Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([N:16]([CH2:20][CH3:21])[C:17](Cl)=[O:18])[CH3:15]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:17](=[O:18])[N:16]([CH2:20][CH3:21])[CH2:14][CH3:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCN(CC)C(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.4 %

Procedure:
In 40 ml of methylene chloride was dissolved 4.0 g (0.02 mole) of 1-(4-chlorophenyl)piperazine at room temperature. Then, a solution of 3.0 g (0.022 mole) of diethylcarbamoyl chloride in 30 ml off methylene chloride was dropped to the above solution over a period of 30 minutes and the mixture was stirred for 4 hours at room temperature. The precipitate was removed and the filtrate was made alkaline by addition of 30 ml of a 35% aqueous solution of sodium hydroxide and extracted with 50 ml of methylene chloride. The organic layer was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to obtain crude 1-(4-chlorophenyl)-4-diethylcarbamylpiperazine as the residue. The low-boiling-point component was removed by distillation under reduced pressure and the residue was recrystallized from n-hexane to obtain 1.8 g of a purified product having a melting point of 63° to 64° C. The yield was 29.9%. The elementary analysis values are as follows.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][S-:14].[Na+]>CN1CCCC1=O>[CH3:13][S:14][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1ccc2ncc(=O)[nH]c2c1
Yield: 90.1 %

Procedure:
A solution of 7-bromo-1H-quinoxalin-2-one (12.0 g, 53.3 mmol, 1.0 eq) and sodium methanethiolate (9.44 g, 133.3 mmol, 2.5 eq) in N-methylpyrrolidone is stirred at 160° C. for 1 hour. Then solvent is evaporated and the residue is dissolved in water, acidified to pH=5 with 20% hydrochloric acid aqueous solution at 0° C., and the resulting precipitate is collected by filtration, washed with water and ethyl acetate to afford 7-methylsulfanyl-1H-quinoxalin-2-one as a yellow solid (9.23 g, 54% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](OB(C=C)OCCCC)[CH2:15]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[N+:11]([C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[CH:14]=[CH2:15])([O-:13])=[O:12]
Reactant: C=CB(OCCCC)OCCCC
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 87 %

Procedure:
To a mixture of 4′-bromo-3′-nitroacetophenone (600 mg, 2.46 mmol), vinylboronic acid dibutyl ester (680 mg, 3.69 mmol), and sodium carbonate (1.83 g, 17.22 mmol) in THF/H2O (12 mL/4 mL) is added dichlorobis(triphenylphospine) palladium (II) (86 mg, 5% mmol). The reaction tube is sealed and the mixture is purged with N2 for 3 min and heated at 70° C. for 1.5 h. Then the mixture is cooled to room temperature and poured into saturated ammonia chloride aqueous solution. The mixture is extracted with ethyl acetate (3×20 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (20% ethyl acetate in hexanes) to afford 1-(3-Nitro-4-vinyl-phenyl)-ethanone as a yellow solid, 87% yield: ESMS m/z 192.0 (M+H+).
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].Cl.[F:14][C:15]([CH3:25])([CH3:24])[C:16](=O)[CH2:17][C:18](OCC)=[O:19]>CO>[F:14][C:15]([C:16]1[N:12]=[CH:10][NH:11][C:18](=[O:19])[CH:17]=1)([CH3:25])[CH3:24]
Reactant: N=CN
Reactant: CCOC(=O)CC(=O)C(C)(C)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(F)c1cc(=O)[nH]cn1
Temperature: 50 °C
Reaction time: 6 h
Yield: 40.9 %

Procedure:
To a solution in which 5.52 g of ethyl 4-fluoro-4-methyl-3-oxopentanoate had been dissolved in 20 ml of methanol were added 11.6 g of a 28 % sodium methoxide methanol solution and 4.0 g of formamidine acetate, and the mixture was stirred at 50° C. for 6 hours. The mixture was cooled to 10° C. or lower, and 7.1 g of conc. hydrochloric acid was added to the reaction mixture and the reaction mixture was concentrated under reduced pressure. To the concentrated solution was added 100 ml of acetone, and the resulting mixture was stirred at 60° C. for 30 minutes and then, insolubles were removed by filtration. The filtrate was concentrated under reduced pressure and the concentrated solution was recrystallized from 20 ml of acetone to obtain 2.0 g of 6-(1-fluoro-1-methylethyl)-4-pyrimidone (isolated yield: 64.0%).
Reaction SMILES: [C:1]([C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>CCO>[C:2]1([C:1]2[N:20]=[N:19][C:15]([OH:17])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=23)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1nnc(-c2ccccc2)c2cccnc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3-benzoylpicolinic acid (0.272 g, 0.120 mmol) and hydrazine hydrate (0.17 mL, 0.37 mmol) in EtOH (3.3 mL) was stirred at 80° C. overnight, concentrated, diluted with saturated aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4), and concentrated to give the title compound as a white solid (0.28 g, 0.12 mmol). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.10 (dd, 1H), 8.09 (dd, 1H), 7.88 (dd, 1H), 7.54-7.63 (m, 5H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:16])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1)([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[CH:1]([O:4][C:5](=[O:16])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:18][OH:19])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)COc1cccc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)OC(=O)COc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.4 %

