Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][N:17]2[CH2:20][C:21]2[CH:38]=[CH:37][C:24]([C:25]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[O:26])=[CH:23][C:22]=2[O:39][CH3:40])=[CH:13][CH:12]=1>>[CH:1]1([CH2:6][C:7]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][C:21]3[CH:38]=[CH:37][C:24]([C:25]([NH:27][S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])=[O:26])=[CH:23][C:22]=3[O:39][CH3:40])=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1ccc2ccc(N)cc21
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1ccc2ccc(NC(=O)CC3CCCC3)cc21

Procedure:
Using a similar procedure to that described in Example 157, but starting with 2-cyclopentylacetyl chloride and N-(4-[6-aminoindol-1-ylmethyl]-3-methoxybenzoyl)benzenesulphonamide, there may be obtained N-(4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoyl)benzenesulphonamide as a solid essentially identical in physical properties to that obtained in Example 280.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([C:11]([O:13]CC)=O)[CH:4]=1)[CH3:2].[OH-].[NH4+:17].CO>>[CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([C:11]([NH2:17])=[O:13])[CH:4]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCCn1nc(C(=O)OCC)cc1CC
Agent: [OH-]
Solvent: CO
Product: CCCn1nc(C(N)=O)cc1CC
Temperature: 125 °C

Procedure:
Ethyl 5-ethyl-1-propyl-1H-pyrazole-3-carboxylate (13.0 g, 62 mmol) in a 4:1 mixture of concentrated ammonium hydroxide/methanol (50 mL) was heated at 125° C. for 18 hours in a pressure vessel. After cooling to ambient temperature, the contents of the vessel were poured into a flask and a precipitate formed immediately. The precipitate was isolated by filtration to yield 5.02 g of analytically pure 5-ethyl-1-propyl-1H-pyrazole-3-carboxamide as off-white crystals, mp 105-106° C. MS (APCI) m/z 182.1 (M+H)+; Anal. calcd for C9H15N3O: C, 59.64; H, 8.34; N, 23.19. Found: C, 59.59; H, 8.54; N, 23.39. An additional 0.50 g of product was obtained in the second crop from the filtrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:6]=O.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[F:17])[CH2:29][CH2:28]2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1cc(C=O)ccc1OC(=O)N(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(CN2CCN(c3ccccc3F)CC2)ccc1OC(=O)N(C)C
Yield: 78 %

Procedure:
To a solution of 3-methoxy-4-(dimethylaminocarbonyloxy)benzaldehyde (1.50 g) in 1,2-dichloroethane (14 ml) was added 1-(2-fluorophenyl)piperazine (1.21 g) in 1,2-dichloroethane (13 ml) and sodium triacetoxyborohydride (2.14 g), with stirring. The reaction mixture was stirred for 4 hrs at ambient temperature, poured into saturated sodium carbonate solution (75 ml) and extracted with dichloromethane. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatographed (silica gel), eluting with dichloromethane, followed by 0.1, 0.2, 0.4, 0.5, 1, and 2% methanol:dichloromethane. The appropriate fractions were combined and concentrated to afford 2.03 g (78%) of product. Recrystallization from ethyl acetate gave the analytical sample, mp 130-133° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[S:31]([CH3:34])(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][C:30]([S:31]([CH3:34])(=[O:32])=[O:33])=[C:25]([F:24])[CH:26]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1F
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)c(F)c4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-4-methylsulfonyl-phenylboronic acid following a procedure analogous to that described for Example 1. LC (method 4): tR=1.71 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:14]([C:15](=[S:16])[NH2:17])[NH2:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNC(N)=S
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: NC(=S)N(N)C(=O)Cc1cc(F)cc(F)c1
Reaction time: 18 h
Yield: 46.9 %

