Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:13]=[C:14]([C:18]#[C:19][CH2:20][OH:21])[CH:15]=[CH:16][CH:17]=1.C(OCC)(=O)C.[I:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[I:30][C:31]1[CH:36]=[CH:35][C:34](/[C:18](/[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:22])([F:23])[F:10])[CH:13]=2)=[CH:19]\[CH2:20][OH:21])=[CH:33][CH:32]=1
Reactant: Ic1ccc(I)cc1
Reactant: OCC#Cc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC/C=C(\c1ccc(I)cc1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (90 mg, 1.67 mmol) was added to 1M solution of lithium aluminum hydride in tetrahydrofuran (33 mL, 33 mmol) under argon. The mixture was cooled to 0° C. and a solution of the above alcohol (6.7 g, 33.5 mmol) in tetrahydrofuran (25 mL) was added over 10 min. The reaction was stirred at 0° C. for 3 h; dry ethyl acetate (10 mL, 103 mmol) was added and the whole mixture was stirred at ambient temperature for 15 min. A degassed solution of 1,4-diiodobenzene (13.25 g, 40.1 mmol) in dry tetrahydrofuran (25 mL), anhydrous zinc chloride (2.73 g, 20.0 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.692 g, 0.66 mmol), and tri(2-furyl)phosphine (0.854 g, 3.6 mmol) were added; the mixture was degassed and then was heated at 60° C. for 15 h under argon. The suspension was cooled down; methanol (16 mL) was added and the mixture was stirred for additional 1 h. The reaction was diluted with ether (350 mL) and saturated aqueous solution of ammonium chloride (9 mL) was added. The mixture was filtered through a paddle of silica gel and the paddle was thoroughly washed with ether (100 mL). The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 5:1) affording (E)-3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)prop-2-en-1-ol as solidifying oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[I:11]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([I:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: II
Reactant: COc1ccc(F)c(Cl)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(Cl)c(F)cc1I
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a solution of 3-chloro-4-fluoroanisole (4.69 g, Lancaster) in chloroform (250 mL) was added silver trifluoroacetate (23.2 g, Aldrich) followed by iodine (15.8 g, Aldrich) in several portions. The reaction mixture was stirred for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried and concentrated. The crude product was purified by crystallization from ether/petroleum ether to give 5-chloro-4-fluoro-2-iodoanisole (5.0 g). MS (M+H)+, 285.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>CO>[NH2:20][C:21]1[CH:22]=[C:23]([NH:24][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cccc(N)c1
Solvent: CO
Product: Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Temperature: 70 °C

Procedure:
N4-(3,4-Ethylenedioxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.18 mmol) was dissolved in dry MeOH (1 ml), to it was added 3-aminoaniline (163 mg, 1.2 mmol) and the mixture was refluxed for 4 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2-(3-aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.66 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=2.1 Hz), 7.09 (t, 1H, J=2.1 Hz), 6.80-6.90, (m, 1H), 6.69 (d, 1H, J=8.1 Hz), 6.57 (m, 1H), 6.20 (m, 1H), 6.60 (m, 1H), 4.10 (m, 4H); LCMS purity: 90.7%; MS (m/e): 354.13 (M+, 100).
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[C:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])[CH3:14].[OH-].[Na+]>C(O)C.O>[C:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH:24]2[CH2:25][C:26](=[O:28])[CH:27]=[C:3]([OH:4])[CH2:2]2)[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])[CH3:14]
Reactant: CC(=O)C=Cc1c(C)cc(C)c(C(C)=O)c1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1c(C)cc(C)c(C2CC(=O)C=C(O)C2)c1C
Yield: 79 %

Procedure:
Diethyl malonate (10.16 g; 69 mmole) was added to a solution of sodium metal (1.46 g; 63 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(3-acetyl-2,4,6-trimethylphenyl)but-1-en-3-one (14.60 g; 63 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. A 30% aqueous solution of sodium hydroxide (100 ml) was added and the mixture was heated under reflux for a further 41/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was washed with diethyl ether (2×100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The product, 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxycyclohex-2-en-1-one (13.55 g; 84.0%), was obtained as a glassy solid. Proton magnetic resonance spectrum (D6 -dimethylsulfoxide; δ in ppm): 2.20 (3H, s); 2.24 (3H, s); 2.38 (3H, s); 2.45 (3H, s); 2.45-3.40 (4H, m); 3.90 (1H, m); 5.25 (1H, s); 6.85 (1H, s); 11.0 (1H, br. s).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccccc1-c1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3Cl)cs2)CC1
Yield: 67 %

