Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[S:3].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=2)[CH2:18][CH2:17]1>O1CCCC1>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=[C:23]2[NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][NH:13][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N+:10]([O-:12])=[O:11])=[S:3])[CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 1.8 parts of 1-isothiocyanato-2-nitrobenzene, 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 3.7 parts (67%) of N-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]-N'-(2-nitrophenyl)thiourea as a residue.
Reaction SMILES: [CH3:1][C:2]([N+:9]([O-:11])=[O:10])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>ClCCl.O.C(N(CC)CC)C>[CH2:24]([NH:31][C:5](=[O:7])[CH2:4][CH2:3][C:2]([CH3:1])([N+:9]([O-:11])=[O:10])[CH3:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(CCC(=O)O)[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCC(=O)NCc1ccccc1)[N+](=O)[O-]
Reaction time: 1 h
Yield: 37.4 %

Procedure:
The 4-methyl-4-nitropentanoic acid (4.3 g) obtained above was dissolved in dichloromethane, and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.1 g) and triethylamine (4.5 ml) were added thereto and stirred for 1 hour. Benzylamine (3.4 g) was added thereto and stirred for 1 day. Water was added to the reaction mixture which was then acidified by 2 N hydrochloric acid and extracted with chloroform. The organic phase was washed with a saturated sodium bicarbonate solution and a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; ethyl acetate:n-hexane 1:1.5) to give N-benzyl-4-methyl-4-nitropentanoic acid amide (2.5 g, Y.:38%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:11]([OH:13])[OH:12])[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.[C:14](Cl)(Cl)=[S:15]>Cl>[N:1]([C:2]1[CH:3]=[C:4]([B:11]([OH:13])[OH:12])[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1)=[C:14]=[S:15]
Reactant: Nc1cc(B(O)O)cc(C(=O)O)c1
Reactant: S=C(Cl)Cl
Agent: Cl
Product: O=C(O)c1cc(N=C=S)cc(B(O)O)c1
Temperature: 25 °C

Procedure:
To a solution of 3-amino-5-carboxyphenylboronic acid (150 mg, 0.08 mmol) in 3N HCl (3 ml) was added thiophosgene (92 mg, 0.08 mmol) in 3N HCl (3 ml) and the reaction mixture was stirred at room temperature. A white solid was formed after 20 minutes. This was recrystallized from hexane/ethyl acetate. M.P. >350° C. Anal. Calcd. for C8H6NO4BS.3H2O. C, 42.06; H, 2.91; N, 6.13. Found: C, 42.51; H, 2.87; N, 5.68.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]([NH:17][C:18](=[O:25])[CH2:19][C:20](OCC)=[O:21])[NH:14][N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:26]O.C(O[CH2:32][CH3:33])(=O)C>CN(C)C1C=CN=CC=1.O>[CH3:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]3[N:17]=[C:18]([OH:25])[CH:19]=[C:20]([OH:21])[N:14]3[N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:26][N:17]([C:15]1[CH:16]=[CH:12][N:13]=[CH:32][CH:33]=1)[CH3:18]
Reactant: CO
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2nc3ccccc3nc2C)n[nH]1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Product: Cc1nc2ccccc2nc1-c1cc2nc(O)cc(O)n2n1
Temperature: 65 °C