Procedure:
2.5 g of 3,5-difluorophenylacetic acid (14.52 mmol, 1 eq.) are placed in 70 mL of dichloromethane with stirring. 1.46 g of thiosemicarbazide (15.98 mmol, 1.1 eq.), 2.22 g of hydroxybenzotriazole (14.52 mmol, 1 eq.) and 2.78 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.52 mmol, 1 eq.) are successively added with continued stirring at room temperature. After 18 hours at room temperature, the dichloromethane is evaporated off. The residue is taken up in ethyl acetate and 1N hydrochloric acid. The precipitate is filtered off and dried to give 1.67 g of [(3,5-difluorophenyl)acetyl]hydrazinecarbothioamide.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH3:22])=[O:20].[F:25][C:26]([F:43])([F:42])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39]CO)[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH2:22][CH2:39][N:36]1[CH2:35][CH2:34][N:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:43])([F:25])[F:42])[CH:28]=2)[CH2:38][CH2:37]1)=[O:20]
Reactant: COC(=O)c1sccc1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1sccc1Nc1ccnc2c(C(F)(F)F)cccc12
Temperature: 60 °C
Reaction time: 10 h
Yield: 92.3 %

Procedure:
A mixture of 7 g of methyl 3-(8-trifluoromethyl-4-quinolylamino)-2-thiophene-carboxylate, 6.17 g of 4-(3-trifluoromethylphenyl)-1-piperazine-ethanol and 50 ml of anhydrous toluene was refluxed for an hour while passing condensed toluene through a column filled with siliporite and the mixture was cooled to 60° C. 150 mg of sodium hydride were added and the mixture was refluxed with stirring for 10 hours. The toluene was distilled and the residue was extracted with ether, washed with water and dried. The product was crystallized from methylene chloride to obtain 10.9 g of 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-ethyl 3-(8-trifluoromethyl-4-quinolylamino)-2-thiophene-carboxylate.
Reaction SMILES: [CH2:1]([C:12]1[O:13][CH2:14][CH2:15][N:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:14][CH2:15][NH:16][C:12](=[O:13])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:18]
Reactant: CCNCC
Reactant: CCCCCCCCCCCC1=NCCO1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Product: CCCCCCCCCCC(=O)NCCN(CC)CC
Yield: 87 %

Procedure:
Undecyloxazoline (53 mmoles), diethylamine (104 mmoles) and 0.9 mmole of zinc acetate are reacted under conditions similar to Example 2 to yield 87 percent of theoretical N-(2-diethylaminoethyl)undecylamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9](O)([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1(/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(C)(O)C1(C(=O)OCC)CC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)/C=C(\C)C1(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A 90.31 g (0.37 mol) portion of ethyl 1-ethoxycarbonyl-β-hydroxy-β-methyl-cyclopropanepropanoate was dissolved in 182 ml of pyridine to which was subsequently added dropwise thionyl chloride at -10° C. to -5° C. After completion of the dropwise addition, this was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction solution was poured into 1 liter of ice water and extracted with dichloromethane (300 ml×3). The organic layers were combined, washed with 1N hydrochloric acid (1 liter×1) and saturated brine (1 liter×1) in that order and then dried on anhydrous sodium sulfate. To the resulting dichloromethane solution was added dropwise 58 ml of 1,8-diazabicyclo[5,4,0]-7-undecene at 0° C., followed by 18 hours of stirring at room temperature. After completion of the reaction, the reaction solution was washed with 1N hydrochloric acid (1 liter×1) and saturated brine (1 liter×1) in that order, and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was applied to a silica gel column chromatography to yield 56.57 g (68%) of the title compound as an oily substance from the eluate of n-hexane:ethyl acetate=9:1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1
Reactant: OCCC1CCNCC1
Reactant: Clc1ccc2ccccc2n1
Product: OCCC1CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed as in Example 4 (step 4.1). Starting with 2 g (12.20 mmol) of 2-chloroquinoline and 1.58 g (12.20 mmol) of 2-(4-piperidyl)ethanol, and after chromatography on silica gel, eluting with a 98/2/0.2 and then 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, 2.36 g of pure product are obtained in the form of a pale yellow oil that crystallizes at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:18]O)[CH:13]=[C:14]([Br:17])[CH:15]=2)[CH:10]=[C:9]1[O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:47])[CH2:32][CH:33]([N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[NH:39][C:38]1=[O:46])[CH2:34][CH2:35][CH3:36])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:39]3[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[N:37]([CH:33]([CH2:32][C:31]([O:30][CH3:28])=[O:47])[CH2:34][CH2:35][CH3:36])[C:38]3=[O:46])[CH:13]=[C:14]([Br:17])[CH:15]=2)[CH:10]=[C:9]1[O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Oc1cc2c(CO)cc(Br)cc2n1C(=O)OC(C)(C)C
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Br)cc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c2ccccc21
Temperature: 0 °C
Yield: 56 %

