Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)=O.CC(C)=O.[CH2:8]([C:24]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]=1[OH:38])[C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[OH:23].C(N(CC)CC)C.Cl[SiH2:47]Cl>O1CCCC1>[C:30]([C:28]1[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]2[O:38][SiH2:47][O:23][C:10]3[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]([C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:14][C:9]=3[CH2:8][C:24]=2[CH:29]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: Cl[SiH2]Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[SiH2]Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Yield: 57.2 %

Procedure:
In a flame-dried flask equipped with a dry ice-acetone filled Dewar condenser and a sintered glass inlet, 42.5 grams (0.1 mole) 2,2'-methylene-bis(4,6-di-t-butylphenol) and 20.2 grams (0.2 mole) triethylamine dissolved in 100 ml tetrahydrofuran are treated slowly with 11.1 grams (0.11 mole) dichlorosilane. Filtration and recrystallization from acetonitrile-toluene gave 25.9 grams (57% yield) of a white solid mp 189°-192° C. The 1H NMR spectrum is consistent with the product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[O:47]1[C:51]2[CH:52]=[CH:53][C:54]([C:56](Cl)=[O:57])=[CH:55][C:50]=2[O:49][CH2:48]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:47]1[C:51]2[CH:52]=[CH:53][C:54]([C:56]([N:43]3[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]4[CH:30]=[CH:31][C:32]5[NH:33][C:34]6[N:35]=[C:19]([NH:20][C:21]7[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=7)[CH2:26][CH2:27][C:28]=4[CH:36]=5)[N:18]=[CH:17][C:16]=6[Cl:15])=[O:39])[CH2:41][CH2:42]3)=[O:57])=[CH:55][C:50]=2[O:49][CH2:48]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)c2ccc3c(c2)OCO3)CC1
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 1,3-benzodioxole-5-carbonyl chloride as starting materials in 16% yield. LCMS for C32H30ClN6O4 (M+H)+: m/z=597.2.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41])=[O:36].N.[OH2:55]>ClCCl.O>[F:19][C:18]([F:21])([F:20])[C:14]([OH:36])=[O:55].[Cl:26][C:23]1[CH:24]=[CH:25][C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[O:36])[CH:38]=2)=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)[CH:22]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: O
Agent: N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 6d (150 mg, 0.39 mmol, 1.00 equiv) in dichloromethane (6 mL), and pyridine (93.6 mg, 1.18 mmol, 3.00 equiv). To this was added dropwise, a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride 1f (147 mg, 0.47 mmol, 1.20 equiv) in dichloromethane (2 mL) over 10 min with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with 2 mL of water, and adjusted to pH 8 with NH3.H2O (2 mol/L). The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 67.2 mg (22%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.67 (s, 1H), 11.54 (s, 1H), 9.62 (s, 1H), 8.68-8.67 (d, J=2.7 Hz, 1H), 8.71-8.38 (d, J=9.0 Hz, 1H), 8.16-8.02 (m, 5H), 7.79-7.65 (m, 5H), 6.968-6.960 (d, J=2.4 Hz, 1H), 4.01 (s, 2H), 3.84 (s, 2H), 3.42 (s, 6H), 3.18 (s, 2H), 2.98 (s, 3H). MS (ES, m/z): 655 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH:8][C:9]2[C:14]3=[N:15][CH:16]=[C:17]([C:18]#[N:19])[N:13]3[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)=[N:3]1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([N:8]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]2[C:14]3=[N:15][CH:16]=[C:17]([C:18]#[N:19])[N:13]3[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)=[N:3]1
Reactant: COc1ccc(CCl)cc1
Reactant: CSc1nc(Nc2nc(C)n(C)n2)c2ncc(C#N)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nc(C)n(C)n2)c2nc(SC)nn3c(C#N)cnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (157 mg, 0.521 mmol) was taken up in DMF (6 mL) under argon and NaH (22.92 mg, 0.573 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, and then alpha-chloro-4-methoxytoluene (0.074 mL, 0.547 mmol) was added. The reaction mixture was heated at 80° C. for 3 h. The reaction was quenched with saturated NaHCO3 solution and extracted 3× with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)(4-methoxybenzyl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (185 mg) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH2:28][OH:29])[CH:3]=1.C(N(CC)CC)C.[C:37]1([CH3:49])[C:38]([S:43]([N:46]=[C:47]=[O:48])(=[O:45])=[O:44])=[CH:39][CH:40]=[CH:41][CH:42]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH:3]=1)[CH2:28][O:29][C:47](=[O:48])[NH:46][S:43]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH3:49])(=[O:44])=[O:45]
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CO
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1S(=O)(=O)NC(=O)OCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 55 °C