Procedure:
A solution of (3-formyl phenoxy)acetic acid isopropyl ester (3.7 g, 17 mmol) in methanol (55 mL) was stirred under nitrogen as hydroxylamine hydrochloride (1.2 g, 17 mmol) and pyridine (6 mL, 74 mmol) were added. The reaction was stirred for 15 h at room temperature. The volatiles were removed in vacuo and the residue was diluted with ethyl acetate. The resulting solution was washed with 1N HCl, and the resulting aqueous solution was washed with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (4.13 g, 100%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (d, 6H) 4.67-4.72 (m, 2H) 5.15-5.34 (m, 1H) 7.01-7.07 (m, 1H) 7.33-7.36-7.43 (m, 2H) 8.17 (s, 1H). LRMS m/z calcd. for C12H15NO4([M+H]+): 237.1. Found: 238.1.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[CH3:30])=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1>>[C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([C:17]3[CH:22]=[CH:21][C:20](/[C:23](/[CH3:30])=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=3)[CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Yield: 67.7 %

Procedure:
(E)-Ethyl 3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enoate (1.02 g, 68% yield) was prepared from 3-biphenylboronic acid (1.31 g, 6.60 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedure analogous to that described in example 52 a.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:24]2[CH2:23][CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:26][CH2:25]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c([N+](=O)[O-])c2)CC1
Temperature: 70 °C
Yield: 96.8 %

Procedure:
To a solution of a mixture of compound 17 (3 g, 13.27 mmol) and 1-boc-piperazine hydrochloride (3.53 g, 15.92 mmol) in DMF (30 mL) was added Et3N (4.4 mL, 31.8 mmol), and the mixture was heated at 70° C. for 6 h. The mixture was cooled to room temperature, extracted with ethyl acetate (100 mL), and the organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated. Trituration with diethyl ether afforded 4.27 g (97%) of compound 18 as bright yellow solid, m.p. 138-139° C.; IR (KBr) νmax. cm−1: 3042 (Ar—H), 2252 (CN), 1690 (C═O), 1610, 1520, 1412 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=1.39 (s, 9H, (CH3)3C); 3.44 (br. s, 4H, 2 CH2); 7.19 (dd, 1H, J=2.6, 9.4 Hz, H-5); 7.46 (d, 1H, J=2.7 Hz, H-2); 8.17 (d, 1H, J=2.7 Hz, H-6); 13C NMR (125.7 MHz, DMSO-d) δ=28.11 (CH3)3C), 45.92 (CH2), 46.02 (CH2), 79.56 (CH3)3C), 109.24 (C-4), 115.61 (C-2), 116.46 (CN), 119.03 (C-6), 128.09 (C-5), 135.85 (C-3), 153.30 (C-1), 154.13 (C═O). Calculated (%) for C16H20N4O4(332.15); C, 57.82; H, 6.07; N, 16.86. found (%); C, 57.76; H, 6.11; N, 16.80.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH:8]1([C:17]#[N:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[O:4]1[CH2:5][CH2:6][O:7][CH:3]1[CH2:2][C:8]1([C:17]#[N:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: BrCC1OCCO1
Reactant: N#CC1CCc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CC2OCCO2)CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
2-bromomethyl-1,3-dioxolane (12.94 ml, 125.0 mmole) was added to a solution of 1-indanecarbonitrile (16.27 g, 113.6 mmole) in 100 ml of THF and cooled to 0° C. After the dropwise addition of 1M LHMDS (125 ml) the solution was stirred at 0° C. for 20 min then at room temperature for 20 min. After the removal of solvent the residue was flashed of silica using 15% EtOAc and Hexanes to afford 19.23 g of 1-(1,3-dioxolan-2-ylmethyl)-1-indanecarbonitrile (74% yield) as a thick oil.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[NH:11][C:12](=[O:15])[CH2:13]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[N:20]([C:13]1[C:12](=[O:15])[NH:11][C:10]2[C:9]([C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N+:21]=[N-:22]
Reactant: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=Nc1c(-c2ccccc2)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a hot solution of 98.5 g. of 2'-benzoyl-2-bromo-acetanilide in 2 l methanol was added in one portion 39.0 g. of sodium azide. The mixture was heated to a slow reflux on a steam bath for 20 minutes. As the mixture cooled partially to room temperature, 18 ml. of benzyltrimethylammonium hydroxide (35% methanolic solution) was added. After standing overnight at room temperature, the orange-yellow needles that formed were collected, washed with methanol and dried at 60° C.; yield 76.6 g. (94%) of 3-azido-4-phenylcarbostyril, having a melting point of 120° - 140° dec. to high melting solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([NH:25][C:22](=[O:24])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)Nc1ccccc1