Procedure:
Method B (DMAP salt): A suspension of ethyl 3-{[3-(3-methylquinoxalin-2-yl)-1H-pyrazol-5-yl]amino}-3-oxopropanoate (1.00 g, 2.95 mmol) and 4-dimethylaminopyridine (DMAP) (1.08 g, 8.84 mmol) in water (7 mL), tetrahydrofuan (7 mL), and methanol (7 mL) was heated at 65° C. for 4 h. After being cooled to ambient temperature, the reaction mixture was diluted with water and ethyl acetate. The aqueous layer was collected and concentrated in vacuo. The residue was triturated with ether acetate to give 2-(3-methylquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol DMAP salt. MS (APCI): m/z 294 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.O[N:17]1C(=O)C2C(=CC=CC=2)C1=O.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.O.NN>C(Cl)Cl.O>[NH2:17][O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CON)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.2 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5 g, 23 mmol) in CH2Cl2 (250 mL) was added 2-hydroxyisoindolin-1,3-dione (5.6 g, 34.5 mmol) and triphenylphosphine (15 g, 57.5 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (11.1 ml, 57.5 mmol) was slowly added dropwise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture H2O (300 mL) was added and extracted with CH2Cl2. The organic layers were washed with brine. Dried over anhydrous MgSO4, filtered and concentrated to provide clear oil, which was purified by flash chromatography (50% EtOAc-Hexane). The resultant clear oily compound 2S was dissolved in CHCl3:CH3OH (50 ml). Hydrazine hydrate (25 mL, 0.25 mol) was added. The reaction mixture was stirred at ambient temperature overnight. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear oil, which was purified by flash chromatography (10% CH3OH—CH2Cl2) to afford 3 g (56%, over two steps) of tert-butyl 2-(aminooxymethyl)morpholine-4-carboxylate (2T) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9H) 3.46-3.62 (m, 2H) 3.61-3.79 (m, 4H) 3.79-4.04 (m, 3H). [M+H] calc'd for C10H20N2O4, 233. found, 233.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1Cl.[H-].[Na+].[C:13](=[S:15])=[S:14].[F:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>CN(C=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][S:14][C:13]3[S:15][C:3]4[C:4](=[O:9])[N:5]([CH3:8])[N:6]=[CH:7][C:2]=4[N:1]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1ncc(N)c(Cl)c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2nc(SCc3ccc(C(=O)c4ccc(F)cc4)cc3)sc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
In DMF (10 ml) was dissolved 5-amino-4-chloro-2-methyl-3(2H)-pyridazinone (638 mg) followed by addition of 60% sodium hydride (384 mg), and the mixture was stirred at room temperature for 10 minutes. Then, carbon disulfide (365 mg) was added and the mixture was further stirred at 80° C. for 1 hour. Thereafter, 4-(4-fluorobenzoyl)benzyl bromide (1.4 g) was added and the mixture was stirred at room temperature for 1 hour. This reaction mixture was extracted with ethyl acetate-THF and the organic layer was washed serially with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate =1:1) to provide 1.2 g of white powder.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
In THF (15.0 ml)/methanol (15.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.75 g). To the solution was added 1N sodium hydroxide solution (7.5 ml), and the mixture was stirred at room temperature for 20 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=6/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.61 g).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH3:13].[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH2:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:13]
Reactant: CCN1CCCCC1CCc1ccccc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCN1CCCCC1CCc1ccccc1NC(=O)c1ccc(OC)cc1

Procedure:
Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with anisoyl chloride according to the procedure of Example 25 provides 2'-[2-(1-ethyl-2-piperidyl)ethyl]-p-anisanilide, m.p. 136.5° -137.5° C. (corr.), from ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH3:36]I>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH3:36])[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CI
Product: Cc1ccccc1N1C(C)N(C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and methyl iodide.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17]OS(C1C=CC(Cl)=CC=1)(=O)=O)=[O:6])[CH:2]=[CH2:3].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.[K].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][N:33]1[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]2[C:29]1=[O:39])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 60.8 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-p-chlorobenzenesulfonyloxymethyl-4-methanesulfonyloxypyrrolidine (23.7 g: ca. 50 mmole) in dimethylformamide (50 ml), potassium phthalimide (10.2 g: 55 mmole) is added in a nitrogen atmosphere, and the mixture is stirred at 60° C. for 3.5 hours. The reaction mixture is poured into a stirring mixture of ice water (500 ml) and ethyl acetate (500 ml). The organic layer is successively washed with water (4 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from a mixture of n-hexane and toluene. The solid is filtered off and the filtrate is purified by silica gel chromatography (toluene-ethyl acetate) to give crude (2S,4R)-1-allyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (12.41 g). Yield: 61%. Colorless oil.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=[C:2]2[NH:29][C:28]2[CH:30]=[CH:31][C:25]([Cl:24])=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: FC(F)(F)c1cc(CBr)ccc1Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: FC(F)(F)c1cc(Cn2c(Nc3ccc(Cl)c(C(F)(F)F)c3)nc3ccccc32)ccc1Cl