Procedure:
6-Bromo-2-tert-butoxycarbonyloxy-4-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (220 mg, 0.50 mmol) is and 3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (151 mg, 0.55 mmol) is taken up in 5 mL of tetrahydrofuran and then triphenyl phosphine is added (157 mg, 0.6 mmol). The reaction is stirred at 0° C. and diisopropyl azodicarboxylate (116 □L, 0.6 mmol) is added drop wise to the reaction. The reaction is stirred at room temperature for 4 hours and then the solvent evaporated in vacuo. Product is purified by preparative TLC 3% methanol in dichloromethane to give the title compound (200 mg 0.28 mmol 57%). LCMS (ESMS): m/z 687.7 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:13]=[C:14](S(C)=O)[NH:15][C:16](=[O:21])[C:17]=2[C:18]([NH2:20])=[O:19])[CH:8]=[CH:9][CH:10]=1)=[O:4].[NH2:25][CH2:26][C:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN1C(=O)CCC1>C(OCC)(=O)C>[NH2:33][C:27]1([CH2:26][NH:25][C:14]2[NH:15][C:16](=[O:21])[C:17]([C:18]([NH2:20])=[O:19])=[C:12]([NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=3)[N:13]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1(N)CCCCC1
Reactant: CNC(=O)c1cccc(Nc2nc(S(C)=O)[nH]c(=O)c2C(N)=O)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(Nc2nc(NCC3(N)CCCCC3)[nH]c(=O)c2C(N)=O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A mixture of 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 311) (234 mg), 1-(aminomethyl)cyclohexaneamine (172 mg) and NMP (2 mL) was stirred at 80° C. for 30 minutes. After cooling, the reaction liquid was diluted with ethyl acetate, and the precipitated solid was collected by filtration. This solid was heated with ethanol-water and washed to give 2-{[(1-aminocyclohexyl)methyl]amino}-4-{[3-(methylcarbamoyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (215 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=O)[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.[OH-].[NH4+]>C(OC(=O)C)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[C:29](=[O:31])[O:30][C:9]3=[N:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:4]3[C:1]=2[CH3:2])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(C)c(-c3cccc(Cl)c3)c(=O)oc2nc1C(=O)OCC
Temperature: 0 °C
Yield: 95.1 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (12.0 g, 0.043 mol), 3-chlorophenyl acetic acid (7.33 g, 0,043 mol) and triethylamine (6.52 g) are refluxed in 120 mL of acetic anhydride for three hours. The reaction mixture is cooled, poured into 120 mL of ice-cold water and made alkaline to pH 8 with an ammonium hydroxide solution. The crystalline solid is filtered and washed with water to give (17.0 g, 95%) of the product after drying. Recrystallization from ethyl acetate affords the pure product (13.29, 74% yield), melting point 170°-172° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[C@:5]3([C@@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:4][CH2:3]1.[CH:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:35]=[C:34](Cl)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[C:23]1([C:26]2[N:35]=[C:34]([O:19][C:16]3[CH:17]=[CH:18][C:13]4[CH2:12][C@H:11]5[N:2]([CH3:1])[CH2:3][CH2:4][C@@:5]6([C:14]=4[CH:15]=3)[C@H:10]5[CH2:9][CH2:8][CH2:7][CH2:6]6)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: CN1CC[C@@]23CCCC[C@@H]2[C@@H]1Cc1ccc(O)cc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2nc(-c4ccccc4)nc4ccccc24)cc13
Yield: 95.7 %

