Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[CH3:24][O:23][C:21]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)=[O:22]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1sc(NC(=O)OC)nc1C
Reaction time: 6 h
Yield: 81 %

Procedure:
2.0g of ethyl 2-amino-4-methyl-thiazole-5-carboxylate and 2.7ml of triethylamine were dissolved in 40ml of dichloromethane and then 1.1ml of methyl chloroformate was added thereto at 0° C. The reaction mixture was stirred for 6 hours at normal temperature, evaporated to remove the solvent and then extracted with 10% aqueous sodium hydroxide solution and ethylacetate. The organic layer was separated, dried over anhydrous magnesium sulfate and then evaporated to obtain 2.1g (Yield 81%) of ethyl 2-methoxycarbonylamino-4-methyl-thiazole-5-carboxylate as a pale yellow solid. The resulting product was hydrolyzed according to the same procedure as PREPARATION 1 to obtain 1.4g (Yield 75%) of the title compound as a pale yellow solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1([F:39])[O:36][C:17]2=[CH:18][C:19]3[N:23]=[C:22]([S:24][CH2:25][C:26]4[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=4)[NH:21][C:20]=3[CH:35]=[C:16]2[O:15][C:14]1([F:38])[F:37].CN(C)C>C(Cl)Cl>[Cl:12][C:13]1([F:39])[O:36][C:17]2=[CH:18][C:19]3[N:23]=[C:22]([S:24]([CH2:25][C:26]4[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=4)=[O:6])[NH:21][C:20]=3[CH:35]=[C:16]2[O:15][C:14]1([F:37])[F:38]
Reactant: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)C(F)(Cl)O4)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CN(C)C
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)C(F)(Cl)O4)c1C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
A solution of 0.42 g of approximately 85% pure m-chloroperoxybenzoic acid in 90 ml of methylene chloride is added dropwise to a solution of 0.9 g of 6-chloro-6,7,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole in 180 ml of methylene chloride at -40° C., with stirring. Stirring is continued for 4 hours and the solution is allowed to come to -20° C. 0.29 ml of trimethyl amine are added, and the organic phase is washed with potassium bicarbonate solution and with water, dried with magnesium sulfate and concentrated in vacuo. The residue is stirred with ethyl acetate and subsequently with acetone. 0.6 g (64%) of the title compound of m.p. 198°-200° C. (decomposition) are obtained.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl chlorooxoacetate (670 mg, 5.45 mmol) in DCM (3 mL) was added in one portion to a solution of trans-ethyl 2-[4-(4-aminophenyl)cyclohexyl]propanoate (1.0 g, 3.63 mmol) and pyridine (0.59 mL, 7.26 mmol) in DCM (22 mL) at 5° C. and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo and EtOAc (30 mL) was added. The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL). The organic layer was dried and concentrated in vacuo to give the title compound (1.3 g, 99%) as a solid; 1H NMR δ (CDCl3) 1.0-1.1.25 (2H, m), 1.1 (3H, d), 1.2 (3H, t), 1.3-1.47 (2H, m), 1.48-1.55 (2H, m), 1.68-1.79 (1H, m), 1.8-1.95 (2H, m), 2.18-2.28 (1H, m), 2.35-2.5 (1H, m), 3.9 (3H, t), 4.08 (2H, q), 7.12 (2H, d), 7.47 (2H, d); MS m/e (M−H)− 360.
Reaction SMILES: [CH3:1][C:2]([N:6]([CH3:8])[CH3:7])([CH2:4][OH:5])[CH3:3].[C:9](O)(=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[C:9]([O:5][CH2:4][C:2]([N:6]([CH3:8])[CH3:7])([CH3:3])[CH3:1])(=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC(=O)O
Reactant: CN(C)C(C)(C)CO
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)OCC(C)(C)N(C)C