Procedure:
The title compound was prepared by Procedure B in two steps from 2-chloro-benzimidazole, 4-chloro-3-trifluoromethylbenzyl bromide and 4-chloro-3-trifluoromethylaniline. The product was isolated by preparative LCMS to give the title compound as the free base (off-white solid, mp 88-92° C.). MS(ES+) m/z 504 (M+, 100). 1NMR (DMSO-d6) δ 5.60 (s, 2H), 7.02-7.15 (m, 2H), 7.25-7.32 (m, 2H), 7.45-7.52 (m, 1H), 7.63-7.70 (m, 2H), 7.81 (s, 1H), 8.23-8.40 (m, 2H), 9.62 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[NH2:16][CH2:17][C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1C=CC=CC=1>[ClH:8].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH:16][CH2:17][C:18]1([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:7]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Solvent: c1ccccc1
Product: COc1cc(C(=O)NCC2(N3CCN(C)CC3)CCCCC2)cc(OC)c1OC
Product: Cl
Yield: 45.4 %

Procedure:
A solution of 3,4,5-trimethoxybenzoyl chloride (2.2 g;) in dry benzene (25 ml) and a solution of 1-[1-(aminomethyl)cyclohexyl]-4-methyl piperazine (2.0g;) in dry benzene (25 ml) were mixed and heated under reflux for 1 hr. The solid which formed was filtered, washed with benzene and was crystallised from isopropanol-ether to give 1-[1-(3,4,5-trimethoxybenzamidomethyl)cyclohexyl]-4-methyl piperazine hydrochloride (1.9 g., 45.4%) m.p. 208°-9° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[CH3:17])[CH3:2].[CH2:19](OC(=O)COC1C=C(C)C=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:19])[C:10]([S:13]([Cl:16])(=[O:14])=[O:15])=[CH:9][C:8]=1[CH3:17])[CH3:2]
Reactant: CCOC(=O)COc1cc(C)ccc1C
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Product: CCOC(=O)COc1cc(C)c(S(=O)(=O)Cl)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.2, using compound 21.1 as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.86 (1H, s); 6.61 (1H, s); 4.74 (2H, s); 4.30 (2H, q, J=7.1 Hz); 2.71 (3H, s); 2.31 (3H, s); 1.32 (3H, t, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[ClH:1].[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]=[C:2]2[NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]
Reactant: COc1cccc2c(Cl)cc(-c3ccccc3)nc12
Reactant: NCC(O)CO
Product: COc1cccc2c(NCC(O)CO)cc(-c3ccccc3)nc12
Product: Cl

