Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[O:21]1[CH2:26][CH2:25][O:24][C:23]2[CH:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:30][C:22]1=2>ClCCl>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:31]([C:28]2[CH:29]=[CH:30][C:22]3[O:21][CH2:26][CH2:25][O:24][C:23]=3[CH:27]=2)(=[O:32])=[O:33])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)OCCO3)CC1
Temperature: 0 °C
Yield: 100.2 %

Procedure:
1-Boc-piperazine (250 mg, 1.34 mmol, 1 equiv.) was dissolved in dichloromethane (2.5 mL) and cooled in an ice bath under nitrogen atmosphere. Triethylamine (375 μl, 2.68 mmol, 2.0 equiv.) was added followed by portionwise addition of 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride (346 mg, 1.48 mmol, 1.1 equiv.). The reaction was stirred in the ice bath for one hour, then quenched with saturated aqueous ammonium chloride (˜3 mL). The organic layer was washed twice with saturated ammonium chloride, once with brine, dried over sodium sulfate and concentrated in vacuo and then purified on silica gel chromatography using a 95/5-5/95, hexane/EtOAc (v/v) gradient to give 1-boc-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)piperazine as a white powder (516 mg, 89% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].C(N(CC)C(C)C)(C)C.[CH2:24]([O:31][C:32](ON1C(=O)CCC1=O)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:24]([O:31][C:32]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(CN)cc1O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Methyl 4-aminomethylsalicylate hydrochloride (5.04 g, 23.2 mmoles) was suspended in chloroform (80 mL) and N,N-diisopropylethylamine (4.10 mL, 23.5 mmoles) and N-(benzyloxycarbonyloxy)succinimide (6.48 g, 26.0 mmoles) were added. The reaction mixture was stirred at room temperature for 4 hours, during which time all solids dissolved. The reaction mixture was then extracted with 1N aqueous hydrochloric acid (100 mL), water (75 mL), and saturated aqueous sodium chloride (50 mL). The chloroform solution was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give a white solid. The product was crystallized from ethyl acetate:hexanes to afford 6.17 g (84% yield) of methyl N-(benzyloxycarbonyl)-4-aminomethylsalicylate (m.p. 91°-92° C., open capillary, uncorrected).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:10]1[N:11]=[N:12][N:13]([CH2:15][C:16]2[CH:47]=[C:19]3[N:20]=[C:21]([CH3:46])[C:22]([C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38]CC)=[O:37])=[C:23]([N:24]4[CH2:29][CH2:28][C:27]([O:31][CH2:32][CH:33]=C)([CH3:30])[CH2:26][CH2:25]4)[N:18]3[N:17]=2)[CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]=C.[OH-].[Na+]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.CO>[C:42]([O:41][C@@H:35]([C:22]1[C:21]([CH3:46])=[N:20][C:19]2=[CH:47][C:16]3=[N:17][N:18]2[C:23]=1[N:24]1[CH2:29][CH2:28][C:27]([CH3:30])([O:31][CH2:32][CH:33]=[CH:2][CH2:1][O:4][CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:10]2[N:11]=[N:12][N:13]([CH:14]=2)[CH2:15]3)[CH2:26][CH2:25]1)[C:36]([OH:38])=[O:37])([CH3:45])([CH3:43])[CH3:44]
Reactant: C=CCOC(CC(C)C)c1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCCl
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CCOC(CC(C)C)c1cn(nn1)C3
Reaction time: 2 h
Yield: 119 %

Procedure:
To a stirred solution of (2S)-ethyl 2-(2-((4-(1-(allyloxy)-3-methylbutyl)-1H-1,2,3-triazol-1-yl)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.080 g, 0.123 mmol) in 1,2-dichloroethane (30 mL) was added Hoveyda-Grubbs catalyst 2nd generation (3.85 mg, 6.14 μmol) at 70° C. After 2 h at 75° C., the reaction mixture was filtered through a plug of silica gel (washed with 10 mL of EtOAC), concentrated and used in the next step without purification. A solution of above crude ester and NaOH (0.491 ml, 0.491 mmol) in MeOH (4 mL) was refluxed for 2 h. Then, cooled and purified by prep-HPLC to afford mixture of diastereomers (0.087 g, 0.146 mmol, 119% yield) as white solid. LCMS (M+H)=596.7.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.[CH3:18][C:19]1[CH:28]=[CH:27][C:22]([C:23](=[N:25]O)[NH2:24])=[CH:21][CH:20]=1.B(F)(F)F>O1CCOCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][N:25]=[C:23]([C:22]4[CH:27]=[CH:28][C:19]([CH3:18])=[CH:20][CH:21]=4)[N:24]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Reactant: Cc1ccc(C(N)=NO)cc1
Agent: FB(F)F
Solvent: C1COCCO1
Product: Cc1ccc(-c2noc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)cc1
Reaction time: 4 h
Yield: 30.8 %