Procedure:
A solution of 2-bromo-4-(2-chlorophenyl)-1,3-thiazole (4.48 g, 16.3 mmol), tert-butyl piperazine-1-carboxylate (6.08 g, 32.6 mmol) and potassium carbonate (2.26 g, 16.3 mmol) in dimethylformamide (50 ml) was stirred at 120° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 4.15 g (66.9%) of the desired product as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.[Cl:51][CH2:52][CH2:53][C:54](Cl)=[O:55]>C(Cl)Cl>[Cl:51][CH2:52][CH2:53][C:54]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:55]
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)CCCl)c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b; 200 mg, 0.44 mmol) in DCM (5 mL) at 0° C. was treated with DIEA (0.19 mL, 1.09 mmol) and cooled in an ice bath at 0° C. The solution was then treated with 3-chloropropionyl chloride (Sigma Aldrich, St. Louis, Mo.; 0.042 mL, 0.44 mmol) dropwise over 10 min and stirred at 0° C. for 30 min then stirred at RT for 2 h. 3 more drops of 3-chloropropionyl chloride was added and the reaction stirred at RT overnight. The reaction mixture was then concentrated, treated with DMSO (8 mL) and purified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated under reduced pressure (rotary evaporator) and the resulting aqueous solution treated with a 10% solution of Na2CO3 and extracted with DCM (4×30 mL), dried over Na2SO4 and concentrated under vacuum overnight affording 3-chloro-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propanamide (57 mg, 0.10 mmol, 23% yield) as a yellow solid. m/z (ESI, +ve ion) 548.0 (M+H)+ in about 65% purity with the mass balance corresponding to the acrylamide. The material was used in the subsequent step without further purification.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].CC(C)([O-])C.[K+].[Br:32][C:33]1[CH:34]=[C:35]([CH:38]=O)[S:36][CH:37]=1.[Br-].[PH4+]>O1CCCC1>[CH:38]([C:35]1[S:36][CH:37]=[C:33]([Br:32])[CH:34]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(Br)cs1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC=Cc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
2.0 grams (10.5 mmols) of (n-pentyl) triphenyl phosphonium bromide was added to 105 ml. of tetrahydrofuran (THF) with stirring. 1.86 gms (15.8 mmol.) of potassium tertiary butoxide was then added to the mixture while stirring at room temperature under an argon atmosphere. After one hour of continued stirring, 2.0 gms (10.5 mmol) of 4-bromo-2-thiophene carboxaldehyde, dissolved in 20 ml of THF, was added to the phosphonium bromide solution. After an additional one hour, the reaction was quenched with water. The organic layer was then separated, washed twice with water and then with brine. After drying over MgSO4 and filtering, the filtrate was concentrated. The concentrate was flushed through a silica plug and eluted with hexane to yield 2.2 gms of a yellow liquid. This liquid included a mixture of cis and trans isomers of the named compound and had the following NMR spectra:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[C:8](Cl)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCN
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of N,N-dimethyl-1,3-propanediamine (1.00 mL, 7.95 mmole) in methylene chloride (20 mL) was added palmitoyl chloride (2.19 g, 7.97 mmole). The reaction mixture was stirred at room temperature over night. The solvent was removed under reduced pressure and the residue titurated with diethyl ether. The precipitate (2.34 g) was filtered and stirred in saturated aqueous sodium bicarbonate over night. The precipitate was filtered to give the title compound (2.00 g, 74%) as a white solid. Analysis calculated for C21H43H2O 1.25H2O: C: 69.46; H: 12.91; N: 7.72. Found: C: 69.30 C: 9.46; H: 12.91; N: 7.72 Found: C: 69.30, H: 12.13; H: 12.13; N: 7.58.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:52]1([CH3:75])[CH:57]=[CH:56][C:55]([S:58]([O:61][CH2:62][CH2:63]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH:14]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]2)[CH2:24]1)=[O:22])[C:10]1[CH:11]=[N:12][CH:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][CH2:63][CH2:62][O:61][S:58]([C:55]2[CH:56]=[CH:57][C:52]([CH3:75])=[CH:53][CH:54]=2)(=[O:60])=[O:59])[CH:9]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2OCCOS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 39.4 %

Procedure:
108.0 mg (0.17 mmol) Tert-butyl 4-{3-[(3R)-3-({1-[5-(2-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8d) were dissolved in 6.7 ml N,N-dimethylformamide. 170 mg (0.52 mmol) cesium carbonate and 96.4 mg (0.26 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 68 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 55 mg (37%) tert-butyl 4-{3-[(3R)-3-{[3-methoxy-1-{5-[2-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([C@@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[C@@H:4]([CH3:7])[CH2:5]O)[CH3:2].S(Cl)([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][CH2:5][C@H:4]([CH3:7])[C@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:1][CH3:2]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CCl
Yield: 88.1 %