Procedure:
The title compound, m.p. 110-116° C., and MS: m/e=325.3 (M+H+), was prepared from 4-chloro-8-methoxy-2-phenyl-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1[C:17]([CH3:25])=[C:18]([F:24])[C:19](OCC)=[O:20])[CH3:2].[H-].[CH2:27]([Al+]CC(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][C:5]=1/[C:17](/[CH2:25][CH3:27])=[C:18](/[F:24])\[CH2:19][OH:20])[CH3:2]
Reactant: CCOC(=O)C(F)=C(C)c1cc2c(cc1OCC)OC(C)(C)C=C2C
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl 3-(7-ethoxy-2,2,4-trimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 80,226 mg, 0.62 mmol) and diisobutylaluminum hydride (1 M in dichloromethane, 1.87 mL, 1.87 mmol) were reacted to give the title compound as yellow solid after purification by flash chromatography (silica gel, 1:4 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[N:16]([CH3:24])[C:17]([CH3:23])=[C:18]([C:20]([OH:22])=O)[N:19]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:20]([C:18]1[N:19]=[C:15]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:25])[N:16]([CH3:24])[C:17]=1[CH3:23])=[O:22])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1c(C(=O)O)nc(-n2ccc(OCc3ccccc3)cc2=O)n1C
Reactant: NCc1ccccc1
Product: Cc1c(C(=O)NCc2ccccc2)nc(-n2ccc(OCc3ccccc3)cc2=O)n1C
Yield: 76 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1,5-dimethyl-1H-imidazole-4-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 76% yield: mp 190-191° C.; 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (m, 10H), 7.21 (d, J=7.7 Hz, 1H), 6.08 (dd, J=7.7, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.04 (s, 2H), 4.56 (d, J=6.1 Hz, 2H), 3.39 (s, 3H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.3, 163.4, 163.1, 138.6, 138.4, 137.1, 134.7, 133.5, 129.1, 128.8, 128.7, 128.5, 127.8, 127.7, 127.2, 102.7, 97.8, 70.6, 42.7, 30.6, 10.0; MS (ES+) m/z 429.3 (M+1).
Reaction SMILES: [CH:1]([C:3]1[O:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]([O:11]CC)=O)=O.O.[NH2:15][NH2:16]>CO>[O:8]1[C:3]2[CH:1]=[N:15][NH:16][C:9](=[O:11])[C:4]=2[CH2:5][CH2:6][CH2:7]1
Reactant: NN
Reactant: CCOC(=O)C1=C(C=O)OCCC1
Solvent: O
Solvent: CO
Product: O=c1[nH]ncc2c1CCCO2
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a stirred 0° C. mixture of ethyl 6-formyl-3,4-dihydro-2H-pyran-5-carboxylate (1.705 g, 9.26 mmol) in methanol (80 mL) was added very quickly 35% hydrazine hydrate (0.311 g, 9.72 mmol). After 20 minutes, the solvent was removed under reduced pressure, and the residue was treated with acetic acid (70 mL) and water (7 mL) and stirred at 110° C. for 20 minutes. The solvents were removed in vacuo. The crude residue was eluted by silica gel chromatography with a 0 to 25% gradient of methanol/dichloromethane to afford the title compound (1.384 g) as a light yellow solid in better than 90% purity. MS (ESI) [m/e, (M+H)+]=153.2. 1H NMR (400 MHz, chloroform-d) δ ppm 10.56 (br s, 1H), 7.53 (s, 1H), 4.17-4.35 (m, 2H), 2.57 (t, J=6.57 Hz, 2H), 1.99-2.08 (m, 2H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.CS([C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[N:21]2[N:34]=[CH:35][N:36]=[C:20]2[N:19]=1)(=O)=O>O>[C:1]1([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][N:25]=3)[N:21]3[N:34]=[CH:35][N:36]=[C:20]3[N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(-c3ccccc3)nc3ncnn23)nc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
0.2 mL of a phenyl magnesium bromide 3.0 M tetrahydrofuran solution was added at 0° C. to a tetrahydrofuran (dehydrated) 3 mL solution of 200 mg of 5-(methylsulfonyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, followed by stirring at 0° C. for 5 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to obtain 93 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC.Cl.C[O:34]C(O)C>C(Cl)(Cl)Cl>[OH2:34].[ClH:1].[C:16]1([C@H:22]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ncnc2cc3ccccc3cc12
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(C)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1ncnc2cc3ccccc3cc12)c1ccccc1
Product: O
Yield: 64 %

Procedure:
4-Chlorobenzo[g]quinazoline (107 mg, 0.5 mmol), [R]-1-phenylethylamine (72 mg, 0.6 mmol) and NEt3 (202 mg, 2.0 mmol) in stirred methoxyethanol (2 mL) are heated under N2 at 100° C. for 90 min. On cooling the reaction mixture is diluted with CHCl3 (10 ML), and is shaken with dilute hydrochloric acid (0.2 M, 15 mL). The heavy yellow precipitate is collected by Buchner filtration, rinsed with water (5 mL), and dried in vacuo at 60° C. to give 4-([R]-1-phenylethyl-amino)benzo[g]quinazoline hydrochloride hydrate (122 mg, 64%) as a yellow solid. 1H NMR (DMSO) δ14.75 (1H brs), 10.85 (1H, d, J=8.0 Hz), 9.61 (1H, s), 8.90 (1H, s), 8.36 (1H, s), 8.18 (1H, d, J=8.2 Hz), 7.82 (1H, t, J=7.6 Hz), 7.74 (1H, t, J=7.4 Hz), 7.56 (2H, d, J=7.5 KHz), 7.39 (2H, t, J=7.6 Hz), 7.30 (1H, t, J=7.4 Hz), 5.92 (1H, pentet, J=7.2 Hz), 1.76 (3H, d, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:31]>P(Cl)(Cl)(Cl)=O>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:31])=[N:7][C:2]=3[N:1]=2)=[CH:16][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)[nH]c2c1=O
Yield: 30.2 %

Procedure:
The above N-(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide (1.0 g, 0.0025 mol) and phosphorous pentachloride (0.64 g, 0.0025 mol) were taken in phosphorous oxy chloride (25 ml) and refluxed for 20 hours The mixture was cooled and solvent was removed. The residue was dissolved in water (20 ml) and extracted with DCM (3×5 ml). The organic layer was washed with sat.NaHCO3 (30 ml) followed by saturated brine solution (2×30 ml) and dried over Na2SO4. Solvent was removed and the residue was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.298 g, 30%) as a yellow solid.