Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1/[CH:21]=[CH:22]/[C:23](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>C(OCC)(=O)C>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[CH3:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:23](/[CH:22]=[CH:21]/[C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: Cc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/c1cccs1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(/C=C/c1cccs1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methyl-2-amino-N-(2-pyridyl)aniline and (E)-3-(2-thienyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 417.42; mp: 181.5-182.0° C.; 1H-NMR (DMSO) δ: 8.78-8.72 (1H, m), 8.16 (1H, t, J=7.7 Hz), 8.00 (1H, d, J=15.8 Hz), 7.69 (1H, d, J=8.1 Hz), 7.62-7.50 (3H, m), 7.39 (1H, br.s), 7.31 (1H, d, J=8.1 Hz), 7.15-7.05 (2H, m), 6.86 (1H, d, J=15.8 Hz), 2.42 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[NH2:36][CH2:37][CH2:38][OH:39].N[C@H]1CC[C@H](NC2C=C(NC3C=CC=C(N[C@H]4CC[C@H](O)CC4)N=3)C3N(C(C(NC4C=CN=CC=4F)=O)=CN=3)N=2)CC1>CO>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:36][CH2:37][CH2:38][OH:39])[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: NCCO
Reactant: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(Br)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Agent: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(N[C@H]4CC[C@H](O)CC4)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(NCCO)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1

Procedure:
The title compound was prepared from 46A and 2-aminoethanol in a similar way as 46B. HPLC Rt=2.373 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=521.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[C:20]5[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd].C(O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[C:20]5[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C3=CCCCC3)c2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C3CCCCC3)c2c1
Reaction time: 72 h
Yield: 80.4 %

Procedure:
A mixture of 1-(3-(cyclohexen-1-yl)indol-5-yl)-5-methylbenzimidazole (0.110 g, 0.34 mmol), 10% Pd on carbon (0.027 g), and absolute ethanol (2 mL) was shaken under an atmosphere of hydrogen (3 atm) for 72 hours. The resulting reaction mixture was filtered through Celite®, and the filtrate was evaporated under reduced pressure to afford the title compound (0.090 g, 80%) as a dark brown foam. Mp, decomposes 120° C.; 1H NMR (DMSO-d6) d 11.5 (br s, NH), 8.41 (s, 1H), 7.73 (s, 1H), 7.56-7.52 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.27-7.24 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 2.88-2.75 (m, 1H), 2.45 (s, 3H), 2.10-1.60 (m, 10 H); IR (KBr) 2924, 2851, 1612, 1580, 1492, 1447 cm-1 ; FAB LRMS (m/z, relative intensity) 331 (25), 330 ([MH]+, 100). HRMS calculated for C22 H23N3 : 329.1887. Found: 329.1874.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][CH:8]=O)[C:4](=[O:10])O1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[OH:6][C@@H:5]1[CH2:7][CH2:8][N:12]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[C:4]1=[O:10]
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](O)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
(R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (16 g, 101 mmol) was dissolved in ClCH2CH2Cl (500 mL) and tert-butyl 4-aminopiperidine-1-carboxylate (40.5 g, 202 mmol) and acetic acid (6.94 mL, 121 mmol) were added and stirred at ambient temperature for 15 minutes. NaBH(OAc)3 (64.3 g, 304 mmol) was added in 3 portions and the reaction stirred at ambient temperature overnight. The reaction was carefully quenched with saturated aqueous NaHCO3. The reaction was partitioned between aqueous NaHCO3 and CH2Cl2, extracted, washed with 10% citric acid, brine, dried over Na2SO4, filtered and concentrated. The solids were purified over silica gel (5 to 10% methanol in EtOAc) to afford (R)-tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (20.5 g, 72.1 mmol, 71.3% yield) as a white solid.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:50]1([O:54][C:55]([N:57]2[CH2:62][CH2:61][N:60]([C:63](=[O:78])[C@@H:64]([NH2:77])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:59][CH2:58]2)=[O:56])[CH2:53][CH2:52][CH2:51]1>CN(C=O)C.C(Cl)CCl>[CH:50]1([O:54][C:55]([N:57]2[CH2:62][CH2:61][N:60]([C:63](=[O:78])[C@@H:64]([NH:77][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[O:30])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:59][CH2:58]2)=[O:56])[CH2:53][CH2:52][CH2:51]1
Reactant: N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
To a solution of 480 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 232 mg HOBt, 290 mg EDC and 0.48 ml DIPEA. After 5 minutes 470 mg (S)-4-(2-Amino-6-benzyloxy-hexanoyl)-piperazine-1-carboxylic acid cyclobutyl ester were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product was obtained by evaporation of the solvent. An aliquot (80 mg) was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 40 mg MS (ES+): m/e=798.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)cnc1Cl

