-one (0.545 g, 2.30 mmol) was taken up in 2 mL acetone, and acetic acid (0.26 mL, 0.28 g, 4.6 mmol) was added. The solution was cooled in an ice water bath, and triethylamine (0.64 mL, 0.47 g, 4.6 mmol) added dropwise via syringe over 30 minutes. The reaction mixture was then stirred overnight. Precipitated triethylammonium chloride was removed by filtration, and the filtrate was evaporated, taken up in 10 mL ethyl acetate, washed twice with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by flash chromatography over silica gel (10-30% ethyl acetate in hexanes) to give a pure product (0.200 g, 33% yield): 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H) 3.71 (s, 2H) 4.71 (s, 2H) 7.05 (dd, J=8.2, 2.2 Hz, 1H) 7.32 (d, J=2.0 Hz, 1H) 7.41 (d, J=8.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](C(O)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)N1CCN(c2ccc(O)cc2)c2ccccc21
Reactant: ClCc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(COc2ccc(N3CCNc4ccccc43)cc2)nc1
Temperature: 100 °C

Procedure:
0.3 g of the tent-Butyl ester of 4-(4-hydroxyphenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is placed in 4.6 ml of dimethylformamide under nitrogen. 0.167 g of 2-(chloromethyl)pyrimidine and 0.508 g of potassium carbonate are added. The reaction medium is heated at 100° C. for 4 h. 0.254 g of potassium carbonate is added and heating is maintained for 1 h 30. After hydrolysis, the reaction medium is extracted with ethyl acetate until the aqueous phase has been completely extracted. The organic phases are combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol in dichloromethane varying from 0% to 9/1. 0.095 g of 1-[4-(pyrimidin-2-ylmethoxy)phenyl]-1,2,3,4-tetrahydro-quinoxaline is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2([CH3:27])[CH2:26][O:25]2)=[O:23])=[CH:17][C:16]=1[CH3:28])#[N:14]>>[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[C:16]([CH3:28])[CH:17]=2)=[O:23])=[CH:7][C:2]=1[F:1])(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(O)cc1F
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1C#N
Product: CC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc(C#N)c(C)c2)cc1F

Procedure:
3-(4-Acetylamino-3-fluorophenoxy)-N-(4-cyano-3-methylphenyl)-2-hydroxy-2-methylpropionamide was prepared as described in Example 1 starting from N-(2-fluoro-4-hydroxyphenyl)acetamide and 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl)amide. 1H NMR (DMSO-d6): 1.41 (3H, s), 2.02 (3H, s), 2.44 (3H, s), 3.95 (1H, d, J=9.8 Hz), 4.26 (1H, d, J=9.8 Hz), 6.21 (1H, bs), 6.72 (1H, m), 6.86 (1H, m),7.56 (1H, m,) 7.69 (1H, d, J=9.0 Hz), 7.78 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 9.51 (1H, s), 9.99 (1H, bs).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(CCl)ccc1[N+](=O)[O-]
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCC
Temperature: 100 °C

Procedure:
A mixture of 4-(chloromethyl)-2-methoxy-1-nitrobenzene (Compound 1H, 1.1 g, 5.46 mmol) and triethyl phosphite (1.09 g, 6.55 mmol) were heated at 100° C. for 16 h in a sealed tube. The reaction mixture was concentrated under reduced pressure to yield a black oil. The crude material was purified by silica gel chromatography on a Teledyne ISCO CombiFlash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the title compound as 1.08 g of an orange oil (65%). MS (ESI): m/z 304.0902 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:12][C:4]1[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: CN1CCNCC1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(C(F)(F)F)cc(Cl)n2)CC1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Dissolve 2,6-dichloro-4-(trifluoromethyl)pyridine (215 mg, 1 mmol) and DIEA (129 mg, 1 mmol) in DMF (2 mL), add 1-methyl piperazine (100 mg, 1 mmol). Stir the reaction at 120° C. overnight. Cool to room temperature; concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, MeOH:DCM=1:10) affords the product (253 mg, 91%). MS: (M+1): 280.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:9][CH2:10][C@H:11]([OH:13])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cccc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@H]1CN[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-4) (890 mg, 3.14 mmol) in DCM (5 mL) at room temperature was added TFA (5 mL). The mixture was stirred at room temperature for 2 hours then concentrated to dryness. The crude was diluted with EtOAc, washed with aqueous NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated to yield (3R,5R)-5-(3-fluorophenyl)pyrrolidin-3-ol (I-32), which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:31][CH3:32].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:14]([S:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:27][CH2:26]3)=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: COc1cc(C(C)(C)c2cnc(SCC3CCNCC3)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCC3CCN(S(C)(=O)=O)CC3)n2-c2ccc(F)cc2)ccc1Cl
Yield: 74.6 %