Procedure:
The O-demethylation procedure described in Steroids 11:151 [1968] was modified for this synthesis. First, 16.1 g (62.3 mmol) of dextrorphan, 2, were dissolved in 500 mL hot acetone, to which 15.5 g (64.4 mmol) AM-ex-OL (Aldrich) and 17.13 g (123.9 mmol) potassium carbonate were added. The reaction mixture was stirred at reflux overnight under an atmosphere of argon. After cooling, the reaction mixture was poured into a separatory funnel to which 500 mL water were added. Extraction with 1×500 and 2×250 mL benzene was followed by washing the combined organics with 1×250 mL water and removing the solvent in vacuo to give 27.51 g (96%) product as a white glass which was homogeneous by TLC. Recrystallization in ethyl acetate gave pure 3 as white crystals, mp 138°-139° C. EIMS m/z 461. Anal. (C31H31N3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.CO[C:23](=O)[CH:24]([C:26]1C=CC=CC=1)N>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@@H:12]([C:17]3[CH:19]=[CH:26][CH:24]=[CH:23][CH:18]=3)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Reactant: COC(=O)C(N)c1ccccc1
Agent: Cl
Product: COC(=O)[C@H](c1ccccc1)N1Cc2ccc(Br)cc2C1=O

Procedure:
The compound of example 344 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and 2-phenyl glycine methyl ester hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[N:12]=[C:13]([C:17]([O:19]CC)=[O:18])[NH:14][C:15](=[O:16])[C:6]1=[CH:5]2.[OH:22][C:23]1C=C2C(=CC=1)N=C1N=C(C(O)=O)NC(=O)C1=C2>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:22][CH3:23])[N:8]=[C:7]1[N:12]=[C:13]([C:17]([OH:19])=[O:18])[NH:14][C:15](=[O:16])[C:6]1=[CH:5]2
Reactant: O=C(O)c1nc2nc3ccc(O)cc3cc2c(=O)[nH]1
Reactant: CCOC(=O)c1nc2nc3ccc(O)cc3cc2c(=O)[nH]1
Product: COc1cc2nc3nc(C(=O)O)[nH]c(=O)c3cc2cc1O

Procedure:
In like manner, ethyl 7-hydroxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate hemitrifluoroacetate (210 mg.) is converted to 7-hydroxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylic acid. Yield - 191 mg., 91%; m.p. 340° C. (dec.)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7](OCC)=[O:8].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][OH:8]
Reactant: CCOC(=O)C(C)(CCCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCCBr)c1ccccc1
Yield: 84.4 %

Procedure:
According to the procedure given for the synthesis of 206e, 205d (52.0 g, 166.0 mmol) was reacted with LiBH4 (5.4 g, 247.9 mmol) and methanol (8.2 g, 255.9 mmol) in CH2Cl2 (180 mL) to afford 206d (38.0 g, 84%) as an oil. 1H NMR (CDCl3): δ 7.5-7.1 (m, 5H), 3.60 (d, 1H, J=10.8), 3.53 (d, 1H, J=10.8), 3.34 (t, 2H, J=7.0), 1.90-1.78 (m, 3H), 1.62-1.26 (m, 3H), 1.35 (s, 3H), 1.14 (m, 1H). 13C NMR (CDCl3): δ 144.4, 128.4, 126.5, 126.1, 72.4, 43.2, 37.4, 33.5, 33.3, 22.5, 21.4.
Reaction SMILES: [NH2:1][C:2]1C=CC=C2C=1CNCC2.C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([S:25](Cl)(=[O:27])=[O:26])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1)(=O)C.CN>>[CH3:2][NH:1][S:25]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH2:16][NH:15][CH2:24][CH2:23]2)(=[O:27])=[O:26]
Reactant: CC(=O)N1CCc2cccc(S(=O)(=O)Cl)c2C1
Reactant: Nc1cccc2c1CNCC2
Agent: CN
Product: CNS(=O)(=O)c1cccc2c1CNCC2

