Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: C=CC(=O)OC
Solvent: C1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 112.5 %

Procedure:
12.0 g (0.08 mol) of ethyl 4-methyl-3-oxo-pentanoate and 0.5 g (0.003 mol) of DBU were placed in a three necked round bottom flask, equipped-with dropping funnel and reflux condenser. At room temperature, 16.0 g (0.18 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior of the reaction leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. The mixture was poured into cyclohexane and was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer was neutral. The organic layer was dried over sodium sulfate, the solvent was removed, and the addition product was isolated by fractional distillation in a vacuum. 15.0 g (0.045 mol) of 4-(ethoxycarbonyl)-4-(2-methyl-1-oxopropyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 56%; boiling point: 145° C. at 0.02 mbar; colorless).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25](Br)[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[C:33]([Cu])#[N:34]>CS(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[CH:28]=[C:27]([F:30])[CH:26]=[C:25]([C:33]#[N:34])[C:24]=4[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(Br)c3C[C@H]2O)C1
Reactant: N#C[Cu]
Solvent: CS(C)=O
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(C#N)c3C[C@H]2O)C1
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 20.2 %

Procedure:
According to Scheme 15: A mixture of 3-[5-acetyl-1-((1R,2R)-4-bromo-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11d) (0.15 g, 0.303 mmol) and CuCN (54 mg, 0.606 mmol) in dimethylsulfoxide (2 ml) was stirred at 180° C. for 90 min under microwave irradiation. The mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 27 mg of (1R,2R)-1-[5-acetyl-3-(3-cyano-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-6-fluoro-2-hydroxy-indan-4-carbonitrile (21b). Rt=1.16 min (LC method 4). Detected mass: 442.12 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36]>>[CH:35]([N:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:9])=[CH:6][CH:7]=1)([CH3:37])[CH3:36]
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(O)cc2)c1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(OCCN(C(C)C)C(C)C)cc2)c1
Yield: 92.5 %

Procedure:
Synthesized from (4-hydroxyphenyl)[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]methanone (1.3 g) and (2-chloroethyl)diisopropylamine hydrochloride (787 mg) according to an analogous synthetic method to Preparation Example 40, the title compound (1.6 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:14])(=[O:13])[NH:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester (2 g, Reference Example 63) in dichloromethane (50 ml) at 0° C., under a nitrogen atmosphere, was added diisopropylethylamine (2.71 ml) and benzylamine (0.850 ml). The reaction was warmed to ambient temperature and stirred for 12 hours. The reaction mixture was then washed with water (2×20 ml) and brine (2×20 ml), dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the title compound (2.29 g) as a brown solid. LC-MS (METHOD J): RT=3.83 minutes, 380.12 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([Cl:26])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:27].Cl>O1CCOCC1.O>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:28])=[O:4])=[C:8]2[CH3:27])(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[CH3:25]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(C)c(Cl)c2)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)cc1Cl
Reaction time: 2.5 h

Procedure:
1M Aqueous NaOH (0.25 mL) is added to a stirring solution of [1-(3-chloro-4-methyl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (80 mg, 0.20 mmol) in 1:1 dioxane/water (2 mL). After 2.5 hours, the reaction mixture is acidified to pH 1 with 1M HCl which leads to the formation of a precipitate. The solid is isolated by filtration, washed with water and dried to afford [1-(3-chloro-4-methyl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=379.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][OH:7].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:7][CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)C#CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 77.6 %

