Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.O.Cl>C(O)C.[Fe]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)cnc1N
Yield: 102.6 %

Procedure:
To a solution of 2-amino-5-fluoro-3-nitropyridine (0.42 g, 2.3 mmol) and iron powder (1.6 g, 28 mmol) in ethanol (10 ml) were added water (0.5 ml, 28 mmol) and hydrochloric acid (27 μl, 0.32 mmol). The mixture was refluxed for 1 h. An additional amount of iron powder (0.2 g, 3.6 mmol) was added and the mixture was refluxed for 30 min. The reaction mixture was filtered through celite and evaporation under reduced pressure of the solvent gave 0.3 g (100%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:22](OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-4,4-dimethylpentanoic acid (50 mg, 0.204 mmol) and iodomethane (0.102 mL, 1.631 mmol) were dissolved in tetrahydrofuran (2 mL) at 0° C. and sodium hydride (24.46 mg, 0.611 mmol) was added. The reaction was stirred at 0° C. for a half hour and at room temperature overnight. The reaction was cooled to 0° C. and ethyl acetate (1 mL) was added followed by dropwise quenching with water (2 mL). The solvent was removed in vacuo and the crude material was partitioned between ether and water. The ether layer was separated. The aqueous layer was acidified to pH˜5 using 1 N citric acid and extracted with ethyl acetate. The organic layer was washed with 1 N sodium thiosulfate and brine, dried (Na2SO4) and concentrated in vacuo. The compound was purified using a 4 g silica gel cartridge with a gradient of 0-3% methanol/dichloromethane over 20 minutes to give (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.63 (s, 1H), 4.57 (ddd, J=74.4, 9.5, 3.1, 1H), 2.69 (s, 3H), 1.83-1.53 (m, 2H), 1.39 (s, 9H), 0.89 (s, 9H); MS (DSI+) m/z 260 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([F:26])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].N(OC(C)(C)C)=O>CC(O)=O>[F:26][C:19]1[CH:18]=[C:17]2[C:16](=[C:25]3[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]3)[NH:15][S:12](=[O:13])(=[O:14])[C:3]1[C:2]2=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][CH:4]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(cc(F)c3cccnc23)-c2cc(C(F)(F)F)ccc21
Yield: 10.4 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-fluoro-quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Intermediate 276) (200 mg, 0.52 mmol), t-butyl nitrite (0.09 ml, 0.78 mmol) and AcOH (2 ml) gave the title compound (20 mg, 11%) after purification by column chromatography with DCM/MeOH (98:2) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](SC)=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:18][NH2:19])=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CSc1nnc(-c2ccc(Cl)cc2)c(C)n1
Solvent: CCO
Solvent: O
Product: Cc1nc(NN)nnc1-c1ccc(Cl)cc1
Yield: 15 %

Procedure:
A solution of 6-(4-chlorophenyl)-5-methyl-3-methylthio-1,2,4-triazine (32.4 g) and hydrazine hydrate (40.8 g) in ethanol (110 ml) was heated for 2 hours. After cooling, the precipitates were collected by filtration, washed with ethanol, dried and recrystallized from ethanol to give 6-(4-chlorophenyl)-3-hydrazino-5-methyl-1,2,4-triazine (4.54 g).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[C:9]1([C@H:15]([NH:17][C@H:18]([CH2:27][C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[OH-].[Na+].N>O>[C:9]1([C@H:15]([NH:17][C@H:18]([CH2:27][C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])[CH2:19][C:20]([OH:22])=[O:21])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H](N[C@@H](CC(=O)OC(C)(C)C)Cc1cc(F)c(F)cc1F)c1ccccc1
Agent: N
Agent: O=C(O)/C=C\C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@@H](N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F)c1ccccc1
Reaction time: 1 h