Procedure:
8.0 g (30 millimoles) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride and 4.5 g (30 millimoles) of 4-methylbenzamidoxime in 250 ml of dioxane were refluxed for 1 hour. 1 ml of boron trifluoride dietherate were added and refluxing was continued for a further 4 hours. The mixture was allowed to cool, poured onto ice/water and extracted with methylene chloride. The organic phase was washed several times with water, dried over magnesium sulfate and evaporated down. The oily residue was purified by column chromatography (silica gel; n-heptane +0.5% of ethyl acetate), and the crude product obtained from the first fractions was recrystallized from methanol to give 3.2 g of the title compound of melting point 106°-109° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:7]=1.[OH-].[K+].[CH3:27]I.O>CS(C)=O>[CH3:27][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:10]1[S:9][CH2:8][C:5]1[CH:4]=[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: CI
Reactant: Cc1cnc(CSc2cc3ccccc3[nH]2)cc1N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cnc(CSc2cc3ccccc3n2C)cc1N1CCCCC1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
2-[(5-Methyl-4-piperidino-2-pyridyl)methylthio]indole (80 mg, 0.24 mmol) was added to a suspension of potassium hydroxide (finely ground) (62 mg) in dimethylsulfoxide (0.5 ml), and the mixture was stirred for 30 minutes. Methyl iodide (34 mg, 0.24 mmol) was then added to the mixture and the stirring was continued at room temperature for further 30 minutes. Then, water (20 ml) was added to the reaction solution and the mixture was extracted with ethyl ether. The ether layer so separated was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (eluent: chloroform), yielding the titled compound (75 mg) as an oil. Yield: 90%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:5]=1.[Li+].[BH4-].O.Cl>C1COCC1>[I:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[O:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1
Reactant: COC(=O)c1ccc(I)c(Oc2ccc3ccccc3c2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(I)c(Oc2ccc3ccccc3c2)c1

Procedure:
4-Iodo-3-(naphthalen-2-yloxy)-benzoic acid methyl ester (0.10 g, 0.25 mmol) dissolved in THF (2 mL) was treated with LiBH4 (2 M solution in THF) (0.247 mL, 0.495 mmol) and heated at reflux for 1.5 hr. The reaction mixture was cooled, added to H2O (50 mL)- concd HCl (4.3 mL), and extracted with EtOAc (3×30 mL). The organics were combined, washed with H2O, aq saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:18]=2)[N:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1>>[F:15][C:14]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([O:36][CH2:35][C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)=[CH:7][C:2]=2[F:1])=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:18]=2)=[N:12][CH:13]=1
Reactant: OCc1ccc(F)cc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(OCc4ccc(F)cc4)cc3F)n2)c1

