Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[S:10][C:9]([CH:11]2[CH2:16][C:15](=[O:17])[O:14][C:12]2=[O:13])=[CH:8][CH:7]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:5][C:6]1[S:10][C:9]2[CH:11]([C:12]([OH:14])=[O:13])[CH2:16][C:15](=[O:17])[C:8]=2[CH:7]=1
Reactant: Cc1ccc(C2CC(=O)OC2=O)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc2c(s1)C(C(=O)O)CC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
21.1 g (0.16 mole) of aluminum chloride was quickly added to 50 cc of nitrobenzene at ambient temperature. Then a solution of 11.3 g (0.058 mole) of (5-methyl-2-thienyl) succinic anhydride in 30 cc of nitrobenzene was added drop by drop in 1 hour 30 minutes. The mixture was stirred for 5 hours at ambient temperature then poured into an ice-hydrochloric acid mixture and extracted with methylene chloride. The organic phase was separated and extracted with an aqueous solution of sodium carbonate. The aqueous phase was acidified with dilute hydrochloric acid then extracted with ethyl acetate. The organic solution was washed with water, dried on sodium sulfate and concentrated under reduced pressure. 7.7 g (yield=68%) of 2-methyl-4-oxo-5,6-dihydro-4H-cyclo-penta[b]thiophene-6-carboxylic acid melting at 137°-139° C. was obtained. By recrystallization in a hexane-ethyl acetate mixture, a product was obtained with a melting point of 140°-143° C. identical in all respects with that obtained in example 2.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)[CH:2]([CH3:4])[CH3:3].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:16][C:7]1[C:8]2[O:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:15]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: CC(C)Cc1ccc2c(c1)C(C)(C)CO2
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)Cc1cc(Br)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a solution of 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (1.59 g, 7.78 mmol) in dichloromethane (40 mL) was added pyridinium tribromide (2.49 g, 7.78 mmol) and the reaction mixture stirred at room temperature overnight. The solution was washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified on silica gel (0% to 2% ethyl acetate in hexane) to give 1.51 g of 7-bromo-5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (68%). 1H NMR (300 MHz; CDCl3): δ 0.90 (d, J=6.3 Hz, 6H), 1.33 (s, 6H), 1.77 (m, 1H), 2.39 (d, J=7.5 Hz, 2H), 4.30 (s, 2H), 6.80 (d, J=1.5 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H).
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Cl:9][CH:10]([Cl:24])[CH:11]=[CH:12][S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-])=O)[CH:15]=1>CO.O>[Cl:24][C:10]([Cl:9])=[CH:11][CH2:12][S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([NH2:21])[CH:15]=1
Reactant: Nc1ccc(SC=CC(Cl)Cl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(SCC=C(Cl)Cl)cc1N

