Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8]([C:10]1[N:11]([CH3:31])[CH:12]=[C:13]([C:29]#[N:30])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27]C)=[CH:17][CH:16]=1)=[O:9])[CH3:6]>C(Cl)Cl>[CH2:5]([O:7][C:8]([C:10]1[N:11]([CH3:31])[CH:12]=[C:13]([C:29]#[N:30])[C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:19][CH:20]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3OC)cc2)c(C#N)cn1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3O)cc2)c(C#N)cn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add boron tribromide (1.60 g, 6.39 mmol) to 4-cyano-3-(2′-methoxy-biphenyl-4-yl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.10 g, 5.81 mmol, prepared in example E-17) in methylene chloride at 0° C. with stirring. The reaction is gradually allowed to warm to ambient temperature. After 18 hours, pour the reaction mixture into ice-water and extract with methylene chloride. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with acetonitrile:methylene chloride to provide the title compound. Mass spectrum (m/e): 345.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=O)=[C:5](C(OCC)=O)[N:6]=1.[O-]CC.[Na+]>>[CH3:1][C:2]1[S:3][C:4]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[C:5]=2[N:6]=1
Reactant: CCOC(=O)CCCc1sc(C)nc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: Cc1nc2c(s1)CCCC2=O
Yield: 26 %

Procedure:
The compound is prepared from the product obtained in step (a), by cyclization with sodium ethoxide, followed by hydrolysis and decarboxylation of the crude ester. B.p.0.2 =130°-140° C. M.p.=86°-87° C. Overall yield: 26%.
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[C:12]([C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=5)[CH:23]=[C:22]([CH3:36])[N:21]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)C(C)=CC=1.Cl.NO>>[CH3:36][C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH2:3])[CH:13]=3)[N:19]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccnc(-n4c(C)ccc4C)c3)n2)n1
Agent: Cl
Agent: NO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccnc(N)c3)n2)n1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
A mixture of the above described 2″-(2,5-dimethyl-pyrrol-1-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,2′;6′,4″]terpyridine (470 mg, 0.969 mmol), hydroxylamine hydrochloride (337 mg, 4.849 mmol) 1.5 M NaOH-sol. (1.62 mL, 2.43 mmol) in 1-propanole (5 mL) was stirred at 120° C. for 3 h in a sealed tube. Cooled to rt, poured the reaction mixture directly on a silica gel column and chromatographed with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 27%) as a light yellow solid. MS (ISP) 407.3 [(M+H)+]; mp 160° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O>>[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: Cc1ccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c(C)c1

Procedure:
6-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,4-dimethylbenzaldehyde. Mass spectrum (ES) MH+=299.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6](N1CCOCC1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([O:22][C:23]([C:25]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:32]2[N:28]([CH:29]=[CH:30][CH:31]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[C:6]([C:29]1[N:28]2[C:32](=[CH:31][CH:30]=1)[C:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:26][CH2:27]2)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1ccccc1)N1CCOCC1
Reactant: CCOC(=O)C1(C(=O)OCC)CCn2cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.2 %