Procedure:
DMAMP 118 g (1 mole) and commercial grade caprylic acid 131 g (1 mole) were dissolved in 35 ml of toluene. The mixture was heated under reflux at about 140°-165° until 20 ml distillate was recovered and no more was being collected. The pressure was then reduced to 10mm and distillation was continued to about 130° C to strip off toluene and water. The pressure was then reduced to about 1 mm and the main product fraction was recovered at a liquid temperature of about 106°-109°. There was obtained 2-dimethylamino-2-methyl-1-propyl caprylate, neutral equivalent 247.9 compared with theoretical 244.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[I:12]I.[OH-].[NH4+]>CN(C=O)C.O>[I:12][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: II
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 1H-pyrrolo[3,2-c]pyridine (20 g, 170 mmol) in DMF (100 mL) was added KOH (33.2 g, 593 mmol) and the mixture was stirred for 10 minutes. A solution of iodine (47.3 g, 186 mmol) in DMF (100 mL) was added at 0° C., and the reaction allowed to warm to room temperature over 1.5 hours. The reaction was poured onto an aqueous solution of Na2S2O5 (17.2 g) and ammonium hydroxide (35%, 170 mL) in water (2.5 L). The resulting precipitate was filtered, washed with water and dried to afford the title compound (33.5 g, 81%).
Reaction SMILES: [CH3:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH3:20]
Reactant: CI
Reactant: CC1(c2ccccc2)NCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2ccccc2C1(C)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of (+)-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.0 g) in N,N-dimethylformamide (10 ml) was added sodium hydride (0.19 g) in ice-bath with stirring. After stirring for 30 minutes at room temperature, to the mixture was added methyl iodide (0.31 ml). And after stirring for an hour at room temperature, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo to give (+)-1,2-dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[Br:26]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([Br:26])=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(Br)c12

Procedure:
Put 1.75 g (5.15 mmol) 6-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]hexanoic acid methyl ester in 5.2 ml tetrachloromethane. At RT, add 1.054 g (5.92 mmol) N-bromosuccinimide and then heat the mixture under reflux for approx. 1 h. After cooling, concentrate by vacuum evaporation and chromatograph the residue on silica gel (solvent: cyclohexane/ethyl acetate 4:1). 0.89 g (41.2% of theor.) of the target compound is obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:13][C:14]=1[CH3:15].O>C(#N)C>[Cl:1][CH2:9][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:13][C:14]=1[CH3:15]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: O
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
N-Chlorosuccinimide (4.5 g) was added to a solution (100 ml) of tert-butyl 4-(4,5-dimethyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (10 g) in acetonitrile at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (0:1-1:4-1:2, v/v) to give tert-butyl 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperazine-1-carboxylate as colorless crystals (6.2 g, yield 55%).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[S:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[S:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 50.1 %

Procedure:
An operation similar to that in Example 69-(9) was performed using 4-(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methoxy)benzoic acid (250 mg) synthesized in Example 69 (8) and ethyl 3-(methylamino)propanoate (80.5 mg) to give the title compound (147 mg, 50%).
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[S:10](Cl)(Cl)(=[O:12])=[O:11]>CCCCCC>[C:1]([NH:9][S:10]([NH:9][C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2])(=[O:12])=[O:11])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)NC(C)(C)CC(C)(C)C

