Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=[CH:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:19]([Zn]CC)C.CCCCCCC.ICI>C1(C)C=CC=CC=1>[CH:6]12[CH2:19][CH:5]1[CH2:4][CH2:3][CH:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:1]2[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: CCOC(=O)[C@H]1CCC=CN1C(=O)OC(C)(C)C
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: ICI
Product: CCOC(=O)C1CCC2CC2N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-1-tert-butyl 2-ethyl 3,4-dihydropyridine-1,2(2H)-dicarboxylate (D20) (260 mg, 1.02 mmol) in toluene (5 ml), cooled to −30° C., diethyl zinc 1M solution in heptane (2.04 ml, 2.04 mmol) was added dropwise followed by addition of diiodomethane (0.33 ml, 4.07 mmol) in toluene (1 ml). (During reactant additions the reaction temperature was maintained between −25° C. and −30° C.). The reaction mixture was stirred at −20° C. for 24 hrs. Diethyl zinc 1M solution in heptane (2.04 ml, 2.04 mmol) and diiodomethane (0.33 ml, 4.07 mmol) were added and the reaction left stirring at −20° C. for other 24 hrs. The reaction was quenched with half saturated NaHCO3 (10 ml) and left stirring for 30 min. The white precipitate was filtered off. The organic phase was washed with water (2×20 ml), dried over Na2SO4 and evaporated in vacuo to afford the title compound (D21) (600 mg) used as such without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][CH:20]([OH:24])[CH2:21][C:22]#[CH:23]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:23]#[C:22][CH2:21][CH:20]([OH:24])[CH3:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CCC(C)O
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCC(C)O)cc1
Temperature: 70 °C
Yield: 91.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 4-pentyne-2-ol (0.47 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid methyl ester (578 mg, 92%) as an amber oil: EI-HRMS m/e calcd for C20H26O3 (M+) 314.1881, found 314.1888.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[O:18]=[C:16]([CH3:17])[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(OCC(C)=O)cc1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 16 g of methyl 4-hydroxycinnamate, 14.9 g of bromoacetone, 20 g of potassium carbonate and 150 ml of dimethylformamide, the title compound was obtained as crystals, melting at 117°-118° C. (after recrystallization from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH:20]([CH3:22])[CH3:21]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][N:9]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: Clc1ccc(-c2cc[nH]n2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 3-(5-chloro-2-thienyl)-1H-pyrazole (1 eq, 0.023 mol) and cesium carbonate (1.2 eq, 0.028 mol) in dry N,N-dimethylformamide (50 mL) was added 1-bromo-2-methylpropane (1.1 eq, 0.025 mol) slowly and the mixture was stirred at room temperature for 3 h. After completion of the reaction monitored by TLC, the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude compound was purified by column-chromatography to afford 4.3 g of 3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazole (76% yield).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:29])[CH2:23][C:24]=1[CH2:25][CH:26](Cl)[Cl:27])[CH:20]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:19]2=[O:38])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:29])[CH2:23][C:24]=1[CH:25]=[CH:26][Cl:27])[CH:20]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C:19]2=[O:38])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CS(=O)C12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCl)CS(=O)C12
Yield: 100.2 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2,2-dichloroethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (product 11f) (3.3 g) and triethylamine (0.88 cc) in dry tetrahydrofuran (50 cc) is stirred at 25° C. for 16 hours and the reaction mixture is then diluted with ethyl acetate (200 cc). The organic solution is washed with distilled water (5×60 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 35° C. This yields a product (11e) (3.1 g) in the form of a hard orange foam.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10]([CH:7]1[C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[CH2:9][CH2:8]1)=[O:12])[CH3:19]
Reactant: Cc1cc2c(s1)C(C(=O)O)CC2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2cc(C)sc21
Yield: 81 %

Procedure:
A solution of 19.3 g of 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid and 10 cc of sulfuric acid in 500 cc of ethanol was refluxed for 8 hours then concentrated under reduced pressure to a volume of 100 cc. The residue was diluted with ethyl acetate and stirred with an aqueous solution of sodium bicarbonate. The organic phase was separated, washed with water and dried over sodium sulfate. After evaporation of the solvent under reduced pressure the residue was distilled. 18.2 g (yield=81%) of ethyl-2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylate was obtained. Bp0.7=90° C.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([OH:18])=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[F:22][C:19]([F:20])([F:21])[C:12]1[N:13]=[C:14]([OH:18])[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[N:11]=1
Reactant: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1nc(C(F)(F)F)nc2c1CCNC2
Yield: 76.5 %