Procedure:
The product of Example 32 (2.6 g, 9 mmol) was dissolved in dichloromethane, the mixture was cooled in an ice-water bath, then N, N-dimethylformamide (2 drops) was added and thionyl chloride (0.64 mL, 10 mmol) was added dropwise, after the addition was complete, the reaction was conducted under reflux for 6 hours and quenched by adding water. After the reaction solution was separated, the aqueous phase was extracted with dichloromethane three times, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound 2.4 g, yield: 90%.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1noc2ccccc12)N1CCN(C(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added 2-furoyl chloride (0.0821 ml, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 100 mg (52.9%) of the desired product as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]3([CH2:35][OH:36])[CH2:34][CH2:33][CH2:32]3)[NH:17][CH:16]2[C:37](O)=[O:38])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:46][C@@H:45]([CH2:47][CH2:48][NH2:49])[CH2:44][O:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:46][C@H:45]([CH2:44][OH:43])[CH2:47][CH2:48][NH:49][C:37]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:40])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]2([CH2:35][OH:36])[CH2:32][CH2:33][CH2:34]2)[NH:17]1)=[O:38]
Reactant: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CCC2)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1F
Yield: 54.9 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 115c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.43 g, 3 mmol), HATU (0.67 g, 1.8 mmol) and iPr2NEt (0.86 mL, 4.9 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.32 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:34](I)[CH3:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][N:21]([CH2:34][CH3:35])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the crude 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{[(2-nitrophenyl)sulfonyl]amino}butanoate from the previous step, ethyl iodide (2.59 mL, 32.4 mmol) and K2CO3 (325 mesh, 6.71 g, 48.6 mmol) in DMF (93 mL) was stirred at room temperature for 60 min. The reaction was diluted with H2O (200 mL) and extracted with Et2O (3×). The organic extracts were washed with H2O (2×), dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[CH:4]=1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:16]([F:25])[C:15]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[F:25][C:16]1[C:15]2[O:2][C:1]([C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]([CH3:12])[CH:4]=3)=[N:13][C:14]=2[CH:19]=[CH:18][C:17]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Solvent: CO
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
In methanol (50 ml), 3-formyl-1-methylindole (796 mg, 5.0 mmol), methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.0 mmol) and Molecular Sieves 4A (10 g) were stirred at room temperature for 5 hours and then, at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and iodobenzene diacetate (5.0 mmol) was added thereto. After stirring at room temperature for 14 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (3/1) eluate fractions, methyl 7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolylacetate (860 mg, including impurities) was obtained as a pale brown solid. The compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]([CH3:27])[CH3:26])=[N:10][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]([CH3:27])[CH3:26])=[N:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CN(C)c1ccccc1CSc1nccn1-c1ccc(N)cn1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-n2ccnc2SCc2ccccc2N(C)C)nc1
Reaction time: 2 h

Procedure:
0.26 ml of acetyl chloride is added to a mixture of 0.98 g of 1-(5-amino-2-pyridyl)-2-[2-(dimethylamino)benzylthio]imidazole, 1 ml of triethylamine and 30 ml of methylene chloride under ice-cooling. The mixture is stirred at the same temperature for 2 hours, washed with water and a saturated aqueous sodium bicarbonate solution, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=30:1), and crystallized with isopropyl ether. The crystals are collected by filtration, whereby 0.82 g of 1-(5-acetylamino-2-pyridyl)-2-[2-(dimethylamino)benzylthio]imidazole is obtained.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)#[CH:9].C(N(CC)CC)C.CN(C)C=O>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:7][N:6]1[C:2]([C:9]#[C:8][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:3][CH:4]=[N:5]1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nccc1C#Cc1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 5-iodo-1-methyl-1H-pyrazole (8.00 g), 1-ethynyl-4-(trifluoromethyl)benzene (6.54 g), copper(I) iodide (110 mg), bis(triphenylphosphine)palladium(II) dichloride (1.35 g), triphenylphosphine (504 mg), triethylamine (8.00 mL) and dimethylformamide (70 mL) was stirred at 75° C. for 2 hours. Thereafter, the reaction solution was added to water, and the obtained mixture was then extracted with ethyl acetate. The organic layer was successively washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=85:15 to 75:25), so as to obtain the title compound (7.74 g) in the form of a yellow solid.