Procedure:
The starting N,N'di-t-octylsulfamide is prepared from commercially available t-octylamine and sulfuryl chloride using either the method of Stowell (J. C. Stowell, J. Org. Chem. 32, p.2360, 1967) or of Timberlake (J. W. Timberlake, J. Alender, A. W. Garner, M. L. Hodges, C. Ozmeral and S. Syilagyi, J. Org. Chem. 46, p.2082-2089, 1981). The reaction is preferably run in hexane and the product isolated as a hexane solution. The hexane solution of the sulfamide can be concentrated prior to oxidizing the sulfamide or it can be concentrated during the oxidation.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[CH3:8][O:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[C:18]([O:25][C@@H:26]([C@H:28]3[CH2:32][NH:31][C:30](=[O:33])[CH2:29]3)[CH3:27])[C:19]3[S:23][CH:22]=[N:21][C:20]=3[CH:24]=2)[CH:13]=[CH:12][C:11]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[C:1]([N:37]1[CH2:36][CH2:35][N:34]([C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[C:18]([O:25][C@@H:26]([C@H:28]4[CH2:32][NH:31][C:30](=[O:33])[CH2:29]4)[CH3:27])[C:19]4[S:23][CH:22]=[N:21][C:20]=4[CH:24]=3)=[N:15][C:10]=2[O:9][CH3:8])[CH2:39][CH2:38]1)(=[O:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1nc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCNCC1
Product: COc1nc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCN(C(C)=O)CC1

Procedure:
(R)-4-((R)-1-((5-(5-(4-acetylpiperazin-1-yl)-6-methoxypyridin-2-yl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one 4.39 was prepared using a procedure analogous to that described for Example 4.31 starting with the TFA salt of (R)-4-((R)-1-((5-(6-methoxy-5-(piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one 4.38.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15]CC2C=CC=CC=2)=[C:10]([F:23])[CH:9]=1)=[O:4]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[CH:9]=[C:10]([F:23])[C:11]([OH:15])=[C:12]([F:14])[CH:13]=1)=[O:4]
Reactant: COC(=O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reaction time: 12 h
Yield: 112.9 %

Procedure:
2-(4-Benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarboxylic acid methyl ester (21 mg, 0.066 mmol) obtained in Step B was dissolved in THF/MeOH (1 mL/1 mL), and Pd/C (10%, 10 mg) was added thereto. The mixture was stirred under hydroten atmosphere for 12 hours, filtered by using celite, and concentrated under reduced pressure to obtain the title compound (17 mg, 99%).
Reaction SMILES: B([C:4]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])(O)O.[NH2:19][C:20]1[C:25](Br)=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:19][C:20]1[C:25]([C:4]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=2[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=1
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1B(O)O
Reactant: Cc1cnc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(N)c(-c2cc(C(F)(F)F)ccc2OCC(=O)O)c1
Temperature: 100 °C

Procedure:
A mixture of the product from step (iv) (0.1 g), 2-amino-3-bromo-5-methylpyridine (0.071 g), tetrakis(triphenylphosphine)palladium(0) (0.046 g), sodium carbonate (0.12 g) in methanol (2 ml) was heated in a CEM microwave (variable wattage up to 150 W) at 100° C. for 10 min. The mixture was loaded onto SCX resin (sulphonic acid resin), flushed with methanol then the product eluted with methanol/ammonia. The methanol/ammonia filtrate was evaporated under reduced pressure then loaded onto bondelut-NH2 resin. The resin was flushed with methanol then the product eluted with methanol/acetic acid. The methanol/acetic acid filtrate was evaporated and the residue purified by RPHPLC. Yield 0.089 g
Reaction SMILES: [CH3:1][C:2](=[C:4]([CH3:6])[CH3:5])[CH3:3].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15](=[O:22])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1>>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[C:4]([CH3:6])([CH3:5])[C:2]([CH3:3])([CH3:1])[O:22]1
Reactant: CC(C)=C(C)C
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Product: CC1(C)OC(Cn2cncn2)(c2ccc(F)cc2F)C1(C)C
Yield: 15 %

Procedure:
Following a procedure similar to that described in Example 39, but using 2,3-dimethyl-2-butene and 2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone, 85 mg (yield 15%) of the title compound, melting at 100°-101° C., were obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C[C:17]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:11]2[CH:2]=[N:3][C:4]([N:18]3[CH2:17][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:9][CH:10]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCCCC3)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.442 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42].Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 82 %