Procedure:
To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)piperidine (0.154 g, 0.33 mmol) and triethylamine (0.089 mL, 0.65 mmol) in DCM (2 mL) was added mesyl chloride (0.027 mL, 0.34 mmol). After 2 h the reaction was concentrated in vacuo and purified by column chromatography, using Hex:EtOAc as eluents, to afford the title compound (0.136 g) as a white solid. MS (EI) m/z 552 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C@@H:26]([CH2:27][C:28]([O:30]CC)=[O:29])[C@H:25]([CH3:33])[C:24]([C:34]([F:37])([F:36])[F:35])=[N:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.C(Cl)(=O)C.Cl.FC1C=CC(OC)=CC=1N1CCC(OC2C=CC(N3[C@@H](CC(O)=O)[C@H](C)C(C(F)(F)F)=N3)=CC=2)CC1.B(Br)(Br)Br>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[C@@H:26]([CH2:27][C:28]([OH:30])=[O:29])[C@H:25]([CH3:33])[C:24]([C:34]([F:35])([F:36])[F:37])=[N:23]3)=[CH:20][CH:21]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(OC2CCN(c3cc(O)ccc3F)CC2)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(F)c(N2CCC(Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)cc3)CC2)c1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)Cl
Product: C[C@@H]1C(C(F)(F)F)=NN(c2ccc(OC3CCN(c4cc(O)ccc4F)CC3)cc2)[C@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2-((4S,5S)-1-(4-((1-(2-fluoro-5-hydroxyphenyl)piperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of EtOH (0.86 mL) was added acetyl chloride (0.18 mL, 2.6 mmol) to generate anhydrous HCl. After addition, the mixture was warmed to room temp, and 2-((4S,5S)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (Example 1, 0.044 g, 0.086 mmol) was added. The mixture was stirred at rt for 1.5 h. The reaction mixture was evaporated to dryness. The residue was dissolved in CH2Cl2 (0.6 mL) and was cooled to −78° C., and BBr3 (0.8 mL, 8.46 mmol) was added. The reaction mixture was stirred for 2 h, and was warmed to −40° C. overnight. The reaction solution was poured over ice and, after 30 min agitation, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 85 mg of a yellow oil that was purified via silica chromatography to give 25 mg of desired product as a clear oil. Anal. Calc'd for C26H29F4N3O4: 523.21, LCMS obs. [M+H]=524.1.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35]Cl)=[N:33][CH:34]=1>CN(C)C=O>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)=[N:33][CH:34]=1
Reactant: ClCc1ccc(Cl)cn1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(Cl)cn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridine-3-yl)-isoxazole-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (20 mg, 0.12 mmol) described in Manufacturing Example 63-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), and stirred for 1 hour at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (41.1 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:35])=[CH:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][C:26]=1[CH3:35])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(OC(C)C)ncc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(OC(C)C)ncc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 5-bromo-2-isopropoxy-4-methyl-pyridine (Intermediate 28) in analogy to Example 1a): MS (ISP): 453.1 and 455.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]([NH2:30])[CH3:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:30]([CH:28]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:16]([Cl:15])[CH:17]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1cnc(OCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 63 %

Procedure:
The title compound is prepared in 63% yield (146 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (165 mg, 0.57 mmol, Amine-8, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[N:5]=1.CO.O.[NH2:25]N>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]=[C:4]([NH:3][NH2:25])[CH2:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[CH:17]=1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 0.67 h

Procedure:
To a suspension of 3.4 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine dihydrochloride in 60 parts by volume of methanol is added 1.25 parts of 80% hydrazine hydrate. The suspension is stirred for 40 minutes, diluted with water and extracted with methylene chloride. The extract is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from a mixture of methylene chloride and benzene to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as colorless prisms. Melting point: around 170° C (browning), 202° C to 204° C (decomposition).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)C[CH2:4][CH2:3][CH2:2]1.CC1[O:28][N:27]=C(N)C=1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:2]=[C:3]([CH3:4])[O:28][N:27]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1cc(N)no1
Product: Cc1cc(Nc2nc(NCc3ccccn3)nc(C)c2C)no1

