Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[C:14]4[CH:22]=[CH:21][CH:20]=[CH:19][C:15]4=[CH:16][CH:17]=3)[NH:12][C:11](=[O:23])[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([Sn]([N:37]=[N+:38]=[N-:39])(CCCC)CCCC)CCC.[OH-].[Na+]>CN(C=O)C>[NH:37]1[C:1]([C:3]2[CH:4]=[C:5]([C:9]3[C:18]4[C:13](=[C:14]5[CH:22]=[CH:21][CH:20]=[CH:19][C:15]5=[CH:16][CH:17]=4)[NH:12][C:11](=[O:23])[N:10]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2][N:39]=[N:38]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1cccc(-c2nc(=O)[nH]c3c2ccc2ccccc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc(-c3nnn[nH]3)c2)c2ccc3ccccc3c2[nH]1
Temperature: 110 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
To a solution of 4-(3-cyanophenyl)-1H-benzo[h]quinazolin-2-one (112 mg, 0.377 mmol) in DMF (2 mL) was added tri-n-butyltin azide (312 μL, 1.13 mmol), and stirred at 110° C. for 18 hours. After cooled to room temperature, the reaction mixture was poured into 1M sodium hydroxide, and washed with ethyl acetate. After aqueous layer was neutralized with 1M hydrochloric acid, the precipitated solid was collected by filtration, washed with methanol, and with water. The obtained crystal was dried to give the titled compound as a yellow crystal (70 mg, yield 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:19]([C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[C:26]([CH2:36][NH2:37])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:19]([C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[C:26]([CH2:36][NH:37][C:15](=[O:17])[CH:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:2]([F:1])[CH:3]=2)[CH3:18])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1cccc(-c2nc(C(C)(C)C)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(C)(C)C)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.3 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (82 mg, 0.297 mmol) and (6-tert-butyl-2-m-tolylpyridin-3-yl)methanamine (76 mg, 0.297 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (85 mg, 0.445 mmol), 1-hydroxybenzotriazole (60 mg, 0.445 mmol) and triethylamine (0.1 mL, 0.742 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-((6-tert-Butyl-2-m-tolylpyridin-3-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide (example 23) (122 mg) was obtained as 80% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17]([C:19]1[C:20](OS(C(F)(F)F)(=O)=O)=[N:21][C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[CH:26][C:25]([Cl:36])=[CH:24][CH:23]=2)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CS(C)=O.O>[C:12]([O:16][C:17]([C:19]1[C:20]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:21][C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[CH:26][C:25]([Cl:36])=[CH:24][CH:23]=2)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirred solution of pyrrolidine (0.047 ml, 0.58 mmol) in DMSO (5 ml) was added K2CO3 (159 mg, 1.15 mmol) and 6-chloro-4-(3-chloro-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step C, 150 mg, 0.29 mmol) at room temperature. The resulting reaction mixture was stirred at 90° C. for 3 h. After cooling, the reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3×30 ml). The separated organic layer was washed with brine (15 ml), dried over sodium sulfate and concentrated under vacuum to give a crude residue which was purified by column chromatography eluting with 5-10% ethyl acetate in hexane to yield 6-chloro-4-(3-chloro-phenyl)-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (90 mg, 71% yield) as a pale yellow solid. LC-MS (ESI): 443 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1(=O)[O:11][CH2:10][CH2:9][CH2:8]1>>[CH3:5][C:2]([N:1]1[CH2:7][CH2:8][CH2:9][C:10]1=[O:11])([CH3:6])[CH2:3][OH:4]
Reactant: O=C1CCCO1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)N1CCCC1=O
Yield: 59 %