Procedure:
To a solution of 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.050 g, 0.12 mmol) in dry toluene (2 mL) was added triethylamine (0.05 mL, 0.36 mmol) followed by o-toluenesulfonylisocyanate (0.05 mL, 0.36 mmol) and catalytic 4-dimethylaminopyridine. After 23 hours the reaction was warmed to 55° C. for 2 hours. After cooling the reaction was evaporated to dryness and the title compound purified by silica gel chromatography (0.074 g, LRMS: 618.1).
Reaction SMILES: [F:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][OH:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:11][C:7]1[CH:6]=[C:5]([C@H:2]([F:1])[CH2:3][O:4][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](F)c1cccc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](F)c2cccc(Br)c2)cc1
Temperature: 25 °C

Procedure:
A solution of (R)-2-fluro-2-(3-bromophenyl)-1-ethanol (5 mmol) and p-toluenesulfonyl chloride (5.1 mmol) in CH2Cl2 at ice bath temperatures is treated with stirring with pyridine. The reaction mixture is heated at reflux temperature under a nitrogen atmosphere for 16 h, cooled to room temperature, washed with 10% HCl, saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to give toluene4-sulfonic acid (S)-2-(3-bromophenyl)-2-fluoro-ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:52])[CH:22]([N:29]3[C:33]4[CH:34]=[C:35]([C:38]#[N:39])[CH:36]=[CH:37][C:32]=4[N:31]([S:40]([C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)(=[O:42])=[O:41])[C:30]3=[O:51])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>C(Cl)Cl>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([S:40]([N:31]2[C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][C:33]=3[N:29]([CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:21](=[O:52])[N:18]3[CH2:17][CH2:16][CH:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:20][CH2:19]3)[C:30]2=[O:51])(=[O:41])=[O:42])=[CH:48][CH:47]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC4CCN(C(=O)OC(C)(C)C)CC4)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC4CCNCC4)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 4-(1-{2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydrobenzoimidazol-1-yl]-2-phenyl-acetyl}-piperidin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.14 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×). The residue was purified by preparative RP-HPLC (eluent: gradient from 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid as modulator) to afford 1-(4-methoxybenzenesulfonyl)-2-oxo-3-{2-oxo-1-phenyl-2-[4-(piperidin-4-ylamino)-piperidin-1-yl]ethyl}-2,3-dihydro-1H-benzoimidazole-5-carbonitrile; compound with trifluoroacetic acid (70 mg, 67%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:12])[O:13][CH2:14][CH3:15]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 99 %

Procedure:
2,4-Dichloroaniline (2.380 g) was dissolved in pyridine (20 ml), and to the solution was added dropwise ethyl chloroformate (1.685 ml) under ice-cooling. After the mixture was stirred for 2 hours, 1N hydrochloric acid was added. The precipitated crystals were filtered, washed with water and then dried to give the title compound (3.4055 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.[C:30]([O-:33])([O-])=O.[K+].[K+].[CH3:36]N(C=O)C>O>[OH:33][CH2:30][CH2:36][O:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(O)cc1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
To a mixture of 5-(4-hydroxybenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (200 mg, 0.5 mmol) and 2-bromothanol (123 mg, 1.0 mmol) in DMF (10 mL) was added K2CO3 (136 mg, 1.0 mmol), and the mixture was stirred at 80° C. for 16 hrs. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography eluted with 3.5% MeOH in DCM to give 40 mg (18% yield) of the titled compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1-2
Product: O=C(CCCCN1CCOCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCOCC3)ccc1-2