Procedure:
A mixture of POCl3 (166 mg, 1.08 mmole) and N-benzoylmorpholine (96 mg, 0.5 mmole) was maintain for 6 hours at 25° C. A solution of diethyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (126 mg, 05 mmole) in dichloroethane (2 ml) was added. Then, the mixture was maintained at 50° C. for 3 days. The reacted mixture was poured with 2.5 ml of 10% aqueous sodium carbonate solution. The mixture was stirred at room temperature for 10 hours, and refluxed for 2 hours. The organic layer was separated, and the aqueous layer was washed with 1,2-dichloroethane. The organic layer was dried using sodium carbonate, and the solvent was removed. Finally, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:9) as an eluting solvent and 178 mg of the product diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (84%) was obtained. The IR and NMR spectral properties were identical to those of an authentic sample.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N+:20]([O-:22])=[O:21])=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Solvent: CC(=O)O
Product: CCCCn1c(=O)c2[nH]c([N+](=O)[O-])nc2n(CCCC)c1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1,3-Di-n-butylxanthine (73 g, 0.28 mol) was dissolved in acetic acid (120 ml) and then treated with concentrated nitric acid (49 g) at 87° C. After 1 hour, the mixture was cooled to 5° C., the resulting yellow precipitate filtered off and washed with water (50 ml). The yellow crystals were dissolved in dichloromethane and washed twice with water. The separated organic layer was then dried (anhydrous sodium sulphate) and concentrated to give a crystalline product, yield 73 g (86%), m.pt 168° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].O>C(O)C.O>[F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:9](=[N:19][OH:20])[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: O=C1CCCc2cc(OCC(F)(F)F)cnc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2cc(OCC(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)-6,7-dihydroquinolin-8(5H)-one (155 mg, 0.63 mmol), hydroxylamine hydrochloride (88 mg, 1.3 mmol), and sodium acetate (104 mg, 1.3 mmol) in ethanol-water (3:1, 4 mL) was refluxed with stirring for 2 hours. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were dried over Magnesium sulfate and concentrated in vacuo to give 167 mg of the crude title compound as a brown solid. This was used for the next step without purification:
Reaction SMILES: [CH2:1]([N:3]([C:5]1[C:6]2[N:7]([CH:15]=[N:16][C:17]=2[C:18]([O:20]CC)=O)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4])[CH3:2].[CH:23]1([C:26](=[N:28]O)[NH2:27])[CH2:25][CH2:24]1.[H-].[Na+].ClCCl>CN(C=O)C>[CH:23]1([C:26]2[N:28]=[C:18]([C:17]3[N:16]=[CH:15][N:7]4[C:8]5[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:14]=[C:5]([N:3]([CH2:1][CH3:2])[CH3:4])[C:6]=34)[O:20][N:27]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1ncn2c1c(N(C)CC)nc1ccccc12
Reactant: NC(=NO)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(C)c1nc2ccccc2n2cnc(-c3nc(C4CC4)no3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A mixture of ethyl 4-(N-ethyl-N-methylamino)-imidazo[1,5-a]quinoxaline-3-carboxylate (1.2 g, 4 mmol), cyclopropanecarboxamidoxime (1.4 g, 14 mmol), crushed 4 Å molecular-sieves (0.5 g), and sodium hydride (0.1 g, 60% in mineral oil) in dry DMF (20 ml) was stirred at ambient temperature for 1 h. Dichloromethane (25 ml) was added and the mixture was filtered through celite. The filtrate was evaporated and the residue was brought to crystallize by the addition of 10 ml of ethyl acetate and cooling to 0° C. The crystals was collected by filtration, rinsed with ethyl acetate and dried to give 0.58 g of the title compound, m.p. 96°-97° C. An additional amount (0.22 g) of the product was obtained from the mother liquour. (Compound 6).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2)(=O)C.[ClH:22]>>[ClH:22].[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2
Reactant: CCOC(=O)CC(C)c1ccc(NC(C)=O)c2c1CCC2
Agent: Cl
Product: CCOC(=O)CC(C)c1ccc(N)c2c1CCC2
Temperature: 118 °C
Reaction time: 48 h

Procedure:
Ethyl 3-[7-acetylamino-indan-4-yl]-butanoate (1.66 g, Reference Example 6) was treated with 6M aqueous hydrochloric acid. The stirred mixture was heated at 118° C. for 4 hours, then left to stand at room temperature for 48 hours and then evaporated. The residue was treated with ethanol (100 mL) and concentrated hydrochloric acid (4 drops). This mixture was heated at reflux for 2.5 hours, then allowed to stand at room temperature for 16 hours and then evaporated. The residue was dissolved in a little ethanol and the solution was evaporated. The residue was dried under high vacuum to give the title compound (1.57 g) as a fine solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[N:10]1[CH:11]=[CH:12][CH:13]=[N:14][C:9]=1[N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: c1cnc(N2CCCNCC2)nc1
Temperature: 25 °C
Yield: 48 %

