Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (32 mg, 0.061 mmol) and TFA (1.2 ml, 15.6 mmol) were combined with dichloromethane (4 ml) to give an orange solution. The reaction mixture was stirred at room temperature until the consumption of starting material (2.5 h). The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (2 mL) and ethylenediamine (300 μl, 4.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (9:1 dichloromethane/heptane) to afford 22 mg (93%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=399; 1H NMR (DMSO-d6) δ: 12.72 (br. s., 1H), 9.11 (s, 1H), 8.53 (d, J=8.7 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=8.7 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.28 (dd, J=8.7, 1.9 Hz, 1H), 4.30-4.45 (m, 1H), 4.18 (s, 3H), 3.50 (qd, J=9.6, 4.7 Hz, 2H), 3.27 (s, 3H), 1.31 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C@H:4]([NH:8][C@@H:9]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])[C:5]([OH:7])=O.C(O)(=O)CCCC.Cl.[NH2:37][C:38]1([C:41]#[N:42])[CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:41]([C:38]1([NH:37][C:5](=[O:7])[C@@H:4]([NH:8][C@@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:10]([F:11])([F:13])[F:12])[CH2:3][C:2]([F:28])([F:1])[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:40][CH2:39]1)#[N:42]
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CC1(NC(=O)[C@H](CC(F)(F)Cc2ccccc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of the above pentanoic acid (S)-4,4-difluoro-5-phenyl-2-((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino)pentanoic acid, (1 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (1.2 mmol), HATU (1.2 mmol) and NMM (4.0 mmol), in DMF, was stirred at RT for 2 hr. Saturated ammonium chloride and ethyl acetate were then added, and the reaction was stirred an additional 20 min at RT, after which product was extracted with ethyl acetate, purified with flash column (30-35% ethyl acetate—hexane), and crystallized with DCM-hexane to give (S)-N-(1′-cyanocyclopropyl)-4,4-difluoro-5-phenyl-2-((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino)pentanamide as a white crystal.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:46]Cl>C(Cl)(Cl)(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:46])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
1.0 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 10 ml of a benzenedioxane (1:2) mixture. To the solution was added 3 g of NaHCO3 and the mixture was stirred at room temperature. Thereto was added dropwise over 3 minutes 1.5 ml of carbon tetrachloride having dissolved therein 2.1 mmol of chlorine and the mixture was stirred for 2 hours. The reaction mixture was extracted with ethyl acetate and the extract was subjected to the same subsequent procedure as in Example 1, affording 1.04 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 98% yield.
Reaction SMILES: N[C:2]1C(I)=C(CCCCCCCCCCCC(O)=O)C(I)=C[C:7]=1I.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].OS(O)(=O)=O>C(O)C>[CH2:2]([O:37][C:36](=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[CH3:7]
Reactant: Nc1c(I)cc(I)c(CCCCCCCCCCCC(=O)O)c1I
Reactant: O=C(O)CCCCCCCCCCBr
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCBr

Procedure:
In this example, 12-(3-amino-2,4,6-triiodophenyl)dodecanoic acid is synthesized. 11-Bromoundecanoic acid (54.0 g, 200 mmol) was refluxed overnight with 150 ml absolute ethanol and a catalytic amount (1.0 ml) H2SO4. The solvent was removed in vacuo and the residue was dissolved in 100 ml CHCl3 and extracted with 100 ml H2O, twice with 100 ml 10% aq. NaHCO3, 100 ml water, and brine, and was dried with MgSO4Removal of the solvent in vacuo and distillation of the remaining yellow liquid under vacuum yielded ethyl-11-bromoundecanoate as a colorless liquid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:23]=O)=[C:13]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH:14]=1)(C(C)(C)C)(C)C.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:34]C(OCC)=O.N1CCCCC1.F.F.F.C(N(CC)CC)C>C(O)C.C(#N)C>[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[C:34]1[C:16](=[O:22])[NH:15][C:13]2[C:12]([CH:23]=1)=[CH:11][CH:10]=[C:9]([OH:8])[CH:14]=2
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)Nc1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Agent: F
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: O=c1[nH]c2cc(O)ccc2cc1-c1nc2ccccc2[nH]1

