Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[CH2:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:41][CH3:42]>C(Cl)Cl>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][CH2:21][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][S:43]([CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])([CH3:18])[NH:14]2
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 25.0 mg, mmol) was dissolved in methylene dichloride (0.5 mL), triethylamine (16.2 μL, 0.116 mmol) and 1-propanesulfonyl chloride (6.5 μL, 0.058 mmol) were added thereto, and then the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.8 mg) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: [Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCC.C([Li])CCC.[CH:32]12[CH2:37][CH:36]1[CH2:35][CH:34]([OH:38])[CH2:33]2.[CH:39]12C[CH:43]1[CH2:42][CH2:41][CH:40]2[OH:45]>CCCCCC.C1C=CC=CC=1>[O:45]1[CH2:39][CH2:43][CH2:42][CH2:41][CH:40]1[O:38][CH:34]1[CH2:35][CH:36]2[CH:32]([CH2:37]2)[CH2:33]1
Reactant: OC1CC2CC2C1
Reactant: OC1CCC2CC12
Agent: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C1CCC(OC2CC3CC3C2)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of hexyltriphenylphosphonium bromide (102 g.) and benzene (1200 ml.) is stirred under nitrogen during addition of a solution of butyl lithium in hexane (146 ml. of a 15% solution - w/v). The resulting mixture is stirred 30 minutes. Then a solution of the mixture (27 g.) of products obtained according to Preparation 4 in 300 ml. of benzene is added dropwise with stirring during 30 minutes. The mixture is heated and stirred at 70° C. for 2.5 hours, and then is cooled to 25° C. The resulting precipitate is collected by filtration and washed with benzene. The filtrate and benzene wash are combined, washed with water, dried, and evaporated to give 58 g. of a mixture of the tetrahydropyranyl ethers of endo-6-(cis- and trans-1-heptenyl)bicyclo[3.1.0]hexan-3-ol and endo-6-(cis- and trans-1-heptenyl)bicyclo[3.1.0]hexan-2-ol.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[C:11](C(C)=O)([CH3:13])=[O:12].ON1[C:22](=[O:23])[C:21]2=CC=CC=C2C1=O.O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:11]([C@@:5]12[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:1][CH2:2][CH2:3][CH2:4]2)(=[O:12])[CH3:13].[C:22]([C@@:5]12[CH2:6][CH2:7][CH2:8][CH2:9][C@:10]1([OH:12])[CH2:1][CH2:2][CH2:3][CH2:4]2)(=[O:23])[CH3:21]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(=O)C(C)=O
Reactant: C1CC[C@H]2CCCC[C@H]2C1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC(=O)O
Product: CC(=O)[C@]12CCCC[C@@]1(O)CCCC2
Product: CC(=O)[C@]12CCCC[C@H]1CCCC2

Procedure:
A mixture of 0.3 mol of cis-decalin, 1.8 mol of biacetyl, 30 mmol of N-hydroxyphthalimide, 1.5 mmol of cobalt(II) acetate, and 300 ml of acetic acid was stirred at 60° C. in an oxygen atmosphere at atmospheric pressure for 4 hours. The reaction mixture was concentrated to about 20% by weight, and was extracted with ethyl acetate, and the extract was concentrated and was then subjected to column chromatography on a silica gel to yield 4a-acetyl-cis-decalin and 4a-acetyl-8a-hydroxy-cis-decalin.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:11]
Reactant: [H][H]
Reactant: O=C1OCc2c1cc(Cl)cc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc2c1COC2=O
Yield: 89.7 %

Procedure:
A suspension of 6-chloro-4-nitroisobenzofuran-1(3H)-one (5 g, 23.5 mmol) and Pd/C (10%, 500 mg) in EtOAc (250 mL) was stirred at 25° C. under 1 atm of hydrogen for 12 hr. The mixture was filtered, and the cake was washed with EtOAc (100 mL×3). The filtrate was concentrated to give the title compound (3.87 g, yield 90%) as a white solid. LC-MS (ESI) m/z: 184 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][OH:14])=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-n2cncn2)c1
Reactant: C=O
Product: OCc1ncnn1-c1cccc(F)c1
Temperature: 150 °C

Procedure:
A mixture of the crude 1-(3-Fluorophenyl)-1,2,4-triazole and formaldehyde (10 mL of 37 wt % in water) is heated at 150° C. in a sealed tube for 48 h. After cooling the reaction vessel, the reaction mixture is extracted with dichloromethane, dried (MgSO4), concentrated, and the residue purified using silica gel chromatography to afford 1-(3-Fluorophenyl)-5-hydroxymethyl-1,2,4-triazole. 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.42-7.53 (m, 3H), 7.22-7.29 (m, 1H), 4.81 (s, 2H). LCMS 194.2 (MH−).
Reaction SMILES: [CH:1]1([N:7]([CH2:27][CH:28](OC)[O:29]C)[C:8](=[O:26])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:27][CH:28]=[O:29])[C:8](=[O:26])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(-c2cccc(CCOCCC(=O)N(CC=O)C3CCCCC3)c2)cn1
Reaction time: 1 h
Yield: 107.1 %