Procedure:
Condensation of BocPro-DPhe-PheNHNH2 (1.98 g.) and HGly-Leu-MetNH2 hydrochloride salt (Example 7, 1.3 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DPhe-Phe-Gly-Leu-MetNH2 in 82% yield. De-t-butoxycarbonylation of BocPro-DPhe-Phe-Gly-Leu-MetNH2 (1.8 g.) using hydrogen chloride in acetic acid gave HPro-DPhe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt monohydrate in 59% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:7]=[CH:6]2)=[O:2].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:2][CH:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:7]=[CH:6]2
Reactant: Br[Mg]c1ccccc1
Reactant: CN(C)C(=O)n1ccc2cc(C=O)ccc21
Solvent: C1CCOC1
Product: CN(C)C(=O)n1ccc2cc(C(O)c3ccccc3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a stirred solution of 5-formyl-N,N-dimethyl-1H-indole-1-carboxamide (0.63 g, 2.9 mmol) in anhydrous THF (5 mL) was added phenyl magnesium bromide solution (3 M in diethyl ether, 1.1 mL, 3.3 mmol) at −78° C. under argon. The reaction mixture was stirred at −78° C. for 1 hr, at rt for 1 hr and quenched by the slow addition of saturated aq ammonium chloride aqueous solution (10 mL) Water (10 mL) was added, the reaction mixture was extracted with ethyl acetate (20 mL) dried (Na2SO4), filtered through a pad of silica gel, and concentrated to give 5-(hydroxy(phenyl)methyl)-N,N-dimethyl-1H-indole-1-carboxamide (0.9 g, 3 mmol, 100% yield) as a syrup, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:5][C:6]=1[CH2:7][CH2:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][CH2:20][CH3:21])=[CH:15][NH:16]2)=[CH:12][CH:11]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[H-].[Na+]>>[C:37]([O:36][C:34](=[O:35])[CH2:33][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([O:9][CH2:8][CH2:7][C:6]3[S:5][C:4]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)=[N:3][C:2]=3[CH3:1])[CH:18]=2)[C:14]([CH2:19][CH2:20][CH3:21])=[CH:15]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCc1c[nH]c2cc(OCCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12
Agent: [H-]
Agent: [Na+]
Product: CCCc1cn(CC(=O)OC(C)(C)C)c2cc(OCCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12

Procedure:
In analogy to the procedure described in example 3 a], 6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-3-propyl-1H-indole was reacted with tert-butyl bromoacetate in the presence of sodium hydride to obtain (6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-3-propyl-indol-1-yl)-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](C=C)=[C:4]([CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11].[OH-].[Li+].S([O-])(O)(=O)=[O:38].[Na+]>CO.O>[OH:38][C:3]1[C:2]([CH3:1])=[C:10]2[C:6]([C:7](=[O:11])[O:8][CH2:9]2)=[C:5]([O:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[C:4]=1[CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: O=S(=O)([O-])O
Reactant: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate (0.37 g) and lithium hydroxide (0.4 g) in methanol (6 ml) and water (6 ml) was heated at 62° C. for 15 hours. The reaction was acidified with aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate/hexane/acetic acid to give (E) 6-(1,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 148°-149° C. (tert-butylmethyl ether/hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3](=O)[C:2]21[CH2:16][CH2:15][C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:8]2.[BH4-].[Na+].C[OH:20]>O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:16][CH2:15][C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:8]2[OH:20]
Reactant: O=C1CCCNC12CCc1ccccc1C2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OC1c2ccccc2CCC12CCCCN2
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol was dissolved 0.80 g of 3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-one and following addition of 0.15 g of sodium borohydride in small portions, the mixture was stirred for 30 minutes. The reaction mixture was then diluted with water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and the solvent was distilled off. The solid group was recrystallized from methylene chloride-ether to provide 0.25 g of white crystals.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)O1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH:29]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCOCC5)c4)nc23)CCCCC1

Procedure:
(1-Methyl-cyclohexyl)-[2-(3-morpholin-4-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine following general procedures as described in these Examples. MP 208-209° C., M+H=405.