Procedure:
In a procedure similar to that of Example 1, 2-amino-2-methylpropanol was reacted with γ-butyrolactone resulting in a 59% yield of N-(1,1-dimethyl-2-hydroxyethyl)-2-pyrrolidinone, b.p. 175°/21 torr, after two cycles. The material melted at 56°-58° with 13CNMR peaks shifted 176.1, 69.7, 58.7, 46.3, 32.9, 23.2 and 18.2 ppm from TMS. The elemental analyses agreed with the theoretical values for the expected compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:10]([O:12][CH3:13])=[O:11])=O)CCC.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:8][C@H:9]([CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCCOC(=O)N[C@H](CCNS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](N)CCNS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Methyl 2(R)-(N-butyloxycarbonylamino)-4-(p-toluenesulfonylamino)butyrate (2.0 g, 5.18 mmol) was dissolved in 10 mL 4N HCl in dioxane and the solution was stirred for 1 hour and then concentrated. The residue was triturated with ether to give 1.16 g (70%) product. ES-MS: calcd M+1 287.2; found 287.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[C:4]([OH:28])[CH:3]=1.Br[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[C:4]([O:28][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:3]=1
Reactant: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)cc1
Reactant: BrCC1CCCC1
Product: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, from 4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-benzonitrile and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown solid (55%). MS (Turbo Spray): m/z=478.3 (M+H).
Reaction SMILES: C[N:2](C)[C:3]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH:8]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=O)[CH2:6]1)=[O:4].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH2:33].O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH:33][CH:9]1[CH:8]([CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]2[CH2:12][CH2:11][CH:10]1[CH:5]([C:3]([NH2:2])=[O:4])[CH2:6]2
Reactant: COc1ccc(OC)c(CN)c1
Reactant: CN(C)C(=O)C1CN2CCC1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(CNC2C3CCN(CC3C(N)=O)C2C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
A mixture of 48 (1.2 g, 3 mmol), 2,5-dimethoxybenzyl amine (0.6 g, 3.3 mmol) camphor sulfonic acid (45 mg) in toluene (15 ml) was heated at reflux with removal of water for 3 hours and then the solvent was removed. The residue was dissolved in small amount of THF (3 ml) and this solution was added to a solution of sodium triacetoxyborohydride (1.7 g, 8 mmol) in acetic acid (40 ml) at room temperature. The mixture was stirred at room temperature for 3 hours and the solvent was removed. Water was added and the mixture was neutralized with NaHCO3 and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated. Recrystallization from MeOH/acetone to give by-product. The mother liquor was concentrated and the residue was purified by recrystallization from MeOH/EtOAc to give 50 (0.27 g, 0.56 mmol, 19%)
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:19]([OH:21])=[O:20])=[CH:12][N:13]2[CH:16]2[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:23].CO>CN1C(=O)CCC1>[CH:16]1([N:13]2[C:14]3[C:9](=[CH:8][C:7]([F:23])=[C:6]([NH:4][CH2:3][CH2:1][OH:2])[CH:15]=3)[C:10](=[O:22])[C:11]([C:19]([OH:21])=[O:20])=[CH:12]2)[CH2:17][CH2:18]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: NCCO
Solvent: CO
Solvent: CN1CCCC1=O
Product: O=C(O)c1cn(C2CC2)c2cc(NCCO)c(F)cc2c1=O
Temperature: 105 °C
Reaction time: 22 h

Procedure:
To a solution of ethanolamine (55.5 ml) in N-methyl pyrrolidinone (500 ml) at 95° C., 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (50.0 g) was slowly added under vigorous stirring. The temperature was increased to 105° C. and the reaction mixture was stirred at this temperature for 22 hours. The reaction mixture was cooled to about 60° C. and poured into MeOH (800 ml). This mixture was stirred in an ice bath and the precipitate was filtered off and dried affording a mixture of Intermediate 29A and Intermediate 29B (49 g ) in a 1:1 ratio.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[CH:3]=1.Cl.[N:13]([O-])=[O:14].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[N:13]=[O:14]
Reactant: O=N[O-]
Reactant: CCn1c(N)cc(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCn1c(N)c(N=O)c(=O)[nH]c1=O