Procedure:
To 7-benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (0.47 g, 1.52 mmol) partially dissolved in methanol (20 mL) was added palladium hydroxide on carbon (70 mg, wet, 20% by weight dry basis). The reaction was stirred for 20 hours in a Parr shaker under a pressure of 50 psi hydrogen. The reaction was then filtered through a Celite plug, eluting with methanol (400 mL). The filtrate was concentrated in vacuo to yield 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol as a light beige solid (255 mg, 77% yield). 1H NMR (400 MHz, MeOD) δ ppm 4.09 (s, 2H), 3.48 (t, J=6.32 Hz, 2H), 2.78 (t, J=6.32 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][CH:24]=2)[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[C:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[CH:27][CH:28]=2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(CN(CCc2ccc(Cl)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl 4-((4-chlorophenethyl)(4-(methoxycarbonyl)benzyl)amino)piperidine-1-carboxylate obtained in Step 1 was dissolved in MeOH (5 mL/mmol), NaOH (5 eqs) (as a 0.5 N aqueous solution) was added and the reaction mixture was stirred at room temperature for 15 hours.). pH of the reaction was made neutral by careful addition of 0.5 N HCl, and methanol was removed in vacuo. The precipitated product was filtered off, washed several times with acetone/diethyl ether mixture (1:2 v/v) and dried in the air. It was found to be of sufficient purity to be used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[CH:23]2[CH2:28][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26](O)[CH:25]([CH3:38])[CH2:24]2)=[O:15])[N:13]=1.CCN(S(F)(F)[F:45])CC>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[CH:23]2[CH2:28][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH:26]([F:45])[CH:25]([CH3:38])[CH2:24]2)=[O:15])[N:13]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1CC(c2ccncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)CC(NC(=O)OC(C)(C)C)C1O
Solvent: ClCCl
Product: CC1CC(c2ccncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)CC(NC(=O)OC(C)(C)C)C1F
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of (+/−)-2-(tert-butoxycarbonylamino)-4-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-6-methylcyclohexyl acetate in MeOH (0.03 M) was added potassium carbonate (3.0 equiv.) and the reaction was stirred at room temperature for 3 h. Upon completion, the reaction was partitioned between water and ethyl acetate. The aqueous phase was further extracted 3 more times with ethyl acetate. The organics were combined, dried with brine and sodium sulfate, filtered, and concentrated. Isolated tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate was obtained as an off-white solid in 87% yield. LC/MS=545.2 (M+H), Rt=0.75 min. To a solution of tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in DCM (0.07M) at 0° C. was added DAST (1.0 equiv.) under a nitrogen atmosphere. The reaction was stirred for 1 h, upon which time, 2 more equivalents of DAST were added. After 30 min, the consumption of the starting material was complete. The reaction was quenched by the addition of water, the organic phase was dried with sodium sulfate, and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to afford tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-fluoro-3-methylcyclohexylcarbamate as a clear oil in 60% yield. LC/MS=547.3 (M+H), Rt=0.92 min. The Boc group was removed by treating with 25% TFA in dichloromethane for 2 hours. Upon concentration under vacuo, the crude was purified via semi-prep HPLC. The pure fractions were lyophilized to yield N-(4-((+/−)-3-amino-4-fluoro-5-methylcyclohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as the desired product as the TFA salt in 74% yield. LC/MS=447.0 (M+H), Rt=0.56 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.9 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (200 mg, 0.81 mmol) and potassium carbonate (214 mg, 2.02 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 30 min. This mixture was then treated with 1-bromo-2-methylpropane (0.13 mL, 1.21 mmol) and heated at 60° C. for 5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (2×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1-(6-chloro-1-isobutyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (282.7 mg) as dark yellow solid which was used without further purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Br:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:22][C:23]([F:36])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:13][C:12]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][C:23]([F:35])([F:22])[F:36])=[CH:26][CH:27]=3)[CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]([CH3:14])[CH:11]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(-c2cccc(NC(=O)Cc3ccc(OC(F)(F)F)cc3)c2)n1
Temperature: 70 °C
Yield: 67.6 %