Procedure:
To a suspension of 2-chloro-5-(trifluoromethyl)nicotinic acid (1.147 g, 4.83 mmol) in DCM (20 mL) was added oxalyl chloride (630 L, 7.35 mmol) dropwise with stirring. A single drop of DMF was added and the reaction mixture was stirred 40° C. for 1 hour. Concentration of the reaction mixture in vacuo resulted in the title compound as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(O)=[O:25].OO>CC(O)C>[O:12]1[C@@H:13]2[C@@:5]34[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:18]([C@:17]3([OH:25])[CH2:16][CH2:15][C:14]2=[O:20])[CH2:19][C:7]2=[C:6]4[C:11]1=[C:10]([O:22][CH3:23])[CH:9]=[CH:8]2
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: O=CO
Agent: OO
Solvent: CC(C)O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C

Procedure:
50 kg thebaine was added to a solution of formic acid (145 kg) maintained at a temperature below 15° C. the solution was heated to 25° C. and maintained at this temperature for 1.0 hr. the reaction mixture was cooled to 0-5° C. and 30% H2O2 aqueous solution (5.5 kg 100% H2O2) was added at 0-5° C. The reaction mixture was maintained at 20-25° C. for 3.0 hrs. After completion of the reaction, it was quenched in 560 lit DM water and treated with charcoal. To the filtrate 5% Pd/C (1.5 kg) was added and hydrogen gas purged at 20-25° C. The reaction mixture was maintained at 20-25° C. for 4-5 hrs. After reaction completion, the catalyst was filtered off and the pH of the filtrate was adjusted to 9-9.5 with aqueous ammonia. The product was extracted with methylene dichloride and subsequently concentrated to obtain a solid which was isolated with IPA. Yield: 41.7 kg
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[C:10](=O)([O:14]CC)[O:11][CH2:12][CH3:13]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:12]([O:11][C:10](=[O:14])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:13]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)CC(=O)C(C)(C)C
Yield: 91 %

Procedure:
325 g of sodium hydride (80% solution in paraffin oil) were suspended in 2500 cc of diethyl carbonate and 500 cc of hexamethyl phosphoric acid triamide, 500 g of pinacolone (92%) were then slowly added dropwise at 45° to 50° C. and, on completion of the addition the reaction mixture was treated as described in 3 above. The yield was 91% of pivaloyl acetic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[F:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:38]2[CH2:39][CH2:40][C:34]3([O:33][CH2:32][CH2:31][N:30]([C:28]([C:26]4[N:27]=[C:23]([CH:20]([CH3:21])[CH3:22])[S:24][CH:25]=4)=[O:29])[CH2:35]3)[CH2:36][CH2:37]2)=[CH:8][C:7]=1[CH2:9][CH2:10][OH:11]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cc(CBr)ccc1F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4)CC3)C2)cs1
Reaction time: 8 h

Procedure:
2-(5-(Bromomethyl)-2-fluorophenyl)ethanol (example 47, step a) (0.16 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.3 g) and triethylamine (0.3 mL) in acetonitrile (10 mL). The resulting mixture was stirred overnight, diluted with acetonitrile (20 mL) and applied to a SCX cartridge (10 g Varian, pre-wetted with acetonitrile (50 mL)). The cartridge was washed with acetonitrile (50 mL) and eluted with 10% ‘880’ aqueous ammonia in acetonitrile solution (50 mL). The eluent was evaporated, azeotroped with toluene and purified by silica gel chromatography eluting with 77.5:17.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated to give to the subtitled compound as a yellow gum. Yield 0.22 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:7]1([C:5]2[N:6]=[C:2]([NH:1][C:22]([NH:21][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[S:23])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1nc(-c2ccccc2)cs1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
3.10 g 2-amino-4-phenylthiazole (176 mmol) and 3.00 g benzoylisothiocyanate were heated in 50 ml acetone for 2 hours at reflux, during which a yellow solid was formed. The reaction mixture was subsequently stirred for 30 minutes at 5° C., the solid was suction-isolated and washed multiple times with n-pentane. After drying, 4.20 g of the target structure was obtained as an amorphous yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]=[N:18]O)[N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]#[N:18])[N:3]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C=NO)n1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from the compound of Example 48 by reaction with trifluoroacetic anhydride in pyridine, mp. 249° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:31][CH2:32][CH3:33])[C:3]([OH:34])=[O:2])=[CH:11][CH:10]=2)=[CH:18][CH:19]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acid methyl ester by the standard hydrolysis procedure C (LiOH). MS(ES) for C27H28O6 [M−H]−: 447.1
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4]([OH:6])=O.S(Cl)(Cl)=O>>[CH2:13]([NH:14][C:4](=[O:6])[C:3]([CH3:2])([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH3:7])[CH2:12][CH3:11]
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C)n2CCC

Procedure:
A quantity of 0.5 g (1.3 m mole) of 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride was warmed for 15 minutes with 4 ml of thionylchloride on a steam bath. Subsequently, the excess thionylchloride was removed in vacuo, and the residue was dissolved in 100 ml of chloroform and 4 ml of propylamine were added dropwise under stirring. After one hour the reaction mixture was evaporated, and the residue obtained was purified on silicagel with ethyl acetate as eluant.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:14]([O:17]C)OC)[CH:10]=[C:11](Br)[CH:12]=1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>CCOCC>[Br:6][C:7]1[CH:12]=[C:11]([B:19]([OH:24])[OH:20])[CH:10]=[C:9]([CH:14]=[O:17])[CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COC(OC)c1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(Br)cc(B(O)O)c1
Reaction time: 0.13 h

