Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:11]2[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8](=[O:16])[NH:7][C:6]=2[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[F:26])[N:3]=1.C(Br)(Br)[Br:28]>>[Br:28][C:2]1[C:11]2[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8](=[O:16])[NH:7][C:6]=2[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[F:26])[N:3]=1
Reactant: BrC(Br)Br
Reactant: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)c(C(F)(F)F)nc12
Product: O=c1[nH]c2nc(SCc3cccc(F)c3F)nc(Br)c2nc1C(F)(F)F

Procedure:
The sub-titled compound was prepared from the product of example 37, step (a) (1.5 g) and bromoform (30 ml) using the method of Example 3, step (b).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]1[C:21]2=[N:22][CH:23]=[C:24]([CH:26]=[CH2:27])[CH:25]=[C:20]2[CH:19]=[CH:18]1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:24]3[CH:25]=[C:20]4[CH:19]=[CH:18][N:17]([CH3:16])[C:21]4=[N:22][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc2c(ccn2C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnc3c(ccn3C)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-methyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[F:18])=O)(C)(C)C>C(OCC)(=O)C>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]([F:16])[C:10]([NH2:9])=[C:11]([F:18])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1c(F)cc(Cl)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.7 %

Procedure:
A saturated solution of hydrogen chloride in ethyl acetate (4 ml) was added to N-t-butoxycarbonyl-4-chloro-2,6-difluoroaniline (330 mg, 1.3 mmol) and the mixture stirred at ambient temperature for 2 hours. The precipitate was collected by filtration to give 4-chloro-2,6-difluoroaniline hydrochloride (140 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:32]2[CH2:38][CH:37]([N:39]([CH3:41])[CH3:40])[C:34]3([CH2:36][CH2:35]3)[CH2:33]2)[C:5]([F:31])=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[CH:7]=1>CO.[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([N:32]2[CH2:38][CH:37]([N:39]([CH3:41])[CH3:40])[C:34]3([CH2:36][CH2:35]3)[CH2:33]2)[C:5]([F:31])=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[CH:7]=1
Reactant: CN(C)C1CN(c2cc(Cl)cc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)CC12CC2
Agent: [Rh]
Solvent: CO
Product: CN(C)C1CN(c2cc(Cl)cc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC12CC2
Reaction time: 8 h
Yield: 56.1 %

Procedure:
[(2R)-3-(2-{5-Chloro-3-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-2-fluorophenyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (300 mg, 0.51 mmol) was dissolved in 5 mL of MeOH. 5% Rhodium on Alumina (240 mg) was added, and the contents were stirred under a hydrogen balloon overnight. The contents were then filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The resulting crude product was purified via reverse phase HPLC to provide [(2R)-3-(2-{5-chloro-3-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-2-fluorophenyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (single unknown diastereomer) (142 mg, 56%). LCMS: (M+H)+: 498.3.
Reaction SMILES: O.NN.[CH2:4]([O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)[CH2:5][CH3:6]>CCO>[CH2:4]([O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)[CH2:5][CH3:6]
Reactant: CCCO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCO[C@H]1CC[C@H](N)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Hydrazine hydrate (1.76 g, 55 mmol) was added to a solution of trans-2-(4-propyloxycyclohexyl)-isoindole-1,3-dione (7.90 g, 27.5 mmol) in absolute EtOH (100 mL). The reaction was stirred at 50° C. for 3 h before the reaction mixture was filtered. The solvent was removed in vacuo and Et2O (250 mL) was added after stirring for 30 min the solid was filtered off and the filtrate was added 150 mL 1N HCl, the phases were separated and the aqueous phase was washed with Et2O (150 mL) before 10 N NaOH was added (until pH=11-12). The aqueous phase was extracted with EtOAc (200 mL+2×100 mL) and the organic fractions were collected and dried (MgSO4) to give 3.11 g (72%) of trans-4-propoxy-cyclohexylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[N:10]1([CH:16]([CH3:20])[C:17](O)=[O:18])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl>C(Cl)Cl.[Cl-].