Procedure:
A solution of tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-formylphenylcarbamate (12-4, 0.57 g, 2.4 mmol, 1 equiv), ethyl 1H-benzimidazol-2-ylacetate (0.50 g, 2.4 mmol, 1.0 equiv, prepared by the method of Rahmouni, M, Derdour, A., Bazureau, J., and Hamelin Tetrahedron Lett. 1994, 35, 4563-4564), and piperidine (0.12 mL, 1.2 mmol, 0.5 equiv) in ethanol (50 mL) was heated at reflux for 20 h. The reaction mixture was cooled and concentrated. A solution of the residue and triethylamine trihydrofluoride (0.38 mL, 2.3 mmol, 0.97 equiv) in acetonitrile (30 mL) was stirred at 30° C. for 2.5 h. The precipitate which formed was filtered and air dried to give 3-(1H-benzimidazol-2-yl)-7-hydroxy-2(1H)-quinolinone (12-5) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 12.19 (s, 1H), 10.45 (br s, 1H), 8.95 (s, 1H), 7.76 (d, 1H, J=8.8 Hz), 7.68 (m, 1H), 7.59 (m, 1H), 7.18 (m, 2H), 6.82 (s, 1H), 6.75 (d, 1H, J=8.8 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([C:10]2[C:11]([CH:22]=[O:23])=[CH:12][C:13]([C:18]([F:21])([F:20])[F:19])=[C:14]([O:16][CH3:17])[CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C.C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:19])[F:20])=[CH:12][C:11]=2[CH2:22][OH:23])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
5′-Isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (692 mg) is dissolved in a mixed solvent of tetrahydrofuran (12 ml), ethanol (3.5 ml) and methylene chloride (1 ml), and thereto is added sodium borohydride (82 mg) and the mixture is stirred at room temperature for 40 minutes. The reaction solution is concentrated under reduced pressure and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give (5′-isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (566 mg). MS (m/z): 337 [M+H—H2O]+
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14]>>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11])[CH3:14]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Yield: 78 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 2.99 mmol) reacted with N,N-diethylethylenediamine (4.62 mL) to give 6.19 g (78%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (200 mg, 0.53 mmol) and trimethyl(trifluoromethyl)silane (0.24 mL, 1.62 mmol) in tetrahydrofuran (10 mL) was added tetra(n-butyl)ammonium fluoride in tetrahydrofuran (1.0 M, 0.053 mL, 0.053 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 hr, 1N hydrogen chloride (2.0 mL) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound (212 mg, 0.475 mmol, 90%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]3[N:28]=[N:29][NH:30][N:22]=3)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C#N)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2cc(-c3nn[nH]n3)cc3[nH]c4ncc(C)cc4c23)c1
Temperature: 158 °C
Yield: 77.5 %

Procedure:
Compound 126 (14 mg, 0.037 mmol), sodium azide (9.7 mg, 0.15 mmol), and ammonium chloride (8.0 mg, 0.15 mmol) were combined in DMF (1 mL) and heated at 158° C. in the microwave for 1 h. Purification by prep-HPLC gave 12 mg (77%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.02-8.11 (m, 2H), 7.94 (t, 1H, J=5.6 Hz), 7.83 (s, 1H), 7.54 (s, 1H), 3.44 (q, 2H, J=7.2 Hz), 2.27 (s, 3H), 1.17 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C21H18N6O2S, 419; found 419.
Reaction SMILES: [SH2:1].[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[NH:17][CH:16]=1.C(N(CC)CC)C.O>CN(C)C=O.CCOCC>[O:12]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:2])[N:4]1[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](=[S:1])[NH2:25])[CH:22]=2)[NH:17][CH:16]=1
Reactant: S
Reactant: N#Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=S)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reaction time: 168 h