Procedure:
A mixture of 4-(trimethylsilyl)but-3-yn-1-ol (1.00 mL; 6.00 mmol), 4-methylbenzene-1-sulfonyl chloride (2.29 g; 12.01 mmol), pyridine (0.970 mL; 12.00 mmol) in dichloromethane (15 mL) was stirred at room temperature for 60 hours. The reaction mixture was washed with an aqueous solution of saturated ammonium chloride, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to yield 1.38 g (76%) of 4-(trimethylsilyl)but-3-ynyl 4-methylbenzenesulfonate.
Reaction SMILES: N1CCOC[CH2:2]1.C[Mg]Br.C[O:11][C:12]([C:14]1([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[C:18]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:16][CH2:15]1)=O>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[C:32]([Si:29]([CH3:31])([CH3:30])[O:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[C:18]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[C:17]([C:14]3([C:12](=[O:11])[CH3:2])[CH2:16][CH2:15]3)[O:21][N:20]=2)=[CH:27][CH:26]=1)([CH3:33])([CH3:34])[CH3:35]
Reactant: C1COCCN1
Reactant: COC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution consisting of morpholine (7.5 mL) in THF (100 mL) is cooled to 0° C. (ice/salt bath) and a solution of methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added by addition funnel while the temperature is maintained between 0 and 5° C. (over 15 minutes.) The orange reaction mixture is stirred at 0° C. for 30 minutes and subsequently a mixture consisting of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarboxylic acid methyl ester (12.8 g) in THF (50 mL) is added by addition funnel over 5 minutes. The flask is removed from the ice bath. The reaction mixture is cooled to 0° C. and a solution consisting of methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added over 10 minutes. After 20 min further methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added over 10 minutes. The ice bath is removed and the reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is poured into an ice/ammonium chloride solution. The mixture is twice extracted with ethyl acetate and the combined extracts are dried and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with a gradient (1% to 5% ethyl acetate in hexanes) afforded 1-(1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-ethanone (4.8 g); MS (APCI+) m/z 434 (MH+.)
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:17]1[C:18]([NH:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1.C(N(CC)CC)C>CN(C=O)C.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][NH:25][C:18]1[C:17]([C:3]#[C:2][CH2:1][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:6][CH2:5]2)=[CH:22][N:21]=[C:20]([C:23]#[N:24])[N:19]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#CCN1CCN(c2ccccn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCN(c2ccccn2)CC1
Temperature: 80 °C
Yield: 97 %