Procedure:
tert-Butyl (3R)-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)-butanoate maleate salt [C] (50 g) was stirred in a mixture of water (250 ml) and conc. sulfuric acid (16 ml) at 70° C. for 2 hours. The pH was adjusted to 4.2±0.2 with aqueous sodium hydroxide solution and then to 7.0±0.2 with ammonia solution. Filtered the solid and purified by suspending in water at 25±5° C. for 1 hr. Filtered and dried to yield 31.3 g (94.5% theoretical yield) of titled product [D], m.p. 144° C., purity by HPLC: 98.8%.
Reaction SMILES: [CH3:1][Mg]Br.C[C:5]1([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]>O1CCCC1>[F:20][C:17]([F:18])([F:19])[C:12]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([CH3:1])[OH:11])([OH:21])[C:13]([F:15])([F:14])[F:16]
Reactant: C[Mg]Br
Reactant: CC1(C(O)(C(F)(F)F)C(F)(F)F)CCCCC1=O
Solvent: C1CCOC1
Product: CC1(O)CCCCC1C(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a flame-dried, nitrogen-purged, 250 mL 3-neck roundbottom flask with 50 mL, pressure-equalized addition funnel and stirbar was added 48 mL of methyl magnesium bromide (143 mmol, 2.1 eq., 3 M in ethyl ether). A degassed solution of 18 g methyl 2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)cyclohexanone (IX) (68 mmol, 1 eq.) in 60 mL anhydrous tetrahydrofuran was charged to the addition funnel and added dropwise to the reaction over the course of 1 hour at room temperature. The reaction was stirred at room temperature for 14 hours, after which it was cooled to 0° C. and carefully quenched with dilute hydrochloric acid solution until the pH was less than 5.0. The reaction solution was neutralized with saturated aqueous sodium bicarbonate until the pH was greater than 8. The product was extracted into ethyl ether and the organic phase washed with brine and dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. Crude 1H and 19F NMR indicated only 42% conversion to a single isomer. The reaction was repeated again and the conversion driven to 69% by NMR. The crude product was taken on to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27]C)[CH:21]=4)[CH2:18][C:17](=[O:29])[NH:16][C:15]=3[CH3:30])=[O:13])[CH:9]=2)[NH:4][N:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.O.[OH-].[Na+]>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:19]2[CH2:18][C:17](=[O:29])[NH:16][C:15]([CH3:30])=[C:14]2[C:12]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[Cl:1])=[O:13])=[CH:21][C:22]=1[OH:27]
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]nc(Cl)c3c2)ccc1Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(Cl)c(O)c2)CC(=O)N1
Temperature: 35 °C
Reaction time: 90 h
Yield: 22.1 %

Procedure:
The product of Example 93, Step 5 (75 mg, 0.168 mmol, 1.0 equiv) was cooled to −78° C. in 1.75 mL CH2Cl2 and BCl3 (1.0 M in CH2Cl2, 2.5 mL, 2.526 mmol, 15.0 equiv) was added dropwise. The reaction was warmed to 35° C. and stirred for 90 hours. An additional portion of BCl3 (2.5 mL, 2.526 mmol, 15.0 equiv) in CH2Cl2 was added dropwise and the reaction was stirred for another 96 hours. The reaction mixture was diluted with EtOAc and water and basified to pH 14 with 6N NaOH. The phases were separated, and the aqueous phase was acidified to pH 4 with 6N HCl. The precipitate was filtered and washed with Et2O. The residue was purified by reverse-phase HPLC (10-90% CH3CN/H2O, 0.1% TFA over 18 minutes, retention time 10.55 min) to provide 16 mg (22%) of the title compound as a white solid. MS (ES+) m/e 432 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4](F)[N:3]=1.O.[NH2:12][NH2:13].C(O)CC>ClC>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([NH:12][NH2:13])[N:3]=1
Reactant: NN
Reactant: Fc1cc(F)c(F)nc1F
Agent: CCl
Solvent: CCCO
Solvent: O
Product: NNc1nc(F)c(F)cc1F
Temperature: 80 °C
Yield: 83.8 %

Procedure:
23.2 g of the compound obtained in Step 1 and 37.3 ml of hydrazine monohydrate were added to 100 ml of n-propanol, and the resulting mixture was heated to 80° C. for 2 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 100 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under a reduced pressure to obtain 21.9 g (yield: 83.8%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CCC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Br)c2)c(Cl)c1CC
Product: CCC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(Br)c2)c(Cl)c1CC
Yield: 86.1 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) propionate (50 mg) was coupled with isobutyryl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 50 mg of ethyl(3,5-dichloro-4-[3-bromo-4-isobutyramidophenoxy]phenyl) propionate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 40 mg of 3,5-dichloro-4-(3-bromo-4-isobutyramidophenoxy)phenylpropionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[N:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1.[CH:28]1([N:34]=[C:35]=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[C:35]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:36])[N:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCOc1cccc(Nc2c3cc(Cl)ccc3nn2-c2ccc(Cl)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOc1cccc(N(C(=O)NC2CCCCC2)c2c3cc(Cl)ccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 1.2, [5-chloro-2-(4-chloro-phenyl)-2H-indazol-3-yl]-(3-ethoxy-phenyl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 days under reflux conditions to give the title compound as colorless foam. MS: m/e=523.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5](Cl)=[N:4][CH:3]=1.[CH3:14][O-:15].[Na+]>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5]([O:15][CH3:14])=[N:4][CH:3]=1
Reactant: Cc1cccc2c(Cl)ncc(Br)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)c2c(C)cccc12
Yield: 91.5 %