Procedure:
Using N-(tert-butoxycarbonyl)-(O-tert-butyl)-L-tyrosine and aniline, and in the same manner as in the method described in Example 1 (3), synthesis was performed.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][C:10]([CH2:15][N:16]4[C:24](=[O:25])[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]4=[O:26])([CH3:14])[C:9]=3[O:27][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[F:43][C:44]1[CH:45]=[C:46]([SH:50])[CH:47]=[CH:48][CH:49]=1>[Cu]I>[F:43][C:44]1[CH:45]=[C:46]([S:50][C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:13][CH2:12][NH:11][C:10]([CH2:15][N:16]5[C:24](=[O:25])[C:23]6[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=6)[C:17]5=[O:26])([CH3:14])[C:9]=4[O:27][C:4]=3[CH:3]=2)[CH:47]=[CH:48][CH:49]=1
Reactant: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(I)ccc21
Reactant: Fc1cccc(S)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Product: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(Sc3cccc(F)c3)ccc21
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To 2-(7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isoindole-1,3-dione (0.192 g, 0.406 mmol) was added sodium tert-butoxide (117 mg, 1.22 mmol), copper (I) iodide (7.74 mg, 0.0406 mmol), 1,2-ethanediol (45.3 μL, 0.812 mmol), N,N-dimethylformamide (4.00 mL, 51.6 mmol), and finally 3-fluorobenzenethiol (36.0 μL, 0.427 mmol). The reaction mixture was flushed with N2 and heated at 120° C. under a N2 atmosphere. After 72 h, the reaction was cooled to room temperature and concentrated. The residual solid was partially dissolved into a 5% MeOH in DCM solution and flushed through a plug of Celite. The concentrated filtrate was chromatographed on silica gel using DCM-MeOH—NH4OH to afford a brownish yellow gum. MS m/z 473 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH:11]=[O:12])[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:22].[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:22])=[O:12])[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)c(C=O)n1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OCc2ccccc2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
4.9 g (18 mmol) of 6-acetylamino-3-benzyloxypicoline aldehyde was added to 100 ml of acetone. 400 ml of an aqueous solution of 4.3 g (27 mmol) of potassium permanganate was added thereto, and the mixture was stirred at room temperature for one hour. Precipitated manganese dioxide was filtered off and washed with 100 ml of hot water. The filtrate was extracted with ethyl acetate, and the aqueous layer was neutralized with citric acid. Precipitated crystals were extracted with chloroform, washed with water, dried and concentrated. The crystals thereby obtained were washed with diisopropyl ether to obtain 6-acetylamino-3-benzyloxy picolinic acid.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:6]=1[C:7]([O-:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:17]([O-])=O.[K+]>CCO.O.[Pd]>[C:1]([C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:6]=1[C:7]([O:9][CH3:17])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C[O-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C(=O)[O-]
Agent: [Pd]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N)ccc1C(C)(C)C
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a refluxing solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38 mmol) in EtOH (2.0 mL) was added potassium formate (400 mg, 4.76 mmol) in water (1 mL), followed by the addition of 20 mg of 10% Pd—C. The reaction mixture was refluxed for additional 40 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give methyl 2-tert-butyl-5-aminobenzoate (E-6) (76 mg, 95%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=8.6 Hz, 1H), 6.67 (dd, J=8.6, 2.7 Hz, 1H), 6.60 (d, J=2.7 Hz, 1H), 3.86 (s, 3H), 1.34 (s, 9H); HPLC ret. time 2.19 min, 10-99% CH3CN, 5 min run; ESI-MS 208.2 m/z (MH+).
Reaction SMILES: [Br:1]Br.[CH:3]1([C:6]([CH:13]2[CH2:15][CH2:14]2)([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[OH:7])[CH2:5][CH2:4]1.CC([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:10]1[S:9][C:8]([C:6]([CH:3]2[CH2:5][CH2:4]2)([CH:13]2[CH2:14][CH2:15]2)[OH:7])=[N:12][CH:11]=1
Reactant: BrBr
Reactant: OC(c1nccs1)(C1CC1)C1CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OC(c1ncc(Br)s1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
Bromine (0.271 mL, 5.26 mmol) was added dropwise to a stirred mixture of the product of Step 1 (411 mg, 2.10 mmol) and NaOAc (863 mg, 10.5 mmol) in acetic acid (9.17 mL) and the mixture was stirred at room temperature for 4 h. The reaction was quenched with brine and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes) to give (5-bromo-1,3-thiazol-2-yl)(dicyclopropyl)methanol (329 mg, 1.20 mmol, 57% yield) as an off-white solid. MS APCI: [M-OH]+ m/z 255.9
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[C:24]([C:26]1([CH3:40])[CH2:31][CH2:30][C:29]2[C:32]([CH3:39])=[C:33]([OH:38])[C:34]([CH3:37])=[C:35]([CH3:36])[C:28]=2[O:27]1)#[CH:25].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][C:26]3([CH3:40])[CH2:31][CH2:30][C:29]4[C:32]([CH3:39])=[C:33]([OH:38])[C:34]([CH3:37])=[C:35]([CH3:36])[C:28]=4[O:27]3)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc3c(c1)C(c1ccccc1F)=NCc1nnc(C)n1-3)O2