Procedure:
By the procedure of Example 15, 8-amino-1,2,3,4-tetrahydroisoquinoline is converted to 2-acetyl-8-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline. Reacting with methylamine by the procedure of Example 27 and hydrolyzing to remove the 2-acetyl group gives 8-methylsulfamoyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:16][C:15]([CH2:25]O)=[N:14]2)=[CH:9][CH:8]=1.[OH-].[Na+]>C(Cl)Cl>[Br:2][CH2:25][C:15]1[CH:16]=[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[N:14]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(-n2nc(CBr)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A solution of phosphorus tribromide (9.31 g, 34.5 mmol) in CH2Cl2 (186 mL) was added drop-wise to a stirred solution of [1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-methanol (7.80 g, 26.5 mmol; prepared analogously to the procedure described in Step C of Example 1) in 50 mL CH2Cl2 at 0° C. The reaction mixture was stirred for an additional 18 h at rt, and then the mixture was neutralized by addition of 40% NaOH with cooling in an ice bath. The organic layer was separated and dried over Na2SO4, and solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2) yielding 8.09 g (86%) of 3-bromomethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole. HPLC: Rt=10.38. (Method A). MS (ES+): mass calculated for C18H17BrN2O, 356.05; m/z found 357.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.42 (s, 4H), 7.39-7.34 (m, 2H), 7.02-6.98 (m, 2H), 6.69 (s, 2H), 4.73 (s, 2H), 3.97 (s, 1H), 2.49 (s, 3H).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.Br[CH2:19][CH2:20][F:21].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN1C(=O)CCC1>[F:21][CH2:20][CH2:19][NH:17][C:14]1[S:15][CH:16]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[N:13]=1
Reactant: Nc1nc(-c2ccc3ccccc3c2)cs1
Reactant: FCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: FCCNc1nc(-c2ccc3ccccc3c2)cs1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
A mixture of 4-(naphthalen-2-yl)thiazol-2-amine hydrochloride (113 mg, 0.5 mmol), 1-bromo-2-fluoroethane (127 mg, 1 mmol), Cs2CO3 (326 mg, 1 mmol), and 15 mg KI in 2 mL of NMP was heated at 80 C for 20 min in a microwave reactor. After cooling to rt, the mixture was taken up to 50 mL EtOAc and washed with water (3×80 mL) and dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford N-(2-fluoroethyl)-4-(naphthalen-2-yl)thiazol-2-amine as a white solid (10 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 1 H), 8.29 (d, J=1.6 Hz, 1 H), 7.95-7.91 (m, 2 H), 7.86-7.83 (m, 1 H), 7.67 (dd, J=8.4, 2.0 Hz, 1 H), 7.57-7.54 (m, 2 H), 6.70 (s, 1 H), 4.79 (t, J=4.8 Hz, 1 H), 4.67 (t, J=4.8 Hz, 1 H), 3.71 (m, 1 H), 3.65 (m, 1 H); MS (ESI) m/z 273 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([CH3:28])=[C:15]3[CH2:29][C:30]([NH2:32])=[O:31])[CH:5]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C>[NH2:32][C:30](=[O:31])[CH2:29][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:33])=[O:2])[CH:13]=2)[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]=1[CH3:28]
Reactant: COC(=O)c1cccc(COc2ccc3c(c2)c(CC(N)=O)c(C)n3Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(CC(N)=O)c2cc(OCc3cccc(C(=O)O)c3)ccc2n1Cc1ccccc1
Reaction time: 7.5 h
Yield: 72.7 %

Procedure:
A mixture of 470 mg (1.06 mmol) of 3-[[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid methyl ester and 2 mL of 2N NaOH in 10 mL of THF and 40 mL of ethanol was stirred for 7.5 hours, the mixture made acidic with 5N HCl and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was crystallized from methylene chloride/ethanol to give 330 mg (72% yield) of 3-[[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid, mp, 176°-179° C.