Procedure:
A solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (35 mg, 0.14 mmol) and triethylamine (23 μL, 0.17 mmol) in DMF (0.5 mL) was added in one portion to a stirred solution of 4-trifluoromethoxyphenylacetic acid (31 mg, 0.14 mmol), HBTU (53 mg, 0.14 mmol) and HOBT (19 mg, 0.14 mmol) in DMF (1 mL). The mixture was heated at 70° C. for 24 h and then quenched with aqueous sodium bicarbonate solution. Ethyl acetate was added and the organic phase separated, washed with water (×3), brine, dried (MgSO4) and evaporated. Chromatography on flash silica (50%EtOAc/hexane) gave the title compound as a colourless solid (43 mg, 68%), m.p. 141.2-142.5° C. (EtOAc/hexane).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:38][C:39]([F:50])([F:49])[O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:46][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([O:40][C:39]([F:49])([F:50])[F:38])=[CH:42][CH:43]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(OC(F)(F)F)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-trifluoromethoxybenzylamine, m.p. 145-149° C. MS [(+)ESI, m/z]: 626 [M+H]+ Anal. Calcd for C36H30F3N3O4: C, 69.11; H, 4.83; N, 6.72. Found: C, 69.08; H, 4.95; N, 6.53.
Reaction SMILES: [NH4+]=[S:2].C(O)C.[CH2:6]([N:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([C:20]#[N:21])[N:12]=[C:11]1[N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:7]#[C:8][CH3:9].C(OCC)(=O)C>O>[CH2:6]([N:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([C:20](=[S:2])[NH2:21])[N:12]=[C:11]1[N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C#N)c1C(=O)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(N)=S)c1C(=O)OCC
Temperature: 60 °C

Procedure:
5 ml of an aqueous solution of 50% ammonium sulfide was added to a 20-ml ethanol solution containing 0.80 g of t-butyl 4-[1-(2-butynyl)-4-cyano-5-ethoxycarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was heated at 60° C. for 14 hours. 100 ml of ethyl acetate and 50 ml of water were added to the mixture, and the organic layer was washed successively with 50 ml of water and 50 ml of a saturated sodium chloride solution. The reaction solution was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.58 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: COCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=O)[NH2:36])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>C1COCC1>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=[S:47])[NH2:36])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=S
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
A mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-piperidine-1-carboxylate (2.2 g, 4.0 mmol) and Lawesson's reagent (1.3 g, 3.2 mmol) in dry THF (40 mL) was heated at 50° C. under N2 atmosphere for 1 h. The solvent was removed, and the residue was dissolved in DCM (100 mL). NaOH solution (0.1 N, 100 mL) was added and the mixture was stirred at it for 10 minutes. The organic phase was separated, dried, and concentrated. The residue was purified by silica gel column chromatography (2:1 petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamothioylpiperidine-1-carboxylate (1.6 g, 75%) as white solid. ESI-MS (EI+, m/z): 573 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([NH2:14])[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CNCC=C1c1ccc(F)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: N[C@@H]1CNCC=C1c1ccc(F)cc1
Yield: 59.5 %

Procedure:
To an ethanol solution (1.0 mL) of (S)-2-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-3-yl]isoindoline-1,3-dione (170 mg, 0.402 mmol) synthesized in Reference Synthesis Example 210, hydrazine monohydrate (150 mg, 3.00 mmol) was added and the resultant mixture was stirred under reflux by heating for 2 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue and the resultant mixture was filtered again, followed by concentrating the resultant filtrate under reduced pressure to obtain the title compound (46.0 mg, yield 59%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH2:3]1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:4][CH2:3]1
Reactant: CC1(C)CC=C(c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(c2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(4,4-dimethylcyclohex-1-enyl)-2-nitrobenzene (16.3 g, 70.5 mmol) prepared in Example (3a), 10% palladium on carbon (1 g, wet) and ethyl acetate (100 mL) was stirred for 14 hours and 30 minutes under a hydrogen atmosphere at atmospheric pressure and room temperature.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:11](O)[O:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[NH2:27][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:29][SH:30].Cl.O>CCO>[CH3:34][O:33][C:31]([CH:28]1[CH2:29][S:30][CH:11]([CH2:12][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])([C:9]([OH:10])=[O:14])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:27]1)=[O:32]
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CC(O)OC1=O
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)C1CSC(CC(NC(=O)OC(C)(C)C)(C(=O)O)c2ccccc2)N1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of compound 14 (5.6 g, 19.1 mmol) in EtOH (80 mL) was added 1 M aq. NaHCO3 solution (19.1 mL, 19.1 mmol), followed by the addition of L-Cys-OMe.HCl (3.3 g 19.1 mmol). The pH value of the resulting mixture was adjusted to 6.5 with 1 M NaHCO3 solution. After stirring overnight, the mixture was poured into water, extracted with ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated to afford product 15 (7 g, 51.1%). MS (M+1): 411. This product was used in the next step without further purification.