[Na+].O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17](=[O:18])[CH:16]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:20])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C(=O)O)N1CCOCC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)NNc1ccc(F)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (1.62 g, 12.8 mmol), 2-(morpholin-4-yl)propanoic acid (Enamine, 2.50 g, 12.8 mmol), HOBt.H2O (196 mg, 1.28 mmol) and Et3N (2.14 mL, 15.3 mmol) in DCM (50 mL) was added EDC (2.94 g, 15.3 mmol) and the brown solution stirred at RT for 16 h. Water (20 mL) and brine (20 mL) were added, and the mixture shaken. The aqueous layer was extracted with DCM (20 mL), then the combined organics were passed through a hydrophobic frit and concentrated in vacuo to give the title compound as a brown foam (3.43 g, >99%). LCMS (Method 3): Rt 0.44 min, m/z 269 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH3:10].[CH2:12](O)[CH:13](C)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH3:10])[CH:13]([CH3:14])[CH3:12]
Reactant: CC(C)CO
Reactant: CCCSCCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCSCCCC(=O)OCC(C)C
Reaction time: 14.5 h

Procedure:
Into a 25 mm micro flask equipped with spin bar, hot plate (having built in magnetic stirrer), reflux condenser and thermometer are placed 5 grams (0.0284 moles) of methyl-4-(propylthio)butyrate; 8.4 grams (0.1136 moles) of isobutanol and 0.05 grams of para-toluene sulfonic acid. The reaction mass is heated to reflux and maintained at reflux with stirring for a period of 14.5 hours. At the end of the refluxing, the reaction mass is cooled and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: C([S:4][CH:5]([CH2:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=O)C.O.NN>C(OCC)C.C(O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([CH2:9][CH:5]([SH:4])[C:6]([OH:8])=[O:7])=[O:18])=[CH:16][CH:15]=1
Reactant: CC(=O)SC(CC(=O)c1ccc(Cl)cc1)C(=O)O
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: O=C(CC(S)C(=O)O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a solution of 2.87 g of 2-acetylthio-3-(4-chlorobenzoyl)propionic acid in 50 ml of diethyl ether was added dropwise a solution of 0.95 g of 80% hydrazine hydrate in 5 ml of ethanol under ice-cooling with stirring over a period of 30 minutes. The mixture was stirred for a further 30 minutes. The reaction solution was washed with water and dried over magnesium sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was purified by silica gel column chromatography using a mixture of hexane and diethyl ether as an eluent and recrystallized from the same mixture to give 1.01 g of 3-(4-chlorobenzoyl)-2-mercaptopropionic acid.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:26])[CH2:23][CH:24]=O)=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][NH2:28].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl.C([O-])(O)=O.[Na+]>CO.CC(O)=O>[C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:26])[CH2:23][CH2:24][NH:28][CH3:27])=[N:18]3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Product: CNCCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a solution of compound 18 (190 mg, 0.435 mmol) in MeOH (1 mL) were added methyl amine (0.04 mL, 0.462 mmol), HOAc (0.005 mL), and NaBH(OAc)3 (200 mg, 0.943 mmol). The reaction was stirred at 25° C. for 20 h. After the reaction was complete, 1 N HCl (0.1 mL) was added to the reaction mixture and then neutralized with saturated aq. NaHCO3. The resulting mixture was extracted with EtOAc, and the organic layers were pooled, washed with brine, and dried over Na2SO4. Solvent was removed in vacuo to afford 19 (160 mg, 0.355 mmol, 81%) as a colorless oil, which was used without further purification. MS-ESI (m/z): [M+H]+ calculated for C19H20BrN2O4S, 451.03 (79Br) and 453.03 (81Br); found 450.89 (79Br) and 453.01 (81Br).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[N+](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CCOC(=O)C1=Nc2ccccc2C1=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccccc2c1OCC1COC(C)(C)O1
Temperature: 85 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Rhodium acetate dimer (30 mg) was added to a solution of solketal (0.87 ml) and ethyl 3-diazoindole-2-carboxylate (3 mg) in dichloroethane (10 ml), and stirred at 85° C. for 3 hours. The reaction was concentrated in vacuo and the residue purified by column chromatography using a gradient of 0% to 20% ethyl acetate:iso-hexane as eluent to afford the product as a pale yellow solid (435 mg, 97%); NMR d (CD3SOCD3) 1.27-1.38 (m, 9H), 3.88 (m, 1H), 4.11 (m, 3H), 4.30 (q, 2H), (m, 1H), 7.01 (t, 1H), 7.24 (t, 1H), 7.36 (d, 1H), 7.65 (d, 1H), 11.27 (s, 1H); M/z (+) 320.3 (MH+).