Procedure:
To a stirred solution of 4-bromo-1-chloro-5-methylisoquinoline (Intermediate-5) (5.0 g, 19.5 mmol) in dry MeOH (100 mL) was added NaOMe (1.3 g, 23.4 mmol) and the reaction mixture was refluxed overnight. Solvent was removed and the resultant crude product was extracted with EtOAc (2×200 mL), washed with water (2×100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to furnished the title compound (4.5 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:4][CH:3]=1
Reactant: COc1ccc(Oc2ncc(Br)cn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Oc2ncc(Br)cn2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
5-Bromo-2-(4-methoxyphenoxy)pyrimidine (2.4 g) was dissolved in methylene chloride (50 ml) and the solution cooled to a temperature of -70° C. Boron tribromide (12.7 g) was added dropwise to the stirred solution, the temperature of the solution being maintained at -65° to -75° C. On completion of the addition the reaction mixture was stirred for a further one hour at a temperature of -65° to -75° C. and then the temperature of the reaction mixture was allowed to rise slowly to room temperature. The reaction mixture was added cautiously, in small portions, to water and the methylene chloride removed by heating the mixture on a water bath. The aqueous suspension was cooled to a temperature of 20° C., the solid was collected by filtration, washed with water and recrystallised from methanol/water to give 4-(5-bromo-2-pyrimidyloxy)phenol (2.1 g) m.p. 178° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:68]([NH2:72])([CH2:70][CH3:71])[CH3:69]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[CH3:11])[N:7]=[C:6]([NH:72][C@H:68]([CH2:70][CH3:71])[CH3:69])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(C(C)(F)F)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(C(C)(F)F)n1
Yield: 86 %

Procedure:
Dissolve 2-chloro-6-(1,1-difluoroethyl)-isonicotinic acid methyl ester (200 mg, 0.85 mmol), palladium (II) acetate (20.0 mg, 0.09 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (56 mg, 0.09 mmol) and cesium carbonate (414 mg, 1.27 mmol) in toluene (3 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen gas. Add (S)-(+)-sec-butylamine (0.10 mL, 1.02 mmol) to the solution under nitrogen and heat the sealed mixture overnight at 100° C. Cool the reaction to room temperature. Dilute with diethyl ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 5:95 ethyl acetate:hexanes) to give the title compound as an oil (86%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1cc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Cl)cn1
Yield: 81.4 %

Procedure:
1.44 g of 4-chloro-1-(chloromethyl)-1H-pyrazole hydrochloride and 1.56 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 30 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.73 g of [(4-chloro-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (19), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:17][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: O=CCc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1cccc(-c2c[nH]c3ccccc23)c1