Procedure:
To 100 g (0.65 mol) of 6-amino-1-ethyl-2,4-(1H,3H)-pyrimidinedione (II), dissolved in 1 liter hot water, was added 145 ml of 5 N HCl and 50 g of NaNO2 (0.72 mol) which was dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 97.7 g (83%) (III) NMR.
Reaction SMILES: [C:1]([C:3]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)([CH3:8])[CH2:4][CH:5]1[CH2:7][CH2:6]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:52][CH3:53])=[C:34]([CH:51]=1)[O:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([NH:45][C:46]([CH:48]3[CH2:50][CH2:49]3)=[O:47])[N:44]=2)[N:41]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([O:52][CH3:53])=[C:34]([O:35][C:36]2[CH:37]=[CH:38][C:39]3[N:40]([CH:42]=[C:43]([NH:45][C:46]([CH:48]4[CH2:50][CH2:49]4)=[O:47])[N:44]=3)[N:41]=2)[CH:51]=1)=[O:14])([CH3:8])[CH2:4][CH:5]1[CH2:6][CH2:7]1)#[N:2]
Reactant: CC(C#N)(CC1CC1)c1cccc(C(=O)O)c1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C#N)CC3CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 48.7 %

Procedure:
Using 3-(1-cyano-2-cyclopropyl-1-methylethyl)benzoic acid (70 mg, 0.31 mmol), oxalyl chloride (33 μL, 0.38 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (86 mg, 0.25 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (67 mg, 48%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:24])[NH:22][C:21](=[O:23])[CH2:20][NH:19]1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:13])[C:14]([N:19]1[CH2:20][C:21](=[O:23])[NH:22][C:18]1([CH3:24])[CH3:17])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC1(C)NCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(NC(=O)OCc1ccccc1)C(=O)N1CC(=O)NC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cold solution of N-(benzyloxycarbonyl)alanine (6.7 g) and 2,2-dimethyl-4-imidazolidinone (3.42 g) in 100 ml of THF, a solution of DCC (6.2 g) in 50 ml of THF was added dropwise during 15 minutes. The suspension was stirred at 0° C. for 2 hours and at room temperature for an additional 2 hours. The insoluble material was filtered off. The solvent was evaporated under reduced pressure. Crystallization of the residue from isopropanol gave the title product as a white powder m.p. 170°-171° C.
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.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: FC(F)(F)c1cccc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 160-162° C.). MS(ES+) m/z 278 ([M+1]+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9](C#N)[C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)O>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCC(=O)C(C#N)c1ccc(C)cc1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(CC(=O)CCC(=O)O)c(C)c1
Yield: 46 %

Procedure:
This acid was prepared by refluxing 106.5 g (0.390 mol) of ethyl 5-(2',4'-dimethylphenyl)-5-cyano-4-ketopentanoate in 350 ml of glacial acetic acid, 122 ml of water, and 122 ml of concentrated sulfuric acid. The procedure is described in Example I, Part B. The product was obtained as a dark-colored viscous oil, 39.2 g (46% yield).
Reaction SMILES: CI.[Mg].[NH:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[NH4+]>CCOCC.O>[NH:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:15]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:16]
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1cc[nH]c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccc[nH]1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Methyl iodide (42.60 g.) in dry ether (150 ml.) was added to a stirred mixture of magnesium turnings (7.30 g.) in dry ether (50 ml.) at such a rate that gentle reflux was maintained. After completion of the addition the mixture was stirred at room temperature for 30 minutes and then pyrrole (20.13 g., 0.44 mole) was added at such a rate that gentle reflux was maintained. After completion of the addition the mixture was heated under reflux with stirring for 30 minutes and then cooled to 0° C. A solution of cyclohexane carboxylic acid chloride (44.0 g., 0.30 mole) in dry ether (100 ml.) was added dropwise with stirring and the resulting mixture was heated under reflux with stirring for 30 minutes. The mixture was cooled and a solution of ammonium chloride (20 g.) in water (200 ml.) was added with stirring. The organic layer was separated, washed once with 0.5 N sodium hydroxide solution (50 ml.), twice with water (100 ml.) and dried over sodium sulphate. The ether was evaporated to give a viscous oil which was distilled to give cyclohexyl pyrrol-2-yl ketone (31.5 g.), B.P. 162°-165° at 15 mm., M.P. 83°-84°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:28][CH2:29][CH3:30])[N:8]3[N:31]=[CH:32][N:33]=[C:7]23)[CH2:3]1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][O:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]#[N:27])=[CH:18][CH:19]=3)=[C:9]([CH2:28][CH2:29][CH3:30])[N:8]3[N:31]=[CH:32][N:33]=[C:7]23)[CH2:3]1)[CH3:41]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](O)C2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.28 g), rhodium(I) acetate (0.0028 g) and toluene (10 mL) was added dropwise ethyl diazoacetate (0.62 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.056 g, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[N+:12]([O-])([OH:14])=[O:13].O1C2C=CC=CC=2N=C1>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2cc(Cl)ccc2o1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Product: Cc1nc2cc(Cl)c([N+](=O)[O-])cc2o1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (150 mL) was stirred mechanically and cooled in an ice/water bath. To this was gradually added 5-chloro-2-methylbenzoxazole (1), (75 g, 0.45 Moles), at such a rate that the temperature stayed at 30° C., over a 15–20 minute period. A solution of concentrated sulfuric acid (40 mL), and concentrated nitric acid (32 mL), was prepared and added drop by drop to the benzoxazole solution at such a rate that the temperature was maintained at approximately 20° C. When this acid solution had been added the cooling bath was removed and the mixture allowed to stir at room temperature for 1 hour. At the end of this period the solution was carefully poured onto ice with good stirring. Sufficient water was then added to get good mixing. The solid was filtered off, washed well with water followed by methanol and finally air dried. Yield 90.6 g.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH:6]1[O:8][CH2:7]1>C(O)C>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:5][CH:6]([OH:8])[CH2:7][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: Clc1ccccc1OCC1CO1
Solvent: CCO
Product: NCCNCC(O)COc1ccccc1Cl