Procedure:
Example 17 was prepared under similar conditions as described in the preparation of Example 16 using 4-(2,4-difluorophenyl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phenyl}pyrimidin-2-amine (Intermediate 16.2) and (4-fluorophenyl)methanol (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:35][C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>CN(C=O)C>[Cl:35][C:36]1[C:37]([C:38]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:16]3[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[N:13]=[CH:14][N:15]=3)[CH2:23][CH2:24]2)=[O:39])=[CH:41][CH:42]=[CH:43][N:44]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(C(=O)c4cccnc4Cl)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A25 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (16 mg, 0.037 mmol), triethylamine (50 μl), 2-chloro-nicotinoyl chloride (10 mg, 0.046 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 1.91 (m,1H), 2.00 (m, 1H), 2.14 (m, 2H), 3.08 (s, 3H), 3.36 (m, 1H), 3.65 (m, 2H), 4.13 (m, 1H), 4.31 (m, 1H), 5.72 (m, 1H), 7.36 (m,1H), 7.69 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41 (m, 1H), 8.47 (m, 1H), 10.20 (s, 1H). Exact mass calculated for C22H21ClN6O6S 532.09, found 533.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24]O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:7][O:6][C:4](=[O:5])[C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: COC(=O)c1c(O)cccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2,6-dihydroxybenzoate (1.0 g, 5.95 mmol) and 4-(Boc-amino)-1-butanol (1.1 mL, 5.95 mmol) in 60 mL THF is added PPh3 (1.7 g, 6.5 mmol) and DEAD (2.97 mL, 6.5 mmol) and the mixture is stirred at RT overnight. The solvent is removed under reduced pressure and the residue is purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 2:1) to give the title compound as a colorless liquid: 1H NMR (CDCl3) δ 11.42 (s, 1H), 7.29 (t, J=8.34 Hz, 1H), 6.57 (d, J=8.34 Hz, 1H), 6.37 (d, J=8.34 Hz, 1H), 4.63 (s, 1H), 3.99 (t, J=6.06 Hz, 2H), 3.93 (s, 3H), 3.22-3.17 (m, 2H), 1.88-1.81 (m, 2H), 1.74-1.67 (m, 2H), 1.43 (s, 9H); (M−1)−=338.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[CH3:29][C:30]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:31]=1[NH2:32].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:30]1([CH3:29])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:31]=1[NH:32][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.4 %

Procedure:
After adding sodium triacetoxyborohydride (7.98 g, 37.6 mmol) to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.1 mmol), 2,4,6-trimethylaniline (3.56 g, 26.3 mmol) and acetic acid (2.9 mL, 50.2 mmol) in methylene chloride (50 mL), the mixture was stirred at room temperature for 3.5 hours. Saturated aqueous sodium hydrogencarbonate (150 mL) was added to the reaction mixture, which was then stirred until bubbling settled. The organic layer was separated and the aqueous layer was extracted with chloroform (100 mL). The organic layers were combined, washed with saturated brine (100 mL) and dried (Na2SO4), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (50 g Merck Art. 9385, hexane:ethyl acetate=9: 1) to obtain the title compound as a brown oil (5.71 g) (71% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3].[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>>[Cl:11][C:12]1[CH:19]=[C:18]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=2)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CCCc1cccc(O)c1
Product: CCCc1cccc(Oc2ccc(C=O)c(Cl)c2)c1

Procedure:
3-Propylphenol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029184 to obtain the target product as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1([C:5]#[C:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH3:1][C:2]1([C:5]#[C:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:8]=2[NH:9][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[CH2:4][CH2:3]1
Reactant: CCCC(=O)Cl
Reactant: CC1(C#Cc2cc([N+](=O)[O-])ccc2N)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC1(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
To a solution of 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (220 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH2Cl2 (20 mL) was added butyryl chloride (140 mg, 1.3 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into ice-water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain N-[2-(1-methyl-cyclopropyl-ethynyl)-4-nitro-phenyl]-butyramide (230 mg, 82%), which was directly used in the next step.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].Cl.[NH2:17][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[CH3:19].C(N(CC)CC)C.C(OC(Cl)=O)C>C1COCC1>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:17][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[CH3:19])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -15 °C
Reaction time: 16 h

Procedure:
The condensation of BOC-Val-OH with HCl. Ala-OMe was carried out by a mixed anhydride method. 12 g (0.055 mol) of BOC-Val-OH was dissolved in 40 ml of dry THF and 5.6 g (0.055 mol) of triethylamine and 6.6 g (0.06 mol) of chloroformic acid ethyl ester was added to the solution after cooling to -15° C. After 10 minutes at low temperature 7.7 g (0.055 mol) of HCl.Ala-OMe and 5.6 g (0.055 mol) of triethylamine were slowly added to the mixture at -15° C. The reaction mixture was stirred for a further 16 hours at room temperature. The THF was evaporated and the product extracted with ethyl acetate. Recrystalization from ether gave 8.1 g of analytically pure BOC-Val-Ala-OMe, m.p. 138°-148° C.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:30]=[CH:29][C:15]([N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>>[CH3:6][N:7]1[C:11]([Sn:35]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:10][CH:9]=[C:8]1[C:12]1[CH:30]=[CH:29][C:15]([N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: Cn1cccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)n1C