Procedure:
N-Cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide (0.5 g) was stirred in DCM (10 mL) followed by the addition of p-toluenesulfonic acid monohydrate (0.43 g). The mixture was stirred for 1 h. Ethyl acetate was added followed by sodium hydrogen carbonate solution. The aqueous phase was removed and the remaining organic phase washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent removed to afford the desired material as an oil (0.48 g). This material was used in the next step directly. MS [M+H]+=398 (MultiMode+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][CH:14]=1)[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:6]2.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([NH:32][C:19]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1)=[O:20])(=[O:31])=[O:30]
Reactant: CS(N)(=O)=O
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(=O)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 15.9 %

Procedure:
Under an argon atmosphere, to a solution of 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carboxylic acid (84 mg) in dichloromethane (2.3 mL) were added methanesulfonamide (22 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg), and 4-dimethylaminopyridine (29 mg). This mixture was stirred for 66 hours at room temperature. To the reaction mixture, 1 mol/L hydrochloric acid was added and stirred vigorously. The organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane-methanol). The solvent was removed under reduced pressure. The residue was recrystallized from ethanol to obtain the title compound (16 mg). 1H-NMR (CDCl3) δ ppm: 3.38 (3H, s), 3.87 (3H, s), 5.49 (2H, s), 6.64 (1H, d, J=0.5 Hz), 6.84 (1H, dd, J=2.4, 8.9 Hz), 6.90-6.95 (1H, m), 7.05 (1H, d, J=8.9 Hz), 7.16 (1H, d, J=2.4 Hz), 7.30-7.50 (5H, m), 7.76 (1H, t, J=7.8 Hz), 8.00-8.10 (1H, m), 10.01 (1H, br s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(#N)C.[Cl:20][Si:21](Cl)([CH3:23])[CH3:22]>C(N(CC)CC)C>[C:12]([C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:16][Si:21]([CH3:23])([CH3:22])[Cl:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(Cl)Cl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(C)(C)C)c(O[Si](C)(C)Cl)c(C(C)(C)C)c1

Procedure:
A mixture of 2,6-di-t-butyl-4-methylphenol (110 g, 0.5M), acetonitrile (500 ml), triethylamine (70 ml, 0.5M) and dichlorodimethylsilane (61 ml, 0.5M) was refluxed for 16 hours. The solvent was evaporated and the residue extracted with toluene (500 ml). The toluene extract was evaporated and the residue recrystallised from acetonitrile to give the title compound (90 g, 57%) m.p. 119°-121° (Found: C,65 65; H,9.4%. C17H29ClOSi requires C,65.2; H,9.3%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:24])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Methanesulfonyl chloride (2.74 mL, 35.41 mmol) was added dropwise to (S)-tert-butyl 1-(4-chlorophenyl)-3-hydroxypropylcarbamate (Intermediate 58) (9.2 g, 32.19 mmol) and triethylamine (5.38 mL, 38.63 mmol) in DCM (161 mL) at 25° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was evaporated to dryness and the residue was purified by flash silica chromatography, elution gradient 40 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (S)-3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (10.03 g, 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19]1>>[O:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:19]1
Reactant: O=C(Cl)c1ccoc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccoc4)nc23)CC1
Yield: 60.9 %

Procedure:
Beginning with 1.0 gm (4.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.68 gm (5.2 mMol) 3-furoyl chloride, 0.85 gm (61%) of the title compound were prepared as an ivory crystalline solid essentially by the procedure described in Example 4.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]1([CH3:28])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=O)[O:12]C(C)(C)C)[C@H:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)(Cl)Cl>[CH3:5][C:6]1([CH3:28])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=[O:12])[O:4][CH2:3][CH2:2][F:1])[C@H:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Reactant: OCCF
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCCF

Procedure:
Using the procedure of Example 48, 2-fluoro-ethanol and the product of Step A were reacted to obtain benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-(2-fluoroethoxy)-1-propenyl]cyclopropane-carboxylate with a specific rotation of [α]D20 =+53° (c=0.5% in chloroform).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]=[S:13])[CH3:2].C([C:16]1C=CC=[C:19](CC)[C:17]=1[NH2:18])C.[C:25](=O)([O-])[O-].[Ca+2].C(Cl)(Cl)=S.C(=O)=O>C(Cl)Cl.O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:18][C:17]([CH3:19])([CH3:25])[CH3:16])=[S:13])[CH3:2]
Reactant: CCc1cccc(CC)c1N=C=S
Reactant: O=C([O-])[O-]
Reactant: CCc1cccc(CC)c1N
Agent: O=C=O
Agent: S=C(Cl)Cl
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: CCc1cccc(CC)c1NC(=S)NC(C)(C)C