Procedure:
A solution of 2-(3-chlorophenyl)-acetaldehyde (5.80 g, 37.5 mmol) and phenylhydrazine (6.22 g, 57.5 mmol) in glacial acetic acid (150 mL) was saturated with nitrogen by bubbling N2 through the solution. The solution was then refluxed for about 2.5 hours. Solvent was removed in vacuo and the residue obtained was dissolved in DCM and washed with 1N HCl aqueous solution (2 times), saturated NaHCO3 aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/hexane 1:6. The title compound was obtained as a reddish oil. Yield: 5.30 g, 62%. Rf=0.26 (silica, EtOAc/hexane 1:4).
Reaction SMILES: [CH:1]([N:3]1[CH:9]([CH2:10][NH:11][CH:12]=O)[C:8]2[CH:14]=[CH:15][CH:16]=[C:17]3[CH2:18][CH2:19][N:6]([C:7]=23)[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]1=2)=O.[ClH:24]>O1CCCC1.CO>[ClH:24].[ClH:24].[CH3:12][NH:11][CH2:10][CH:9]1[C:8]2[CH:14]=[CH:15][CH:16]=[C:17]3[CH2:18][CH2:19][N:6]([C:7]=23)[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]1[CH3:1]
Reactant: O=CNCC1c2cccc3c2N(CC3)c2ccccc2N1C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNCC1c2cccc3c2N(CC3)c2ccccc2N1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-[7-formyl-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-ylmethyl]-formamide (8.27 g) in tetrahydrofuran (220 ml) was added borane-dimethylsulfide complex in tetrahydrofuran (2M, 67 ml) at room temperature under nitrogen over a period of 30 minutes. The mixture was stirred at room temperature for 2 hours and thereafter refluxed for 30 minutes. The mixture was cooled to room temperature and treated slowly with methanol to destroy the excess borane. The solvent was removed with a rotary evaporator to afford an oil. This was dissolved in methanol (25 ml) and concentrated hydrochloric acid (8 ml), and the mixture was refluxed for 30 minutes. The mixture was concentrated on a rotary evaporator to dryness (55° C., high vacuum) to afford an oil. The oil was crystallized from a mixture of methanol (small amount) and ether (200 ml) to give 9.27 g of crystals. This solid was recrystallized from hot methanol (25 ml) to give 6.37 g of crystals, m.p. 194°-196.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[NH:26][CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][C:21]4[N:26]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(S(C)(=O)=O)CCO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.11 mmol) in dry DCM (1 ml) was added triethyl amine (46 μl, 0.33 mmol) and methanesulfonyl chloride (26 μl, 0.33 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 50% EtOAc in cyclohexane) to give the title compound (45 mg, 77%). 1H NMR (500 MHz, CDCl3): 8.00 (1H, s), 7.25 (2H, d), 7.19-7.17 (5H, m), 7.11-7.10 (2H, m), 4.95 (1H, s), 4.43 (2H, t), 3.90 (2H, t), 2.55-2.25 (7H, m), 2.06-1.98 (1H, m), 1.82-1.73 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:40][N:41]([CH:43]=[O:44])[OH:42])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:40][N:41]([CH:43]=[O:44])[OH:42])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2nccc(-c3ccccn3)n2)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1nccc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of phenylmethyl (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-3-({[4-(2-pyridinyl)-2-pyrimidinyl]amino}carbonyl)-1-pyrazolidinecarboxylate (32 mg, 0.053 mmol) in methanol (3 mL) was added Pd(OH)2/C (7 mg). The mixture was degassed and then stirred under an H2 atmosphere for 2 h at rt. The catalyst was filtered off. The filtrate was concentrated and the residue was purified by pre-HPLC to provide the title compound (14 mg, 56%). LCMS: (M+H)+: 468.2.
Reaction SMILES: CO[C:3]1C=CC=C(OC)[C:8]=1[C:9]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[OH:30][CH:31]([CH2:40][CH2:41][CH2:42][N:43]([C:48]1[N:53]=[C:52]2[O:54][C:55]([C:61]3[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=3)=[C:56]([C:57](=[O:60])[NH:58][CH3:59])[C:51]2=[CH:50][C:49]=1I)[S:44]([CH3:47])(=[O:46])=[O:45])[C:32]([CH3:39])([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34].B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH2:36]([O:35][C:33](=[O:34])[C:32]([CH3:38])([CH3:39])[CH:31]([OH:30])[CH2:40][CH2:41][CH2:42][N:43]([C:48]1[N:53]=[C:52]2[O:54][C:55]([C:61]3[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=3)=[C:56]([C:57](=[O:60])[NH:58][CH3:59])[C:51]2=[CH:50][C:49]=1[CH:9]1[CH2:8][CH2:3]1)[S:44]([CH3:47])(=[O:45])=[O:46])[CH3:37]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CCOC(=O)C(C)(C)C(O)CCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)C(O)CCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 115 °C

Procedure:
To a solution of S-Phos (0.4 eq., 15 mg), Pd(OAc)2 (0.2 eq., 4.0 mg) and PhMe (3 ml) was added ethyl 3-hydroxy-6-(N-(5-iodo-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)-2,2-dimethylhexanoate (1 eq., 60 mg). A solution of boronic acid (30 eq., 232 mg) and Na2CO3 (2 N aqueous solution, 40 eq., 0.54 ml) was added. The mixture was heated in a sealed tube under nitrogen at 115° C. for 60 min, cooled, and diluted with DCM and water. The aqueous layer was extracted with DCM. Orgnic layers were washed with saturated aqueous Na2CO3 solution and concentrated to yield the crude title compound which was used in next step without purification.