Procedure:
4.2 mL (10.5 mmoles) of 2.5 m n-butyllithium was added to a solution of 3.1 g (10.5 mmoles) of 3,5-dibromo(dimethoxymethyl)benzene in 50 mL of ether at -78° under nitrogen over a period of 2 minutes. The reaction mixture was stirred 8 minutes and 2.415 mL (10.5 mmoles) of triisopropyl borate was added. The reaction was stirred 5.5 hrs at room temperature after cooling to 0°, 21 mL of 2N hydrochloric acid was added. After stirring 1 hour at room temperature, ether layer was separated and washed with saturated sodium chloride solution. After drying over anhydrous MgSO4, solvent was removed to give a solid, which was triturated with petroleum ether. The resulting solid was dried in vacuo to give the desired boronic acid.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C[Si]([C:23]#[N:24])(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[NH2:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:23]#[N:24]
Reactant: C[Si](C)(C)C#N
Reactant: N#Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CC(N)c1ccccc1
Temperature: 0 °C
Yield: 62 %

Procedure:
10 millimoles (1.031 g) of benzonitrile are dissolved in 10 ml of anhydrous toluene at 0° C., under an argon atmosphere. 15 millimoles of a toluenic solution 1.5 M of diisobutylaluminum hydride (10 ml) are added dropwise, at this temperature. The reaction mixture is maintained at 0° C. for 1 hour, then 2 ml (1.5 eq) of trimethylsilyl cyanide are added. The stirring is maintained for 3 hours at room temperature, then the mixture is hydrolyzed with 10 ml of methanol, then with pasty sodium sulfate. After purification of α-aminonitrile by an acid-base extraction there are obtained 0.820 g of 2-amino-2-phenyl-acetonitrile, with a yield of 62%.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH2:19][CH:20]([OH:24])[C:21]([OH:23])=O)=[O:17])=[CH:10]2>>[OH:24][CH:20]([C:21](=[O:23])[N:3]([O:4][CH3:5])[CH3:2])[CH2:19][NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17]
Reactant: CNOC
Reactant: O=C(NCC(O)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: CON(C)C(=O)C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 69 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.0 mmol) and 3-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2RS)-hydroxy-propionic acid (0.95 mmol) were coupled according to Procedure A (0-25° C., washed with acid, then base) and the crude product triturated with ether giving a colorless solid: Yield 69%; HPLC (60/40) 3.18 minutes (96%); mp 192-192.5° C.; PBMS 326/328 (MH+, 100%);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: Oc1c(Br)cc(Br)cc1I
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(Br)cc(Br)c3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 2,4-Dibromo-6-iodo-phenol [53872-06-3] (0.7 g, 1.8 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH and filtered to give 87 as a solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[C:5](=[O:18])[CH2:4][CH2:3]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([N:36]2[CH:40]=[C:39]([CH:41]=O)[N:38]=[CH:37]2)[CH2:32][CH2:31]1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C@H:2]1[CH2:7][NH:6][C:5](=[O:18])/[C:4](=[CH:41]/[C:39]2[N:38]=[CH:37][N:36]([C@H:33]3[CH2:34][CH2:35][C@H:30]([CH3:29])[CH2:31][CH2:32]3)[CH:40]=2)/[CH2:3]1
Reactant: C[C@H]1CC[C@H](n2cnc(C=O)c2)CC1
Reactant: C[C@@H]1CCC(=O)N(C(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CNC(=O)/C(=C/c2cn([C@H]3CC[C@H](C)CC3)cn2)C1
Reaction time: 1 h

Procedure:
Benzyl (5R)-5-methyl-2-oxopiperidine-1-carboxylate (Org. Lett, 2009, Vol. 11, p. 5410) (772 mg) was dissolved in tetrahydrofuran (15 mL). To the solution, lithium hexamethyldisilazide (LHMDS, 1 N tetrahydrofuran solution, 3.12 mL) was added dropwise at −78° C., and the mixture was stirred for 1 hour. Subsequently, a solution of 1-(trans-4-methylcyclohexyl)-1H-imidazole-4-carbaldehyde (600 mg) in tetrahydrofuran (5 mL) was added dropwise thereto at −78° C., and the mixture was stirred at 0° C. for 3 hours. To the reaction solution, aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate-ethyl acetate/methanol=92/8) to obtain the title compound (500 mg).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: O=C(O)c1cc(Br)sc1Br
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2,5-dibromothiophene-3-carboxylic acid (33.5 g) synthesized above in ethanol (300 mL) was added dropwise thionyl chloride (4.23 mL), and the mixture was stirred at room temperature overnight and then stirred with heating under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1, volume ratio) to give the title compound (33.4 g, 92%) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1csc(-c2cccnc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccnc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(3-pyridyl)thiazole (316 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (657 mg, yield: 84%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).