Procedure:
2,6-Diethyl-phenyl isothiocyanate can be prepared as follows: 100 g of 2,6-diethylaniline in 200 ml of methylene chloride are added dropwise at 0°-5°, whilst stirring, to a mixture of 500 ml of methylene chloride, 300 ml of water, 120 g of calcium carbonate and 92 g of thiophosgene. The mixture is then heated to the reflux temperature until the evolution of CO2 has ended. The cooled batch is filtered and the methylene chloride layer is separated off, dried with calcium chloride and fractionated.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:7][N:6]=1.O1CCCC1.Cl[CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28]>CCOCC>[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][N:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1)[C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13]
Reactant: COCCOCCl
Reactant: COc1ccc(NC(=O)C2CC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOCN(C(=O)C1CC1)c1ccc(OC)nc1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
Sodium hydride (0.33 g, 0.014 mol) and N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide (92.5 g, 0.014 mol) were added to dry tetrahydrofuran (THF). This mixture was stirred under N2 for one hour when methoxyethyl chloromethyl ether (1.6 g, 0.014 mol) was added dropwise to the stirred mixture. The reaction was stirred overnight and diluted with ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo nto give 2.4 g of a yellow oil of the title compound. The structure was confirmed by mass spectroscopy (MS), IR and NMR analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C@H:9]([C:11](=[O:34])[NH:12][C@@H:13]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[CH:22]=[N:23][CH:24]=[C:25](Br)[CH:26]=1)=[O:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:36]([O-:39])([O-])=[O:37].[Na+].[Na+].[C:42]1(C)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)C>CCOC(C)=O>[C:1]([O:5][C:6](=[O:35])[N:7]([C@H:9]([C:11](=[O:34])[NH:12][C@@H:13]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:42]2[CH:47]=[CH:46][C:45]3[O:37][CH2:36][O:39][C:44]=3[CH:43]=2)[CH:26]=1)=[O:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1CCC[C@H]1c1cncc(Br)c1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H](C(=O)N[C@H](C(=O)N1CCC[C@H]1c1cncc(-c2ccc3c(c2)OCO3)c1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
The mixture of ((S)-1-{(S)-2-[(S)-2-(5-Bromo-pyridin-3-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester 5 (168 mg, 0.31 mmole), 3,4-(methylene dioxy)pheny boronic acid (60.7 mg, 0.37 mmole), Na2CO3 (1.8 mL, 1.8 momle, 1 M aqueous) in a mixed solution of 8 mL of toluene and 3 mL of ethanol was degaseq under vacuum. After heat at 80° C. for 1.5 hours, the reaction mixture was cooled to room temperature and diluted with 30 mL of EtOAc, and washed by 3×15 mL of water. The organic layer was filtered and concentrated to give 3-(5-{(S)-1-[1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester 6 as crude producte without further purification for next step reaction.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7])(=O)[OH:2].[CH3:12][NH2:13]>>[CH3:12][NH:13][C:1]([O:4][C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7])=[O:2]
Reactant: CN
Reactant: O=C(O)Oc1ccccc1O
Product: CNC(=O)Oc1ccccc1O
Yield: 98 %