Procedure:
By the procedure of Example 7, 20.2g (0.05 mole) of 2,7-bis(5-chlorovaleryl)fluorene, prepared in Example 2, 34.9g (0.4 mole) of morpholine were reacted to give the desired product which was recrystallized twice from methylene chloride-methanol. M.P. 134°-136.5° C, λmax0.1NHCl 325, Elcm1% 776.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:24]=[CH:23][N:16]4[C:17](=[O:22])[CH2:18][C:19](=O)[N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(C(C)C)CC)(C)C.[OH:51][CH:52]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53]1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C>[CH:1]1([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:24]=[CH:23][N:16]4[C:17](=[O:22])[CH:18]=[C:19]([N:54]5[CH2:55][CH2:56][CH2:57][CH:52]([OH:51])[CH2:53]5)[N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC(=O)N2C=CC(C(=O)Nc3nc(C4CCC4)cs3)=CC2=N1
Reactant: OC1CCCNC1
Agent: O=C([O-])O
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc(C2CCC2)cs1)c1ccn2c(=O)cc(N3CCCC(O)C3)nc2c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
N8-(4-Cyclobutyl-1,3-thiazol-2-yl)-2,4-dioxo-3,4-dihydro-2H-pyrido[1,2-a]-pyrimidine-8-carboxamide (100 mg, 0.29 mmol) was added with acetonitrile (2 ml) and dimethylformamide (1 ml), cooled to −10° C. with ice, then added with diphenyl chlorophosphate (0.2 ml, 0.96 mmol), and further added dropwise with diisopropylethylamine (0.3 ml, 1.74 mmol). The reaction solution was stirred at −10° C. for 30 minutes, then added with 3-hydroxypiperidine (90 mg, 0.89 mmol), warmed to room temperature, and then further warmed to 80° C. As the reaction was not completed, the reaction solution was further added with 3-hydroxypiperidine (60 mg), stirred for 1 hour, and further added with 3-hydroxypiperidine (70 mg). After the disappear of the starting material was observed, the reaction was stopped with saturated aqueous sodium hydrogencarbonate, and the reaction solution was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=15:1) to obtain 85.2 mg (69%) of the title compound as yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[CH2:27]([OH:30])[CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:30][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: OCCO
Product: CCCOc1ccc(COCCO)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 45 %

Procedure:
This compound was prepared from 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one and ethylene glycol following the procedure of Example 38 and was obtained as a white solid (45%), m.p. 101°-102° C. Found C,63.13; H,6.88; N,13.98. C21H28N4O4 requires C,62.98; H,7.05; N,13.99%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=2)[CH:7]=1.[NH3:29]>>[C:21]([CH2:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[CH:26]=[CH:27][CH:28]=[C:2]([CH3:1])[CH:3]=2)[N:11]=[CH:10][N:9]=1)(=[O:22])[NH2:29]
Reactant: CCOC(=O)COc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Reactant: N
Product: Cc1cccc(Nc2cc(Nc3cccc(OCC(N)=O)c3)ncn2)c1
Yield: 81 %

Procedure:
Using an analogous procedure to that described in Example 25, 6-(3'-methylanilino)-4-[3'-(ethoxycarbonylmethoxy)anilino]pyrimidine was reacted with saturated methanolic ammonia to give 4-[3'-(carbamoylmethoxy)anilino]6-(3'-methylanilino)pyrimidine in 81% yield, m.p. 192°-194° C.;
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.N1CCCCC1.[NH2:33]/[C:34](/[CH3:43])=[CH:35]\[C:36]([O:38][CH2:39][CH2:40][C:41]#[N:42])=[O:37]>CC(O)C.O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:4]([C:3](=[O:8])[N:2]([CH3:1])[CH2:9][CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:5]([CH3:6])[NH:33][C:34]([CH3:43])=[C:35]2[C:36]([O:38][CH2:39][CH2:40][C:41]#[N:42])=[O:37])[CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: CC(=O)CC(=O)N(C)CC=Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)N(C)CC=Cc2ccccc2)=C(C)N1
Temperature: 120 °C