Procedure:
In 340 cc of a 1:1 (by volume) mixture of methanol-water containing 43 g of Na2S2O4 were suspended 34.4 millimols of 4-[(3,3-dichloropropenyl)-thio]-2-nitroaniline. The reduction of the nitro-group was achieved in very short times (10-15 min.) as was ascertained by thin-layer chromatography. After the reduction was completed, the methanol and part of the water were removed under vacuum thereby obtaining an oily suspension which was then extracted with chloroform. The organic extracts, after drying on anhydrous Na2SO4, and evaporation of the solvent under vacuum, yielded, with practically quantitative yields, the raw diamine (an intensely colored thick oil) which was directly used for the successive stage.
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH3:24][C:25]1([CH3:41])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([N:34]2[C:38]([CH:39]=O)=[CH:37][N:36]=[CH:35]2)[CH2:26]1>C1COCC1>[CH3:24][C:25]1([CH3:41])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([N:34]2[C:38]([CH:39]=[CH2:2])=[CH:37][N:36]=[CH:35]2)[CH2:26]1
Reactant: CC1(C)CC(n2cncc2C=O)c2ccccc21
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1cncn1C1CC(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide/sodium amide [2.4 mmol/gram of salt (0.86 g, 2.06 mmol)] in THF (3.0 mL) is added a solution of 3-(3,3-dimethyl-indan-1-yl)-3H-imidazole-4-carbaldehyde (165 mg, 0.69 mmol) in THF (2 mL). The reaction is permitted to stir at room temperature for 30 minutes and is then quenched with saturated aqueous NH4Cl. The reaction is diluted with ethyl acetate and the layers are separated. The aqueous layer is extracted with ethyl acetate and the organic layers are combined, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:4) to furnish semi-pure 1-(3,3-dimethyl-indan-1-yl)-5-vinyl-1H-imidazole. Further purification via semi-preparative reverse phase HPLC (5 to 100% acetonitrile/water w/0.1% NH4OH), affords 1-(3,3-dimethyl-indan-1-yl)-5-vinyl-1H-imidazole; MS: (ESI) m/z 239 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 3 H), 1.39 (s, 3 H), 2.11 (dd, J=13.0, 7.7 Hz, 1 H), 2.54 (dd, J=12.9, 7.8 Hz, 1 H), 5.20 (dd, J=11.4, 1.3 Hz, 1 H), 5.62 (dd, J=17.4, 1.3 Hz, 1 H), 5.72 (t, J=7.7 Hz, 1 H), 6.42 (dd, J=17.4, 11.1 Hz, 1 H), 7.09 (dd, J=7.6, 0.8 Hz, 1 H), 7.23-7.30 (m, 3 H), 7.32 (s, 1 H), 7.37 (t, J=7.5 Hz, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether, followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-(3,3-dimethyl-indan-1-yl)-5-vinyl-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([CH3:1])=[O:3])=[CH:6][CH:7]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Oc1ccc(CCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
55 g (0.305 mole) 2-(4-methylcarbonyloxyphenyl)-1-ethanol and 34.4 g (0.341 mole) triethylamine in 300 ml dichloromethane were cooled on an ice bath. 38.5 g (0.336 mole) methanesulfonyl chloride was slowly added. The ice bath was removed and the mixture was stirred for 3 hours at room temperature. Water was added and the phases were separated. The organic phase was washed with saturated sodium hydrogen bicarbonate and brine, dried (magnesium sulfate), filtered and evaporated in vacuo to give 76.6 g (yield 97%) of 4-(methylcarbonyloxy)phenethyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:9][CH:8]=1
Reactant: CO/N=C(\COc1ccc(C=O)cc1)c1ccccc1
Reactant: COC(=O)CCc1ccc(N)cc1
Product: CO/N=C(\COc1ccc(CNc2ccc(CCC(=O)O)cc2)cc1)c1ccccc1

Procedure:
Compound 4 was synthesized from 4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzaldehyde and methyl 3-(4-aminophenyl)propanoate by following the procedure described in Scheme 3.
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][S:12]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)(=[O:14])=[O:13])[CH2:7]1)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])=[CH:25][C:24]=1[F:36]>>[Cl:20][C:17]1[S:16][C:15]([S:12]([NH:11][C@@H:8]2[CH2:9][CH2:10][N:6]([CH2:5][C:4]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]4=[O:35])=[CH:25][C:24]=3[F:36])=[O:21])[CH2:7]2)(=[O:13])=[O:14])=[CH:19][CH:18]=1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CCOC(=O)CN1CC[C@@H](NS(=O)(=O)c2ccc(Cl)s2)C1
Product: O=C(CN1CC[C@@H](NS(=O)(=O)c2ccc(Cl)s2)C1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
8.2 Using general procedure F [(R)-3-(5-chloro-thiophene-2-sulfonylamino)-pyrrolidin-1-yl]-acetic acid ethyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to WO 2003045912) to give 2-[(R)-3-(5-chloro-thiophene-2-sulfonylamino)-pyrrolidin-1-yl]-N-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-acetamide. White solid. MS 511.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:36]#[N:37])=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][N:25]4C(=O)C5C(=CC=CC=5)C4=O)(=[O:22])=[O:21])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.NN.Cl>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:36]#[N:37])=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(CNS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c2)c(C#N)c2ccc(Cl)cc21
Agent: Cl
Agent: NN
Solvent: CO
Product: Cn1c(-c2cncc(CNS(=O)(=O)CCN)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide (0.065 g, 0.109 mmol) and MeOH (4 mL). Hydrazine (0.069 mL, 2.183 mmol) is added and the reaction is stirred at room temperature overnight. 2M aqueous HCl is added, followed by concentration in vacuo. Dichloromethane is added and the mixture is filtered through celite. The organic layer is washed with water once and the aqueous layer is basified to using 4M aqueous NaOH and extracted with dichloromethane thrice. The combined dichloromethane fraction is dried over sodium sulfate and concentrated in vacuo to afford a residue which is purified by reverse-phase HPLC to afford 2-amino-ethanesulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.12 (t, J=6.6 Hz, 2H), 3.29 (t, J=6.6 Hz, 2H), 3.84 (s, 3H), 4.49 (s, 2H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 8.19 (t, J=2.1 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.82 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 404.0944 [(M+H)+ Calcd for C18H19ClN5O2S: 404.0948].
Reaction SMILES: C1(C(=O)CC#[N:7])CC1.[NH2:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[C:12]([C:14]1C=CC(F)=[CH:16][CH:15]=1)=O>>[N:9]1[C:10]2[C:11](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:14][C:15]=1[C:16]#[N:7]
Reactant: N#CCC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Product: N#Cc1ccc2ccccc2n1