Procedure:
50 ml of acetonitrile was added to 10.0 g (0.1 mole) of homopiperazine, 2.9 g (0.025 mole) of 2-chloropyrimidine, 6.9 g (0.05 mole) of potassium carbonate and a catalytic amount of potassium iodide, and the mixture was refluxed under heating for 11 hours. The mixture was cooled to room temperature and then filtered, the filtrate obtained was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (eluent; a chloroform:methanol=8:2 mixed solution) to obtain 2.14 g of 1-(2-pyrimidyl)homopiperazine as a pale yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][SH:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]3[CH:32]=[CH:33][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:29][CH:28]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(COc2ccc(CS)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(OCc3ccc(F)cc3)cc2)CC1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
5.84 g (23.5 mmol) 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester were added to a solution of 6.0 g (24.2 mmol) 4-(4-fluoro-benzyloxy)-phenyl-methanethiol in 14.6 ml pyridine. The solution was heated to 100° C. for 3.5 h, then cooled to rt, 10 ml of water added and the volume reduced to a third. The resulting precipitate is collected, washed with water and dried. The crude product is re-crystallized from hexane/AcOEt. Flash chromatography on silica gel provided 4.90 g 4-[4-(4-fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylic acid tert-butyl ester as colourless powder, mp: 123–124° C. 1H-NMR (CDCl3): 1.46 s, 9H; 3.38–3.60 m, 8H; 4.13 s, 2H; 5.00 s, 2H; 6.89 d, 2H, 7.06 t, 2H, 7.28 d, 2H and 7.40 dd, 2H.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]3[CH2:15][C:16](=O)[CH2:17][CH:12]3[C:11]2=[O:19])=[CH:6][CH:5]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH2:22]([NH:29][CH:16]1[CH2:17][CH:12]2[C:11](=[O:19])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:20])=[CH:5][CH:6]=3)[CH2:14][CH:13]2[CH2:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C2CC(NCc3ccccc3)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a solution of 2-(4-Trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrole-1,5-dione (0.5 g, 1.6 mmol) and benzylamine (0.34 g, 3.2 mmol) in dichloromethane (10 mL) were added NaBH(AcO)3 (1.0 g, 4.7 mmol). The mixture was stirred for 6 h at ambient temperature. The mixture was extracted with dichloromethane (2×15 mL), washed with brine (30 mL), dried over anhydrous Na2SO4. The solvent was removed, and the crude product was purified by silica column (MeOH/dichloromethane=1/30) to yield the title compound (0.4 g, 63%). 1H NMR (300 MHz, CDCl3): δ 7.67-7.63 (m, 2H), 7.32-7.07 (m, 7H), 4.08 (t, 1H, J=9.3 Hz), 3.76-3.56 (m, 3H), 3.34-3.31 (m, 1H), 3.16-3.09 (m, 1H), 2.88-2.83 (m, 1H), 2.21-2.02 (m, 3H), 1.65-1.58 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:12]3[CH:11]=[CH:15][N:14]=[CH:13]3)=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.3 g (25 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid are suspended in 50 ml of N,N-dimethylformamide, whereupon the suspension is treated with 5.67 g (34 mmol) of 1,1'-carbonyldiimazole and the mixture is stirred at room temperature for a further 0.75 hour and subsequently at 60° for 2 hours. The mixture is then poured into 100 ml of water, the product is filtered off under suction after 1 hour, rinsed with water and dried at 80° in a high vacuum. There is obtained 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole of decomposition point 242°-244°.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].C(=O)([O-])O.[Na+].C(=O)C1C=CC=CC=1.C([O:26][CH:27]=[C:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])C.Cl>O.C(O)C>[CH2:7]([N:9]1[CH:34]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:27]([OH:26])=[N:10]1)[CH3:8]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCNN
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Solvent: O=Cc1ccccc1
Product: CCOC(=O)c1cn(CC)nc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
A mixture of ethylhydrazine oxalate (5.0 g), sodium hydrogen carbonate (5.60 g), water (10 mL) and ethanol (50 mL) was stirred at room temperature for 15 min. Benzaldehyde (3.53 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ethoxymethylenemalonate (7.91 g), and the mixture was heated under reflux for 2 hrs. The reaction mixture was cooled to room temperature, concentrated hydrochloric acid (3 mL) was added and the mixture was further heated under reflux for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-ethyl-3-hydroxy-1H-pyrazole-4-carboxylate as pale-yellow crystals (1.72 g, yield 28%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 109-110° C.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][O:8]C(C)(C)[N:6]1C(OC(C)(C)C)=O)([CH3:4])[CH3:3].[ClH:19]>C(O)C>[ClH:19].[NH2:6][C@@H:5]([C:2]([CH3:4])([OH:1])[CH3:3])[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(C)(C)O)COC1(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)(O)[C@H](N)CO
Temperature: 85 °C
Reaction time: 2 h