Procedure:
306 mg (1.32 mmol) of N-methyl-3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 0.150 ml (1.32 mmol) of 3-chlorobenzaldehyde and 0.013 ml (0.132 mmol) of piperidine were heated under reflux overnight while water was removed. After washing with water, the organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue and 204 mg (1.32 mmol) of 2-cyanoethyl 3-aminocrotonate were heated at 85° C. under stirring in 6.6 ml of 2-propanol overnight. The reaction mixture was further heated at 120° C. under stirring under atmospheric pressure for 3 hours while 2-propanol was evaporated. The residue was purified by the high-performance liquid chromatography to obtain the title compound.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[CH:14]=2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[N:9]1([CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[CH:14]=2)[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)C1CN(CCc2ccc3c(c2)COC3=O)CCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: O=C1OCc2cc(CCN3CCNCC3)ccc21
Temperature: 25 °C

Procedure:
To 1,1-dimethylethyl-4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (120 g, 347 mmol) in dioxane (800 mL) was added 4 N HCl in dioxane (87.0 mL, 347 mmol) and the resulting mixture was stirred at room temperature over night. The reaction mixture was concentrated and stored under vacuum overnight to afford 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride. This can be used as is or converted to the free base by partitioning between an organic solvent and saturated NaHCO3 solution. LC-MS (IE, m/z): 247 (M+1)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.Cl>C(Cl)Cl>[O:9]1[C:18]2[C:13](=[CH:14][C:15]([C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: c1ccc2c(c1)CCCO2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCCO2
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a stirred solution of acetyl chloride (4.78 mL, 67.1 mmol) in dry CH2Cl2 (20 mL) in a −10° C. bath is added aluminum trichloride (4.76 g, 35.7 mmol) in small portions. The mixture is stirred for 15 min until the solution became homogeneous. The solution is added via canula to a separate solution of chromane (4,79 g, 35.7 mmol) in CH2Cl2 (30 mL) all at −10° C. After complete addition, the solution is stirred at −10° C. for 30 min. The solution is poured over a mixture of crushed ice and concentrated HCl. The mixture is extracted with CH2Cl2. The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The remaining residue is purified via crystallization from hexanes to give 4.0 g (64%) of 1-(3,4-dihydro-2H-chromen-6-yl)ethanone as a white solid. 1H NMR (400 MHz, CDCl3) δ7.76-7.73, 6.75, 4.27, 2.86, 2.57, 2.09-2.03.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:31][C:32]1[C:38]([N+:39]([O-:41])=[O:40])=[CH:37][C:35]([NH2:36])=[C:34]([O:42][CH3:43])[CH:33]=1>CC(O)CCC>[Cl:18][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)=[N:7][C:2]([NH:36][C:35]2[CH:37]=[C:38]([N+:39]([O-:41])=[O:40])[C:32]([F:31])=[CH:33][C:34]=2[O:42][CH3:43])=[N:3][CH:4]=1
Reactant: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 125 °C
Yield: 72.2 %

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)-1-methylindole (Intermediate 88, 1281 mg, 4.60 mmol), p-toluene sulphonic acid monohydrate (964 mg, 5.07 mmol) and 4-fluoro-2-s methoxy-5-nitroaniline (Intermediate 23, 900 mg, 4.84 mmol) in 2-pentanol (50 mL) was heated at 125° C. for 18 h. A precipitate formed from the solution upon cooling. The precipitate was collected by filtration, washed with CH3OH (10 mL) and diethyl ether (20 mL) and dried on the filter to give the title compound (1.42 g, 72%) as a tan solid, which was used without further purification; 1H NMR: 3.91 (3H, s), 3.96 (3H, s), 7.05 (1H, t), 7.23-7.3 (1H, m), 7.39 (1H, d), 7.53 (1H, d), 8.33 (1H, d), 8.47 (1H, s), 8.58 (1H, s), 8.65 (1H, d), 8.76 (1H, s); m/z: ES+ MH+ 428.10.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[CH3:15][N:16]([CH3:19])[CH:17]=O.COC(OC)N(C)C>C(OCC)(=O)C>[CH3:15][N:16]([CH3:19])/[CH:17]=[CH:1]/[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cnc(C(=O)OC(C)(C)C)cn1
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)/C=C/c1cnc(C(=O)OC(C)(C)C)cn1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A mixture of t-butyl 5-methylpyrazine-2-carboxylate (1.35 g), N,N-dimethylformamide (25 mL) and N,N-dimethylformamide dimethylacetal (25 mL) was stirred at 130° C. for five hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with a saturated sodium chloride solution three times. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was separated by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (648 mg).