Procedure:
The cyclization reaction step of the present invention is a step of reacting 3-cyclopropyl-3-oxopropanenitrile of the formula (1) with 2-amino-4′-fluorobenzophenone of the formula (2) preferably in the presence of an acid to obtain a quinolinecarbonitrile derivative [2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile] of the formula (3).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc2[nH]ccc2cc1O
Yield: 86.4 %

Procedure:
5-Benzyloxy-6-methoxyindole (253 mg, 1.0 mmol) was hydrogenated at 1 atmosphere pressure in methanol (10 ml) with 10% palladium on carbon (50 mg) for 2 hours at 25° C. The catalyst was filtered off and the filtrate evaporated to give 5-hydroxy-6-methoxylindole (141 mg, 87%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)=[O:15])(=[O:9])=[O:8])=[N:5][N:4]=[N:3]1.OO.S([O-])(O)=[O:25].[Na+].C(OO)=O>C(O)=O.O>[CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)(=[O:25])=[O:15])(=[O:8])=[O:9])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S(=O)CCCCS(=O)(=O)c1nnnn1C
Reactant: O=S([O-])O
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1S(=O)(=O)CCCCS(=O)(=O)c1nnnn1C
Reaction time: 5 h

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)sulfinylbutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (3.2 g) is dissolved in formic acid (30 ml), and thereto is added with stirring 30% hydrogen peroxide (2.3 g) at room temperature, and the mixture is stirred for 5 hours. Sodium hydrogensulfite is added to the mixture under ice-cooling in order to decompose excess performic acid. Water is added to the mixture and the precipitated crystals are collected by filtration and recrystallized from N,N-dimethylformamide to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfonylbutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (2.1 g) as colorless prisms, m.p. 192°-194° C.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH3:23][CH:24]([NH2:27])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:24]([CH3:23])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Reactant: CC(N)CO
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NC(C)CO)cn1
Yield: 87 %

Procedure:
As described in example 4, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (100 mg, 0.28 mmol) instead of 6-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-nicotinic acid methyl ester, and DL-2-amino-1-propanol instead of ethanolamine, was converted to the title compound (85 mg, 87%) which was obtained as a light yellow oil after purification by chromatography (silica, dichloromethane:methanol 100:0 to 94:6). MS: m/e=364.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([CH3:4])([CH3:3])[CH3:2].[C:15](=S)=[S:16].N#CN>C1COCC1.CCN(CC)CC>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[C:15]=[S:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: S=C=S
Agent: N#CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCN=C=S
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.6 %

Procedure:
To a solution of 2 g (9.9 mmol) (5-Amino-pentyl)-carbamic acid tert-butyl ester in 40 ml THF at 0° C. was added 896 μl (14.83 mmol) CS2 and allowed to stir at room temperature for 14 h. 623 mg (14.83 mmol) cyanamide and 4 drops NEt3 was added and the mixture was heated to 4° C. for 3 h. The mixture was extracted with diethyl ether and the combined organic layers were dried with MgSO4. After filtration and removal of the volatiles the residue was purified by flash column chromatography on silica eluting with ethyl acetate/cyclohexane 1:1. The evaporation of the product fractions yielded 2.24 g (93%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](Cl)=[O:8].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:25])=[C:17]([CH:24]=1)[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:25][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:7]([C:6]2[C:5]([CH3:10])=[C:4]([CH3:11])[O:3][C:2]=2[CH3:1])=[O:8])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1oc(C)c(C(=O)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)c1C
Temperature: 60 °C
Yield: 42.6 %