Reaction SMILES: CON(C)[C:4](=[O:23])[CH:5]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[S:17][CH2:16][CH2:15][C:14]2([CH3:22])[CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:21][C:14]1([CH3:22])[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:4]=[O:23])[CH:12]=2)[S:17][CH2:16][CH2:15]1
Reactant: CCCCCC(C(=O)N(C)OC)c1ccc2c(c1)C(C)(C)CCS2
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCC(C=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
0.49 g of (RS)-N-methoxy-N-methyl-2-(4,4-dimethyl-thiochroman-6-yl)-heptanoic amide was dissolved in 5 ml THF and treated with 1.6 ml of 1M lithium aluminium hydride solution in THF at −40° C. The mixture was stirred at −40° C. for 30 min. then allowed to warm to room temperature over 1.5 hour. The mixture was cooled back to −40° C. and 3.5 ml of 20% aqueous KHSO4 solution was added over 5 min. The mixture was stirred at room temperature for one hour. The reaction mixture was partitioned in 100 ml ethyl acetate/50 ml water and the phases were separated. The aqueous phase was extracted with three portions of 15 ml of ethyl acetate. The combined organic extracts were washed with one portion of 25 ml of water, one portion of 25 ml of 1 N hydrochloric acid, one portion of 25 ml of saturated aqueous sodium bicarbonate solution and one portion of 25 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo, giving 0.35 g of the titled compound which was used without purification. 1H NMR (CDCl3): 9.61 (d, J=2.2 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.86 (dd, J=8.1, 2.0 Hz, 1H), 3.45-3.35 (m, 1H), 3.05-3.00 (m, 2H), 2.10-1.90 (m, 3H), 1.70-1.50 (m, 1H), 1.32 (s, 6H), 1.35-1.20 (m, 6H), 0.86 (br.t, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[N:11]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[C:3]1=O.Cl.O>C1COCC1>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]2[N:11]3[C:10]4[C:9]([C:13]=2[CH2:14]1)=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]([CH3:23])[CH2:3][C:2]3([CH3:1])[CH3:25])=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)C(=O)N4C)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)CN4C)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
To a solution of ethyl 1,1,3-trimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (240 mg, 0.7 mmol) in THF (20 mL) at 25° C. was added BH3/THF complex (0.7 mL, 0.7 mmol). The mixture was stirred at 80° C. for 5 hours then cooled to rt and added 6N HCl (10 mL) with stirred for another 1 hr. About 30 mL of H2O was added and then was extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to give ethyl-1,1,3-trimethyl-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as an oil (152 mg, 66%). MS [M+H]+327. 1H NMR (CDCl3, 300 MHz) δ 7.01 (t, 1H, J=7.7 Hz), 6:97 (d, 1H, J=7.7 Hz), 6.41 (d, 1H, J=7.7 Hz), 4.68 (s, 2H), 4.23 (m, 2H), 3.84 (m, 2H), 3.11 (m, 2H), 2.99 (s, 3H), 1.54 (s, 6H), 1.27 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [OH:1][C@H:2]([CH2:26][OH:27])[CH2:3][NH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1.[CH3:28][O-:29].[Na+].CO>C(=O)(OCC)OCC>[OH:27][CH2:26][C@H:2]1[O:1][C:28](=[O:29])[N:4]([C:5]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:23])[F:24])[NH:11][C:12]3=[O:15])=[CH:7][CH:6]=2)[CH2:3]1
Reactant: C[O-]
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@H](O)CO)cc12
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CO
Product: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 105 °C
Reaction time: 13 h
Yield: 78 %

Procedure:
The 7-((S)-2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (281.9 mg, 0.745 mmol) obtained in step A was suspended in diethyl carbonate (2.93 ml), and thereafter, a 28% sodium methoxide-methanol solution (117 μl) was added thereto. The obtained mixture was stirred at 105° C. for 13 hours. Thereafter, diethyl carbonate was distilled away under reduced pressure. The obtained residue was dissolved in methanol (15 ml), and the obtained solution was stirred under heating to reflux for 10 minutes. Thereafter, the reaction solution was concentrated, and a saturated ammonium chloride aqueous solution was then added to the residue, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1 to 20:1), so as to obtain 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (233.8 mg; yield: 78%).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C([O:35][N+:36]([O-])=[O:37])C(C)C.C(O)(=O)C>C(O)(C)(C)C.ClCCl>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:36]([O-:37])=[O:35])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: CC(C)CO[N+](=O)[O-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium tert-butoxide (7.6 g, 67.8 mM), (20S)-20-hydroxymethylpregn-4-en-3-one (6.6 g, 20 mM) in tert-butanol is heated at reflux temperature for 60 minutes under an argon atmosphere. Isobutylnitrate (2.34 ml, 20 mM) is then added in one continuous portion. After 20 minutes of further refluxing, the reaction vessel is cooled to room temperature. Acetic acid (10 ml) is then added, and the reaction vessel stirred for 18 hours, after which the combination is diluted with dichloromethane (200 mL). The solids are removed, washed, and recombined with the washing residue and subsequently purified as described in Example 1 to give crystallized (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[I:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.O>ClCCl>[C:1]([N:15]1[CH:14]=[C:13]([I:12])[CH:17]=[N:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Ic1cn[nH]c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1cc(I)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Acetyl chloride (38.2 mL, 1.07 equiv) and triethylamine (86 mL, 1.2 equiv) were added at 0° C. to a solution of 4-iodo-1H-pyrazole (100 g, 0.515 mol) in dichloromethane (1 L). The mixture was stirred overnight at room temperature. The reaction mixture was poured into water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and filtered. The residue obtained by concentration was purified by silica gel column chromatography (Hexane/EtOAc 20:1 to 1:1) to give N-acetyl 4-iodo-1H-pyrazole as a solid (110 g, 91%).