Procedure:
The title compound was prepared by coupling 6-(2-fluoro-phenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with rac-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol [ref. H. Mayer et al., Helv. Chim. Acta, 67, 650 (1963)]under the conditions described in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The clean fractions containing product were combined and evaporated. The residue was crystallized from ethanol/ethyl acetate to give colorless crystals of rac-2-{[6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with m.p. 265°-267°.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Br[C:6]1[C:7]([C:12]#[N:13])=[N:8][CH:9]=[CH:10][CH:11]=1>C1COCC1>[C:12]([C:7]1[C:6]([S:3][CH2:1][CH3:2])=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:13]
Reactant: N#Cc1ncccc1Br
Reactant: CC[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1cccnc1C#N

Procedure:
To a stirred suspension of sodium ethanethiolate (600 mg, 5.75 mmol) in dry THF (25 mL) was added 3-bromo-2-cyanopyridine (700 mg, 3.83 mmol). The reaction mixture was heated to reflux under N2 for 3 h. The solvent was removed in vacuo and the resulting residue was taken Lip in CH2Cl2 (35 mL). The solution was filtered to remove precipitated sodium bromide and the filtrate was concentrated at reduced pressure to afford the title compound as a yellow oil:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:26])[CH2:10][N:11]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([O:25][C@H:23]([CH3:24])[CH2:22][N:11]([C:12]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21])[CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:26])(=[O:48])=[O:47]
Reactant: C[C@@H](O)CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of benzyl {(2S)-2-[(tert-butoxycarbonyl)amino]propyl}[(2R)-2-hydroxypropyl]carbamate (1.95 g, 5.32 mmol) and diisopropylethylamine (1.85 mL, 10.64 mmol) in anhydrous dichloromethane (110 mL) was added dimethylaminopyridine (135 mg) and methane sulfonyl chloride (0.535 mL, 6.92 mmol). The mixture was stirred at room temperature for 1 hour. Reaction was complete as determined by TLC. The reaction mixture was concentrated and purified using flash column chromatography. (1R)-2-([(benzyloxy)carbonyl]{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}amino)-1-methylethyl methanesulfonate was obtained in 97.0% yield (2.29 g) as light yellow oil.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[C:12]([C:15]1[S:19][CH:18]=[N:17][C:16]=1[CH3:20])(=[O:14])[CH3:13].O>C(OCC)C>[O:4]1[CH:5]=[CH:6][C:2]([C:12]([C:15]2[S:19][CH:18]=[N:17][C:16]=2[CH3:20])([OH:14])[CH3:13])=[CH:3]1
Reactant: Brc1ccoc1
Reactant: CC(=O)c1scnc1C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ncsc1C(C)(O)c1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromofuran (6.8 g) in diethylether (15 ml) was added dropwise to n-butyllithium (2.5M solution in hexane, 18.4 ml) in diethylether (20 ml) at -70° C. under a nitrogen atmosphere. After 1 hour, 5-acetyl-4-methylthiazole (5 g) in diethylether (15 ml) was added dropwise. After a further 3 hours at -70° C., the mixture was allowed to warm to room temperature and was then left overnight. The mixture was poured into water and extracted with diethylether. The product thus obtained was crystallised from diethylether, m.p. 102°-104° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=[O:20])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cc(C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(OCc2ccccc2)c2cc(C(=O)O)[nH]c2c1
Yield: 95 %

Procedure:
31.0 4-benzyloxy-2-ethoxycarbonyl-6-methyl indole (see preparation of the primary products in connection with Example 1) are heated to boiling in a mixture of 100 ml ethanol and 100 ml water during addition of 7.0 potassium hydroxide, for 2 to 3 hours. The ethanol is then evaporated in vacuum and the remaining, water alkaline solution is acidified with conc. hydrochloric acid. The resulting precipitate is aspirated, thoroughly washed with water and dried. There is obtained 27.6 g (~95% of theory) 4-benzyloxy-2-carboxy-6-methyl indole; m.p. 178°-180° C.