Procedure:
A solution of 2,4,5-trimethyl-3-furancarbonyl chloride (7.8 g, 0.045 mole) in toluene (25 ml) was added to 1-methylethyl 5-amino-2-chlorobenzoate (10.6 g, 0.050 mole) and triethylamine (6 g) in toluene (25 ml). The mixture was warmed to 60° C. for about 1 hour, then washed in sequence with dilute hydrochloric acid, water, aqueous 5% sodium bicarbonate and water. The solution was dried with magnesium sulfate, filtered and evaporated. The residue was crystallized from toluene/petroleum ether to give 6.7 g of a pale yellow solid, m.p. 83°-85° C.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]([C:24]2[CH:29]=[C:28]([C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])[CH:27]=[CH:26][C:25]=2[CH3:36])[C:17]3=[O:37])[CH2:10][CH2:9]1)(C)(C)C.Cl.O>C(Cl)Cl.O1CCOCC1>[CH:33]1([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]([CH3:36])=[C:24]([N:18]3[C:17](=[O:37])[C:16]4[C:21](=[CH:22][CH:23]=[C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:38])=[O:5])[CH2:13][CH2:12]5)[CH:15]=4)[N:20]=[CH:19]3)[CH:29]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCN(CC(=O)OC(C)(C)C)CC3)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCN(CC(=O)O)CC3)cc2c1=O
Yield: 84.1 %

Procedure:
To a stirred solution of tert-butyl-[4-(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)piperazin-1-yl]acetate (0.28 g) in methylene chloride (10 ml) was added 4N HCl in dioxane (3 ml). After 72 hours water (15 ml) was added and the solution poured onto an ion exchange column (isolute SCX-2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK). The column was washed with water (2×50 ml), methanol (2×50 ml) and the product eluted with 2N ammonia in methanol. The fractions containing product were evaporated in vacuo, triuration with iso-hexane/ethyl acetate gave the title compound (0.21 g); NMR Spectrum: (DMSOd6) 0.61 (m, 4H), 2.12 (s, 3H), 2.70 (m, 4H), 2.84 (m, 1H), 3.09 (s, 2H), 3.28 (m, 4H), 7.49 (m, 2H), 7.62 (m, 2H), 7.81 (d, 1H), 7.89 (m, 1H), 8.07 (s, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 462.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1[CH:30]=[CH:31][C:26]([C:24]2[CH2:23][C:22](=[O:38])[NH:21][C:9]3[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=3[N:7]=2)=[CH:27][C:28]=1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from [2-(3-[2,3′]bipyridinyl-4-yl-3-oxo-propionylamino)-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M295) (288 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (195 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.COC(=O)CC[SH:23].[H-].[Na+].Cl>O.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][SH:23])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: COC(=O)CCS
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CS)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
To the solution of 2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (8.0 g) and 3-mercaptopropionic acid methyl ester (11.2 ml) in dimethylformaide (160 ml) was added 60% sodium hydride suspension in oil (4.0 g), and the mixture was stirred for 15 minutes. 1N aqueous hydrochloric acid solution (101 ml) was added dropwise to adjust pH to 7, and dimethylformamide and water were evaporated off under reduced pressure. To the residue was added 20 ml of water, followed by extraction with ethyl acetate (50 ml×3). The extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography (6.0×9.0 cm) and eluted with ethyl acetate-hexane (3:1). The desired fraction was concentrated, and to the residue was added diethyl ether, to give 2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (6.44 g) as colorless needles. mp. 112°-113° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: ClCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CC(OCc3cccs3)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-diphenylmethylazetidin-3-ol (359 mg, 1.5 mmol) in DMF (1 mL) at 0° C. under nitrogen was added NaH (60% in oil, 66 mg, 1.65 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with 2-(chloromethyl)thiophene (464 mg, 3.5 mmol; which may be prepared as described in Step 1) dissolved in DMF (2 mL).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2cccc(Cl)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (72 mg, 86%), MS (ISP) m/z=336.4 [(M+H)+], mp 209° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:33].O1CCOCC1>>[ClH:33].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cncn3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ncn(-c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)n1
Yield: 80 %

Procedure:
The title compound (80 mg, 80%) was prepared from the product of step 1 (130 mg, 0.30 mmol) and 4M HCl in dioxane (0.75 ml, 3 mmol) using the procedure of Example 146, step 4; 1HNMR (400 MHz, CD3OD) δ 10.15 (br, 1H), 9.80 (br, 1H), 7.82 (br, 2H), 7.00 (m, 8H), 4.12 (br, 2H), 4.01 (br, 1H), 3.36 (m, 2H), 2.18-1.96 (m, 4H); LC/MS (ESI+) 99%, 337 (100, M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:19])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1csc2ccc(F)cc12
Reactant: O=Cc1ccccc1
Product: Cc1c(C(O)c2ccccc2)sc2ccc(F)cc12

Procedure:
Using general procedure B, 5-fluoro-3-methyl-benzo[b]thiophene was reacted with benzaldehyde to give (5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol as a pale yellow oil. MS: 255.3 ([M+H—H2O]+).