Reaction SMILES: [OH:1]C1C2C(=CC=CC=2)C(O)=CC=1C(O)=O.[OH-].[Na+].BrC(CC(OCC)=O)C(OCC)=O.C(NCCCC)CCCCCCCCCCC.[CH:48]1([N:54]=[C:55]=[N:56][CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>CN(C=O)C.O1CCOCC1>[CH:57]1([NH:56][C:55](=[O:1])[NH:54][CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Agent: CCCCCCCCCCCCNCCCC
Agent: CCOC(=O)CC(Br)C(=O)OCC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3.5 h

Procedure:
0.05 mole of 1,4-dihydroxy-2-naphthoic acid was dissolved in 70 ml of DMF, and 10 ml of a 40% aqueous solution of sodium hydroxide was added dropwise to the solution while introducing nitrogen gas. Then, 0.05 mole of diethyl α-bromo-succinate dissolved in 15 ml of DMF was added dropwise, and the reaction was conducted at 50° C. for 3 to 4 hours under agitation. After completion of the reaction, the reaction mixture was poured into ice-hydrochloric acid, and crystals were recovered by filtration and recrystallized from acetonitrile to obtain a compound having a melting point of 176° C. Then, 0.01 mole of the so obtained compound and 0.01 mole of n-dodecylbutylamine were dissolved in 60 ml of dry dioxane, and 0.01 mole of dicyclohexylcarbodiimide was added to the solution and the reaction was carried out at 50° C. for about 30 minutes. After completion of the reaction, the reaction mixture was filtered and dicyclohexyl urea formed as a by-product was removed. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain a compound having a melting point of 68° C. (the yield being 35%). From results of the elementary analysis and the like, it was confirmed that the so obtained compound was the compound (4) illustrated above.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:8]([N:10]2[CH:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC=C)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCOCC1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:6][C@H:7]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCOC(=O)N1CCC(C(=O)Nc2ncccn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ncccn1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
Pd(Ph3P)4 (4.63 mg, 4.01 μmol) was added to a solution of 2-propen-1-yl 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-[(2-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (32 mg, 0.057 mmol) and morpholine (15.87 μl, 0.182 mmol) in dichloromethane (DCM) (0.8 ml). The mixture was stirred at ambient temperature for 15 min. The solvent was removed to give a residue which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-N-2-pyrimidinyl-3-pyrazolidinecarboxamide (13 mg, 0.027 mmol, 60% yield). MS (ES+) m/z 475.1 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14](O)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].[F:39][C:40]([F:46])([F:45])[C:41]1([NH2:44])[CH2:43][CH2:42]1>>[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:44][C:41]3([C:40]([F:46])([F:45])[F:39])[CH2:43][CH2:42]3)=[O:15])=[N:12][CH:13]=2)[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)nc5)C4)c3)ncnc21
Reactant: NC1(C(F)(F)F)CC1
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(c2ccc(C(=O)NC3(C(F)(F)F)CC3)nc2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 12, Step 3 starting from 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylic acid (Example 12, Step 2) and 1-(trifluoromethyl)cyclopropanamine (Oakwood Products, Inc., Cat. #: 038175). LCMS (M+H)+: m/z=508.2. 1H NMR (400 MHz, DMSO-d6): δ 12.69 (br, 1H), 9.12 (s, 1H), 9.11 (d, J=2.9 Hz, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.95 (d, =2.7 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.84-7.80 (br, 1H), 7.26 (dd, J=2.1, 1.3 Hz, 1H), 7.11 (dd, J=8.7, 2.8 Hz, 1H), 4.70 (d, J=9.1 Hz, 2H), 4.44 (d, J=9.2 Hz, 2H), 3.80 (s, 2H), 1.28 (m, 2H), 1.17 (m, 2H).