Procedure:
Hydrogen sulphide gas was passed through a stirred solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-carbonitrile (4 g) and triethylamine (3 ml) in dry dimethylformamide (100 ml) for 6 hours. and the reaction mixture was stirred for a further 7 days. Hydrogen sulphide gas was passed through the reaction mixture for 0.5 hours on each day. Water (200 ml) was added and the mixture was extracted with ethyl acetate (3×200 ml). Evaporation of the washed (H2O) and dried (MgSO4) extracts gave a yellow residue which gave a yellow powder (4.1 g) on trituration with ether. A sample was crystallised from ethanol to give the title compound as yellow microcrystals m.p. 195°-8° C. (dec.)
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:27])(=O)=O.[NH2:28][CH2:29][C@@H:30]([OH:43])[CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1.[OH-].[Na+].Cl>C(O)C>[OH:43][C@@H:30]([CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)[CH2:29][NH:28][CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:27]
Reactant: NC[C@@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCOC(=O)c1ccc(-c2cc(C)c(OCCOS(C)(=O)=O)c(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCNC[C@@H](O)COc1cccc2[nH]c(=O)[nH]c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
A mixture of ethyl 4′-(2-methanesulfonyloxyethoxy)-3′,5′-dimethylbiphenyl-4-carboxylate (0.10 g) and 4-((R)-3-amino-2-hydroxypropoxy)-1,3-dihydrobenzimidazol-2-one (0.057 g) in ethanol (2 mL) was stirred at 80° C. overnight. After being cooled to room temperature, a 2 mol/L aqueous solution of sodium hydroxide (0.5 mL) was added to the reaction mixture, and the mixture was stirred at 70° C. for 3 hrs. After being cooled to room temperature, to the mixture was added 2 mol/L hydrochloric acid (0.5 mL). The precipitated insoluble materials were collected by filtration, and purified by preparative reverse phase column chromatography (Shiseido Capcell Pak C18 ODS, 5 μm, 20×50 mm, linear gradient 0.1% aqueous formic acid/acetonitrile=90/10-60/40) to afford the title compound (0.027 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1O>O1CCCC1>[C:1]1([CH:7]2[CH2:8][C:9](=[O:14])[C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[NH:15][C:11]=3[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1CCCCC1O
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)Cc2[nH]c3c(c21)CCCC3
Temperature: 150 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (4.0 g), 2-aminocyclohexanol (3.2 g), molecular sieves 4A (24 g) and tetrahydrofuran (60 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (100 ml). To the solution were added 2-bromomesitylene (4.2 g), tetrakistriphenylphosphine palladium (0.6 g) and potassium carbonate (5.9 g), and the mixture was stirred at 150° C. for 4 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazol-4-one (3.4 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>ClCCl>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:29]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccc(Br)c1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (5.0 g, 27 mmol) and N,N-diisopropylethylamine (7.5 mL, 43 mmol) in dry dichloromethane (135 mL) was added 3-bromobenzoyl chloride (2.9 mL, 22 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was then washed with 1 M hydrochloric acid (5×200 mL), 1 M sodium hydroxide (200 mL), and brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow solid (7.2 g). Recrystallization from ethyl acetate gave the title compound (5.8 g, 72%) as a white crystalline solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[C:11]([N+:22]([O-:24])=[O:23])=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]3)=[C:7]([O:27][CH3:28])[CH:6]=1)([OH:3])=[O:2].[CH3:29][Si](Cl)(C)C>CO>[CH3:28][O:27][C:7]1[CH:6]=[C:5]([CH2:4][C:1]([O:3][CH3:29])=[O:2])[CH:26]=[CH:25][C:8]=1[O:9][C:10]1[C:11]([N+:22]([O-:24])=[O:23])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]2
Reactant: C[Si](C)(C)Cl
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C(=O)O)cc2c1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2[N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.4 (0.37 g, 0.96 mmol) in CH3OH (10 mL), was added TMSCl (0.1 g, 0.92 mmol). The mixture was stirred at room temperature for 3 h. Solvent was removed to give a residue, which was used without further purification. MS ESI (pos.) m/z: 401.0 (M+H)+.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[C:3]1[CH2:11][NH2:12].S1C2C=CN=CC=2C=[C:14]1C(O)C.N1C2=NC=CC=C2C(CN)=C1>>[S:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[C:3]1[CH:11]([NH2:12])[CH3:14]
Reactant: NCc1cc2cnccc2s1
Reactant: CC(O)c1cc2cnccc2s1
Agent: Cl
Agent: NCc1c[nH]c2ncccc12
Product: CC(N)c1cc2cnccc2s1

Procedure:
Intermediate D′ was prepared from 1-(thieno[3,2-c]pyridin-2-yl)ethanol (D′-4) following similar procedures for synthesizing intermediate A from A-3, as described above.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1.[C:13]1([CH3:22])[C:14]([C:19](Cl)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>COCCOC.[Zn]>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:19](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:22])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [Zn]
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(=O)c2ccccc2C)cc1
Reaction time: 3 h
Yield: 39.2 %

Procedure:
4-Chloromethylbenzoic acid methyl ester (26.36 g) is dissolved in 1,2-dimethoxyethane (700 ml), and thereto are added with stirring zinc powder (20.6 g) and bistriphenylphosphine palladium dichloride (5 g) over an ice-bath. To the mixture is added dropwise o-toluoyl chloride (26.5 g), and the mixture is stirred over an ice-bath for three hours, and then stirred at room temperature for three days. The insoluble materials are removed by filtration, and the residue is washed with ethyl acetate. To the mother liquor is added a saturated sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a saturated sodium hydrogen carbonate solution, a 0.5N hydrochloric acid and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=50:1~10:1), and recrystallized from toluene/n-hexane to give 4-[(2-methyl-benzoyl)methyl]benzoic acid methyl ester (15 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:16].CO>ClCCl>[CH3:1][C:2]1[C:10]2[C:5](=[N+:6]([O-:16])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1c[nH]c2c1ccc[n+]2[O-]
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A little at a time, 3.00 g (22.70 mmol) of 3-methyl-1H-pyrrolo[2,3-b]pyridine (Hands, David; Bishop, Brian; Cameron, Mark; Edwards, John S.; Cottrell, Ian F.; Wright, Stanley H. B.; Synthesis 1996, 877-882.) are added to a solution of 10.45 g (45.40 mmol) of meta-chloroperoxybenzoic acid in 250 ml of dichloromethane, and the mixture is stirred at 10° C. for 2 h. Addition of methanol gives a clear solution which is subjected directly to column chromatography on silica gel (mobile phase: dichloromethane/methanol 100:4 to 3:1). A further purification step by preparative HPLC yields the target compound.