Procedure:
tert-Butyl (4R)-4-(1-hydroxy-1-methylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (7.32 g, 27.8 mmol), prepared by the method of Joullie, Tetrahedron, 52, pp. 11673-11694, (1996), was dissolved in 20 mL of ethanol. A 4.3 M solution of hydrochloric acid in ethanol (15 mL) was then added and the reaction mixture was heated 85° C. After 2 hours, the solution was cooled and concentrated under reduced pressure. The resulting residue was concentrated with 2-propanol several times and then with Et2O to give crude (2R)-2-amino-3-methylbutane-1,3-diol hydrochloride (4.32 g) as a brown oil. This was used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:22]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:22])=[O:7]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(C#N)(CCC(=O)O)CCC(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(C)cc2)CCC1=O
Yield: 99 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 42.44 gm. (0.14 mole) of the dimethyl ester of 4-cyano-4-(p-tolyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 900 ml. of the tetrahydrofuran, 31.5 gm. (0.28 mole) of the potassium tert-butoxide, and 225 ml. of the 2.5 N aqueous acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 39.3 gm. (99% yield) of 2-carbomethoxy-4-cyano-4-(p-tolyl)cyclohexanone as a gum.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:19][CH3:20])=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:8]=2)[N:3]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH:1]([C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:19][CH3:20])=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:8]=2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc2nc(N)ncc2cc1-c1ccccc1C
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2nc(Nc3ccccc3)ncc2cc1-c1ccccc1C
Temperature: 100 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
2-Amino-7-methoxy-6-(2-methylphenyl)quinazoline (150 mg, 0.565 mmol) obtained in Example 174 was dissolved in dioxane (5.7 mL) and the solution was added with iodobenzene (70 μL, 0.622 mmol), tris(dibenzylideneacetone)dipalladium (25.9 mg, 0.028 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36 mg, 0.062 mmol) and cesium carbonate (258 mg, 0.791 mmol), followed by stirring at 100° C. for 20 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (ethyl acetate/hexane=3/7) to obtain 2-anilino-7-methoxy-6-(2-methylphenyl)quinazoline (164 mg, 85%). In a similar manner to Example 19, Compound 178 was obtained using the above-obtained 2-anilino-7-methoxy-6-(2-methylphenyl)quinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1

Procedure:
Using 3,5-dichlorophenol and 4-fluorobenzaldehyde, the reaction was carried out in the same manner as in Reference Example 1 to obtain 4-(3,5-dichlorophenoxy)benzaldehyde. Subsequently, the same procedure as in Reference Example 189 was followed using sodium borohydride in place of the lithium aluminum hydride. This gave 4-(3,5-dichlorophenoxy)benzyl alcohol. The resulting alcohol (2.03 g), along with carbon tetrabromide (2.75 g), was dissolved in methylene chloride (30 mL). While this solution was stirred at 0° C., triphenyl phosphine (2.17 g) was added. The mixture was stirred at 0° C. for 1 hour and at room temperature for the subsequent 30 min. The solvent was removed under reduced pressure and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired product as a colorless oil (3.12 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[Cl:52][C:53]1[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:54]=1[CH2:55][SH:56].[CH2:62]([O:64][C:65](=[O:84])[CH2:66][C:67]1[C:71]2[CH:72]=[CH:73][C:74](OS(C(F)(F)F)(=O)=O)=[CH:75][C:70]=2[S:69][CH:68]=1)[CH3:63]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:62]([O:64][C:65](=[O:84])[CH2:66][C:67]1[C:71]2[CH:72]=[CH:73][C:74]([S:56][CH2:55][C:54]3[CH:57]=[CH:58][C:59]([Cl:61])=[CH:60][C:53]=3[Cl:52])=[CH:75][C:70]=2[S:69][CH:68]=1)[CH3:63]
Reactant: CCOC(=O)Cc1csc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: SCc1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc2cc(SCc3ccc(Cl)cc3Cl)ccc12

Procedure:
To a solution of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.71 mg), DIPEA (0.187 ml), 2,4-dichlorobenzyl mercaptan (0.085 mL) and ethyl(6-(((trifluoromethyl)sulfonyl)oxy)-1-benzothiophen-3-yl)acetate (200 mg) in toluene (6 mL) was added tris(dibenzylideneacetone)dipalladium(0) (24.86 mg) at room temperature. The mixture was refluxed 1.5 h. After cooling, water was poured into mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (238 mg).