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 5-methylisoxazol-3-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.06 (s, 3H), 2.35 (s, 3H), 4.75 (d, J=2.8 Hz, 2H), 5.92 (bs, 1H), 6.54 (s, 1H), 7.18 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.5 Hz, 1H), 8.59 (d, J=4.0 Hz, 1H); MS (ESI) m/z 311.5 (M+1)+.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>C(OCC)(=O)C>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:27][CH2:28]2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To tetrahydrofuran (120 mL) were added 4-bromobenzoyl chloride (25 g), (4-chlorophenyl)piperidin-4-ylmethanone hydrochloride (30 g) and 1N aqueous sodium hydroxide solution (250 mL), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was recrystallized to give the title compound (46 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:18]=[CH:17][C:11]([C:12](=[CH2:16])[C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=1)(O)=[O:6]>>[Cl:3][C:5]([C:8]1[CH:18]=[CH:17][C:11]([C:12](=[CH2:16])[C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: C=C(C(N)=O)c1ccc(C(=O)O)cc1
Product: C=C(C(N)=O)c1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 50 cc. of thionyl chloride and 0.05 moles of p-carboxyatropamide is heated at reflux on the steam-bath for 1/2 hour. The reaction is concentrated in vacuo to give p-chlorocarbonylatropamide suitable for use in the following step.
Reaction SMILES: [C:1]([C:5]1[NH:14][C:8]2=[CH:9][N:10]=[C:11]([NH2:13])[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:13][C:11]4[CH:12]=[C:7]5[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[NH:14][C:8]5=[CH:9][N:10]=4)=[O:28])[CH2:25][CH2:26]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: CC(C)(C)c1cc2cc(N)ncc2[nH]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ncc2[nH]1
Reaction time: 16 h
Yield: 665.7 %

Procedure:
2-tert-Butyl-1H-pyrrolo[2,3-c]pyridin-5-amine (325 mg, 0.158 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (300 mg, 1.58 mmol) were dissolved in acetonitrile (10 mL) containing triethylamine (659 μL, 0.470 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (608 mg, 1.60 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 hours during which time a large amount of precipitate formed. The reaction mixture was filtered and the filtercake was washed with acetonitrile and then dried to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (397 mg, 67%). ESI-MS m/z calc. 377.2, found; 378.5 (M+1)+; Retention time 1.44 minutes. 1H NMR (400 MHz, DMSO) 11.26 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.13 (d, J=1.5 Hz, 1H), 7.04-6.98 (m, 2H), 6.20 (d, J=1.0 Hz, 1H), 6.09 (s, 2H), 1.49-1.45 (m, 2H), 1.38 (s, 9H), 1.12-1.08 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([N:7]1[C:11]2=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:15]=[C:10]2[C:9]([NH2:25])=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)=[C:27]=[O:28].O>CC(N(C)C)=O>[C:3]([N:7]1[C:11]2=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:15]=[C:10]2[C:9]([NH:25][C:27]([NH:26][C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:33][CH:34]=2)=[O:28])=[N:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CN1CCN(c2ccc(N=C=O)cc2)CC1
Reactant: CC(C)(C)n1nc(N)c2cc(Sc3cc(F)cc(F)c3)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCN(c2ccc(NC(=O)Nc3nn(C(C)(C)C)c4ncc(Sc5cc(F)cc(F)c5)cc34)cc2)CC1
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
0.048 g (1.19 mmol) of sodium hydride is added at 0° C. to 0.200 g (0.598 mmol) of 1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine dissolved in 10 ml of anhydrous dimethylacetamide. The reaction is left under stirring for 10 minutes. 0.130 g (0.598 mmol) of 1-(4-isocyanatophenyl)-4-methylpiperazine is then added at 0° C. The mixture is left under stirring for 3 hours at room temperature. The reaction is treated by adding 20 ml of water drop by drop at 0° C. and then is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The product is purified by silica chromatography to yield 0.150 g (yield=45%) of 1-(1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea in the form of a light brown solid.