Procedure:
1-(2-Propynyl)-4-(2-pyridinyl)-piperazine (prepared from 1-(2-pyridinyl)-piperazine and propargyl bromide) (1.5 mmol) is dissolved in DMF at room temperature under nitrogen atmosphere. To the solution, 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (1 mmol), triethylamine (3 mmol), copper(I) iodide (0.1 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol) are added successively. The mixture is heated at 80° C. under nitrogen atmosphere for 3 h. After cooling at room temperature, the mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:5) to give 4-(2,2-dimethyl-propylamino)-5-[3-(4-pyridin-2-yl-piperazin-1-yl)-prop-1-ynyl]-pyrimidine-2-carbonitrile. Yield 97%. Rf=0.30 (n-hexane:AcOEt=1:5). 1H NMR (400 MHz, CDCl3) δ 0.95(s, 9H), 2.75-2.73(m, 4H), 3.36(d, 2H), 3.63-3.60(m, 4H), 3.69(s, 2H), 5.78(brs, 1H), 6.63-6.67(m, 2H), 7.47-7.52(m, 1H), 8.19-8.21(m, 2H).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[F:8][C:9]([F:23])([F:22])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[NH:17][O:18][C:19](=[O:21])[N:20]=2)[CH:11]=1.[Cl-].[NH4+].C[CH2:27][O:28][CH2:29][CH3:30]>>[CH2:29]([O:28][CH2:27][N:20]1[C:19](=[O:21])[O:18][N:17]=[C:16]1[C:12]1[CH:11]=[C:10]([C:9]([F:8])([F:22])[F:23])[CH:15]=[CH:14][N:13]=1)[C:30]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CCOCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1onc(-c2cc(C(F)(F)F)ccn2)n1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.16 g of benzyl=chloromethyl=ether was added, and the mixture was stirred at 60° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.24 g of 4-benzyloxymethyl-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (Present compound (33)).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:31])=[O:30])[C:9]1[CH:28]=[CH:27][C:12]2[N:13]([CH3:26])[C:14]([CH2:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:18]=3)=[N:15][C:11]=2[CH:10]=1)=[O:6])[CH3:3].Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>CC(C)=O.O>[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:30])=[O:31])[C:9]1[CH:28]=[CH:27][C:12]2[N:13]([CH3:26])[C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[N:22][C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:44])=[CH:24][CH:25]=3)=[N:15][C:11]=2[CH:10]=1)=[O:6])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCc3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethyloxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and benzyl chloroformate in acetone/water.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2nc(C3CCNCC3)oc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
560 mg tert-butyl 4-(4,5-diphenyloxazol-2-yl)-piperidine-1-carboxylate are placed in 2 ml dichloromethane, then 1.1 ml trifluoroacetic acid are added. The reaction mixture is stirred for 15 hours at ambient temperature, then evaporated to dryness. The residue is combined with toluene and evaporated to dryness again. The residue is combined with diethyl ether and the precipitated solid is suction filtered and dried. 510 mg (V-26) are obtained.
Reaction SMILES: C([Li])CCC.CC(C)=O.[C:10](=[O:12])=[O:11].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]#[CH:36])=[C:22]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]>CCCCCC.O1CCCC1>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]#[C:36][C:10]([OH:12])=[O:11])=[C:22]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: O=C=O
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=C(COCC#CC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
A 1.6M solution of n-butyllithium in hexane (36 ml) was added dropwise over 40 minutes to a stirred, cooled (acetone/cardice bath) solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}prop-2-yne (11.0 g) in tetrahydrofuran (110 ml) and the mixture allowed to warm to -40° over one hour. The mixture was then cooled to -60° and carbon dioxide bubbled through the stirred solution at that temperature for one hour. Carbon dioxide was then bubbled through the mixture for a further one hour whilst it was allowed to warm up to 0°. The mixture was then diluted with water (100 ml) and the layers separated. The aqueous layer was washed with diethyl ether, acidified to pH 1.0 with concentrated hydrochloric acid and extracted into dichloromethane. The combined dichloromethane extracts were dried over MgSO4 and evaporated and the residue triturated with methanol. The resulting solid was collected, washed with methanol and dried to give the title compound (8.87 g) as a hemihydrate containing half a mole of methanol of crystallisation, m.p. 100°.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:20][CH:19]=1
Reactant: Clc1ccc(I)cc1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.77 g (20 mmole) of para-chloro iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with cold ethanol and dried under vacuum to obtain 2.53 g (56%) of 2-(4-chloro-phenyl)-indene.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([OH:9])=[CH:3][CH:2]=1.[OH:10][C:11]1[C:12]([C:21]([NH:23][NH2:24])=[O:22])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2>>[OH:9][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[N:24][NH:23][C:21]([C:12]1[C:11]([OH:10])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:22]
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1ccccc1O
Product: O=C(NN=Cc1ccccc1O)c1cc2ccccc2cc1O
Yield: 94 %