Procedure:
In fact, the reaction of pyrocatechol carbonate with methylamine in the presence of not less than 1 mol equivalent of the abovementioned secondary amines gives pyrocatechol monomethylcarbamate in a yield of 98-99%. The subsequent reaction of the reaction mixture with 1,2-dichloroethyl methyl ether in turn takes place with a yield of above 90%. Compared with the reaction with tertiary amines, the conversion takes place substantially more rapidly (on the bas-is of experience, from eight to ten times faster) and with better selectivity, and consequently a purer and more stable end product is obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[CH2:19][C:20](OC)=[O:21]>C(O)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[NH:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:20](=[O:21])[CH:19]=1
Reactant: COC(=O)CC(=O)c1ccco1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Solvent: CC(=O)O
Product: O=c1cc(-c2ccco2)[nH]c2cc(-c3ccccc3)nn12
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of 3-phenyl-1H-pyrazol-5-amine (90: 0.318 g, 2.0 mmol, 1.0 eq) and methyl 3-(furan-2-yl)-3-oxopropanoate (0.370 g, 2.2 mmol, 1.10 eq) was heated in acetic acid (2.0 mL) at 100° C. for 4 hr. After cooling down to rt, the precipitate was collected by filtration. The precipitate was rinsed with EtOH (15 mL) and dried under air to afford 5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (0.358 g, 65%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.06 (m, 1H), 8.00 (m, 1H), 7.98 (m, 1H), 7.51-7.47 (m, 3H), 7.44-7.42 (m, 1H), 6.81 (dd, J=3.7, 1.8 Hz, 1H), 6.64 (s, 1H), 6.15 (s, 1H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([O:32][CH2:33][CH:34]1[C:38](CO)=[CH:37][CH2:36][CH2:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Si:25]([O:32][CH2:33][CH:34]1[C:35]([CH2:1][Br:5])=[CH:36][CH2:37][CH2:38]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
The carbon tetrabromide (8.5 g, 25.7 mmol) and triphenylphosphine (8.4 g, 3.22 mmol) were added in dichloromethane solution of (5-t-Butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl alcohol (5.2 g, 21.4 mmol) under ice bath and then stirred for 30 min at 0° C. The reaction mixture was stirred for overnight at room temperature, extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product (3.08 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.[CH3:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:18]=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:18]2[N:19]([N:26]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])[C:20]3[C:25]([C:17]=2[CH3:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cn(N2C(=O)c3ccccc3C2=O)c2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)c2ccc(F)cc2)n(N2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 8.14 ml of 4-fluorobenzoyl chloride and 450 ml of dry DCM was cooled in an ice/salt bath to 0° C. To the stirred solution was added 7.74 ml of tin (IV) chloride. The mixture was stirred at -5° C. to 0° C. for 10 minutes after which was added 18.0 g of 2-[(3-methyl-1H-indol-1-yl]-1H-isoindole-1,3-(2H)dione (Example 10b). The reaction mixture was stirred at 0° C. for 1.5 hours, allowed to warm to room temperature for 2 hours, cooled again in an ice bath, poured onto ice, extracted twice with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated to a yellow solid. Chromatography (15% acetone/heptane) provided a solid weighing 56.8 g. Recrystallization from ethyl alcohol gave 21.1 g of the product, m.p. 227°-228° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][C:31]2[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=2)=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl.CN(C=O)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:1][S:36]([C:34]1[S:35][C:31]([CH2:30][NH:29][C:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)=[O:28])=[CH:32][CH:33]=1)(=[O:38])=[O:37])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)s1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
H-Gly-OtBu.HCl (263 mg, 1.57 mmol) is dissolved in 20 ml CH2Cl2. pH is adjusted to 9 using i-Pr2NEt as a base (537 μl, 3.14 mmol). To this solution is added dropwise 1b (500 mg, 1.43 mmol) in 10 ml DMF. The reaction is stirred overnight. 30 ml of CH2Cl2 are added and the organic phase washed with HCl (0.1N) and sat. NaCl sol. Drying over MgSO4 and evaporating the solvent to dryness affords 1c (400 mg, 63%) as a white solid. mp °C., 1H NMR (d6-DMSO) δ 9.34 (t, J=6.40 Hz, 1H), 8.25 (t, J=6.40 Hz, 1H), 7.89 (d, J=8.67 Hz, 2H), 7.56 (d, J=8.67 Hz, 2H), 7.41 (d, J=3.77 Hz, 1H), 7.05 (d, J=3.7 Hz, 1H), 4.62 (d, J=6.40 Hz, 2H), 3.59 (d, J=6.40 Hz, 2H), 1.3 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[C:18]([O:21][CH2:22]C)(=[O:20])C>N1C=CC=CC=1.[Cu-]=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:18]([O:21][CH3:22])=[O:20])[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(Br)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=[Cu-]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2ccn(-c3ccc(C)cc3)c12

Procedure:
The title C indole (1.001 g, 5.713 mmol, 1.0 eq.) was dissolved in pyridine (11.4 ml, 0.5M) and treated with 4-bromotoluene (1.76 ml, 22.85 mmol, 4 eq.) and copper(I) oxide (1.635 g, 11.43 mmol, 2.0 eq.). The mixture was heated in a bath maintained at 130°±5° C. for a total of nine hours. During this period, at 3, 5.5 and 7.5 hours, additional 4-bromotoluene (0.44 ml, 5.71 mmol, 1 eq.) and copper(I) oxide (409 mg, 2.85 mmol, 0.5 eq.) were added. After cooling, the mixture was diluted with ethyl acetate (~10 ml) and filtered through Celite. The filtrate was washed with water (3×50 ml), 0.5N hydrochloric acid (2×50 ml), 1.0N hydrochloric acid (50 ml) and saturated sodium hydrogen carbonate solution. The organic solution was dried over anhydrous magnesium sulfate and freed of solvent in vacuo. The remaining material was first chromatographed on silica gel, eluting with 5% ether in hexane to give a mixture of the desired product and starting material but free of the large amount of excess 4-bromotoluene. The mixture was then rechromatographed on silica gel, eluting with 3% acetone in hexane to give the title D compound (467 mg).