Procedure:
120 g of ethylenediamine are dissolved in 150 ml of ethanol. A solution of 20 g of o-chlorophenyl glycidyl ether ##STR18## in 40 ml of ethanol is added to the above solution, and the mixture is heated under reflux for 20 hours. Excess ethylenediamine and ethanol are then distilled off in vacuo, and the residue is then distilled in vacuo. The N-[3-(o-chlorophenoxy)-2-hydroxy-propyl]-ethylenediamine is thus obtained as an oil which can be distilled at a boiling point of 190° C./0.4 mm. The 4,5-dichloro-pyridazin-3-one used as the starting material is prepared in a known manner by the reaction of muccochloric acid with hydrazine (for example according to K. Dury, Angew. Chemie 77, page 282 (1965).
Reaction SMILES: N.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH2:24][CH3:25])[N:4]=1.C1COCC1.C(#[N:33])C>O>[NH2:33][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH2:24][CH3:25])[N:4]=1
Reactant: CC#N
Reactant: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CCSc1ccccc1-c1nc(N)c2ccc(C(F)(F)F)cc2n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4.5 ml of a 28% aqueous ammonia solution was added to a mixture of 500 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline, 8 ml of THF and 5 ml of acetonitrile, and the mixture was stirred at 50° C. for 2 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 396 mg of 4-amino-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 5).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Br.Br.Br.[CH2:14]([C:16]1[C:17]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([C:33]4[NH:42][C:36]5[CH2:37][CH2:38][NH:39][CH2:40][CH2:41][C:35]=5[N:34]=4)=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:18][C:19]([F:23])=[C:20]([OH:22])[CH:21]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[C:20]([OH:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:33]3[NH:42][C:36]4[CH2:37][CH2:38][N:39]([C:6]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)=[O:8])[CH2:40][CH2:41][C:35]=4[N:34]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:15]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(F)cc3)CC4)n[nH]c2c1
Yield: 35.3 %

Procedure:
The title compound was prepared from 4-fluoro-benzoic acid (12.5 mg, 85 μmol) and 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) using the method of Example 8. The crude material was purified by HPLC Method B to afford 14.5 mg of the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>C(O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Solvent: CCO
Product: CC(=O)OC1CCc2c(Nc3ccc(C#N)cc3)ncnc21
Yield: 55.2 %

Procedure:
39.3 g of 7-acetoxy-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine [prepared as described in step (b) above] and 24 g of p-aminobenzonitrile were dissolved in 180 ml of ethanol, and the solution was heated under reflux for 1.5 hours. At the end of this time, the solvent was evaporated off under reduced pressure, and the resulting residue was washed with a 1:1 by volume mixture of ethanol and toluene, to give 30 g of the title compound as pale grayish crystals, melting at 215°-217° C.