Procedure:
Following the general procedure of Example 1, condensation of salicylic aldehyde and 3-hydroxy-2-naphthoic hydrazide gave a pale yellow solid (94%): mp >285° C.; 1H NMR d 11.69 (br s, 1H), 10.97 (br s, 1 H), 10.79 (s, 1 H), 8.24 (s, 1 H), 8.02 (s, 1 H), 7.45 (d, 1 H, J=8.1 Hz), 7.31 (d, 1 H, J=8.1 Hz), 7.12 (dd, 1 H, J=7.8, 0.9 Hz), 7.05 (t, 1 H, J=7.5 Hz), 6.89 (s, 1 H), 6.86 (m, 2H), 6.51 (d, 1 H, J=8.1 Hz), 6.48 (t, 1H, J=7.5 Hz); 13C NMR d 163.62, 157.54, 154.08, 148.83, 135.94, 131.64, 130.37, 129.49, 128.70, 128.33, 126.79, 125.89, 123.86, 119.99, 119.44, 118.68, 116.48, 110.63; HRMS Calcd for C18H14N2O3 :306.1004, found 306.0977; Anal. (C18H14N2O3) C, H, N.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:14]([CH2:15][N:16]2[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])=[C:18]([Cl:33])[C:17]2=[O:34])=[CH:13][N:12]=[C:11]([CH3:35])[N:10]=1.C(N(CC)CC)C.C([O:46][CH2:47][C:48](Cl)=[O:49])(=O)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:33][C:18]1[C:17](=[O:34])[N:16]([CH2:15][C:14]2[C:9]([NH:8][C:47](=[O:46])[CH2:48][OH:49])=[N:10][C:11]([CH3:35])=[N:12][CH:13]=2)[C:21]([CH3:22])=[CH:20][C:19]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ncc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(N)n1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(NC(=O)CO)n1
Temperature: -20 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
To a chilled solution of 1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one trifluoroacetate (0.200 g, 0.38 mmol) in DMF (20 mL) and a catalytic amount of DMAP was added triethylamine (0.064 mL, 0.38 mmol). The reaction stirred at −20° C. and acetoxyacetyl chloride (0.082 mL, 0.76 mmol) was added. The reaction stirred cold for 15 minutes and then allowed to warm up to room temperature for 3 hours. The reaction was monitored by LR-ESMS m/z=466. The reaction was incomplete after 3 hours. Added acetoxyacetyl chloride (0.05 mL, 0.466 mmol), and triethylamine (0.2 mL, 1.43 mmol) to the reaction mixture and continued to stir overnight at room temperature. The next morning the reaction heated at 65° C. for 3 hours. The solvent was removed in vacuo and 1N LiOH (2.5 mL) was added to the residue. The reaction was heated at 60° C. for 5 hours. The reaction was diluted with acetonitrile and water (1:1) and purified by reverse phase HPLC in 10-90% CH3CN/water (30 minute gradient) at a flow rate of 50 mL/min. The appropriate fractions were freeze dried to afford the desired product (0.020 g, 9%). 1H NMR (CD3OD, 400 MHz) δ 8.04 (s, 1H), 7.6 (m, 1H), 7.02 (m, 1H), 6.59 (s, 1H), 5.30 (s, 2H), 5.24 (s, 2H), 4.26 (s, 1H), 2.60 (s, 3H), 2.43 (s, 3H); ES-HRMS m/z 465.1161 (M+H calculated for C21H20N4O4F2Cl requires 465.1136).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:17]3[CH2:18][CH2:19][CH2:20][N:14]([CH3:13])[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCCNCC1
Reactant: Cc1cc(C)c2oc(S)nc2c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c2oc(N3CCCN(C)CC3)nc2c1

Procedure:
5,7-Dimethyl-2-mercaptobenzoxazole (220 mg) was dissolved in chloroform (20 ml), N-methylhomopiperazine (0.76 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5,7-dimethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (110 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:14]1[N:19]=[C:18]2[NH:20][C:21](=[O:34])[N:22]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=3[Cl:33])[C:23](=[NH:24])[C:17]2=[CH:16][N:15]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:31][C:30]1[CH:29]=[C:28]([F:32])[CH:27]=[C:26]([Cl:33])[C:25]=1[N:22]1[C:23](=[NH:24])[C:17]2[C:18](=[N:19][C:14]([NH:12][C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]4)=[CH:8][CH:7]=3)=[N:15][CH:16]=2)[NH:20][C:21]1=[O:34]
Reactant: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cc(F)cc1Cl
Reactant: CN1CCc2ccc(N)cc2C1
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: CN1CCc2ccc(Nc3ncc4c(=N)n(-c5c(Cl)cc(F)cc5Cl)c(=O)[nH]c4n3)cc2C1

Procedure:
15 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichloro-4-fluorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 4 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.