Procedure:
As shown in scheme 1, 4-bromo-N,N-diphenylaniline (11) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12). n-butyl lithium is reacted with 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12), and then tributylstannylchloride is added thereto to obtain 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13). 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13) is reacted with 4-bromobenzaldehyde by Stille coupling reaction to obtain 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a). Finally, 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[4-(5-(4-(diphenyl-amino)phenyl)-1-methyl-1H-pyrrol-2-yl)]phenyl)acrylic acid (15a) is synthesized.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1>>[CH3:17][C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[O:16][N:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: Cc1cc(N)on1
Product: Cc1cc(NS(=O)(=O)c2ccc(Br)s2)on1

Procedure:
N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was prepared in the same manner as described in Example 14 from 5-bromothiophene-2-sulfonyl chloride and 5-amino-3-methyl isoxazole. Purification was achieved by extraction of the crude sulfonamide into aqueous 2N NaOH, washing of the aqueous layer with ethyl acetate and acidification, using concentrated HCl, to pH˜2. Re-extraction into ethyl acetate was followed by washing of the organic material with water, brine and drying over magnesium sulfate. After evaporation of solvents, a brownish solid remained which was sufficiently pure to use in the next step.
Reaction SMILES: [C:1]1(=[O:13])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[CH3:14][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[OH:13][C:1]1([CH3:14])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=C1CCn2c1cc1ccccc12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(O)CCn2c1cc1ccccc12
Reaction time: 0.08 h

Procedure:
To 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (613 mg, 3.58 mmol) suspended in toluene (12 mL), at 0° C. there was added methyl magnesium bromide 1.5M in toluene/THF (75:25) (3.0 mL, 4.5 mmol). The mixture was stirred at 0° for 5 minutes, then at room temperature for 20 minutes. After quenching with saturated aqueous NH4Cl solution, the mixture was partitioned between H2O and EtOAc. The crude product obtained from the organic fraction was chromatographed on a column of silica gel eluting with a 1:2 mixture of EtOAc and hexane to afford the title product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:23])[CH:16](Cl)[C:17](=O)[CH:18]([F:20])[F:19])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[CH:18]([F:20])[F:19])=[O:23])[CH3:13]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)F
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C(F)F
Temperature: 50 °C
Yield: 42.6 %

Procedure:
8.84 g 4-Methoxythiobenzamide were dissolved in 100 ml ethanol and warmed to 50° C. Then 10.59 g 2-chloro-4,4-difluoro-3-oxo-butyric acid ethyl ester were added and the reaction mixture stirred under reflux for three hours. The cooled reaction mixture was evaporated in vacuo and the residue purified by chromatograph on silica gel with the eluent ethyl acetate/petroleum benzene=1:4 to obtain 7.04 g 4-difluoromethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH:13][CH3:14].[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH3:16].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Br:1][C:2]1[C:3]2[N:13]([CH3:14])[C:20]([C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[S:17][CH2:15][CH3:16])=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CNc1c(N)cc(C(F)(F)F)cc1Br
Reactant: CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(Br)c2n1C
Temperature: 115 °C
Yield: 43.2 %

Procedure:
A mixture of 3-bromo-N2-methyl-5-trifluoromethylbenzene-1,2-diamine (2.22 g), 2-ethylsulfanylbenzoic acid (1.80 g), WSC (1.40 g), and pyridine (10 ml) was stirred under reflux at 115° C. for 6 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.48 g of 7-bromo-2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter referred to as Present Compound 74).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:27]([CH3:26])[C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=4)=[CH:22][CH:23]=3)=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1cccc(Cl)c1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2cccc(Cl)c2)cc1)c1ccc(OC(F)(F)F)cc1
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 3-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide, and N-methyl-4-(trifluoromethoxy)aniline, the title compound was isolated as a yellow solid in 69% yield (94% purity by HPLC).