Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[NH:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].[C:43](OC)(OC)(OC)[CH3:44]>CN(C=O)C>[CH3:43][C:44]1[N:12]2[C:3]([C:4]3[CH:5]=[C:6]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:7]([C:13]4[CH:18]=[CH:17][C:16]([CH2:19][N:20]5[CH2:21][CH2:22][CH:23]([C:26]6[N:30]=[C:29]([C:31]7[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=7)[NH:28][N:27]=6)[CH2:24][CH2:25]5)=[CH:15][CH:14]=4)=[N:8][C:9]=3[CH:10]=[CH:11]2)=[N:1][N:2]=1
Reactant: COC(C)(OC)OC
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Solvent: CN(C)C=O
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CN5CCC(c6n[nH]c(-c7ccccn7)n6)CC5)cc4)nc3ccn12
Temperature: 100 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To 5-hydrazino-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridine (2-1) (55 mg, 0.101 mmol) in DMF (1.0 mL) was added trimethyl orthoacetate (0.63 mL, 5.04 mmol). The reaction mixture was stirred at 100° C. for 3 hours, and then concentrated in vacuo, and chromatographed to furnish the desired 3-methyl-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine (2-2) (28 mg) as its trifluoroacetic acid salt. 1H NMR: (500 MHz, CDCl3) δ 8.87 (s, 1H), 8.65 (d, J=6.4 Hz, 1H), 8.33 (d, J=7.5 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.49-7.41 (m, 3H), 7.36-7.30 (m, 8H), 3.61 (s, 2H), 3.02-3.00 (m, 2H), 3.00-2.84 (m, 1H), 2.25-2.21 (m, 2H), 2.10-1.83 (m, 4H), 1.97 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[NH:7]2.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[N:7]3[CH:24]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17](=[O:16])[C:5]([C:6]=23)=[CH:4][CH:3]=1
Reactant: CC1CN(C)c2c(Cl)cccc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(Cl)ccc3c1=O)N(C)CC2C

Procedure:
A mixture of 0.0765 mole (15 g) of 8-chloro-1,3-dimethyl-1,2,3,4-tetrahydroquinoxaline and 0.0765 mole (16.5 g) of diethyl ethoxymethylenemalonate was heated under a nitrogen atmosphere at 145° to 150° C. for about 75 minutes. The solution was cooled, 70 g of polyphosphoric acid were added and the mixture was heated under nitrogen at 110° to 120° C. for 45 minutes. The hot solution was poured into water with stirring and a white solid precipitated. The product was recrystallized from ethanol to provide ethyl 10-chloro-2,3-dihydro-1,3-dimethyl-7-oxo-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate, m.p. 259°-261° C. Analysis: Calculated for C16H17ClN2O3 : %C, 60.0, %H, 5.35; %H, 8.75; Found: %C, 60.0; %H, 5.3; %N, 8.9.
Reaction SMILES: [CH3:1][C:2]1[CH:35]=[C:5]2[N:6]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:7](=[O:28])[C:8]([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]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.C([Sn](=O)CCCC)CCC.[N:46]([Si](C)(C)C)=[N+:47]=[N-:48].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:35]=[C:5]2[N:6]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:7](=[O:28])[C:8]([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]4[NH:48][N:47]=[N:46][N:27]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
A mixture of 4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.1 g), dibutyltin oxide (0.011 g), azidotrimethylsilane (0.74 g) and toluene (10 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.035 g, 31%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].Br[CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1>CS(C)=O.O>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:11]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrC1CCN(Cc2ccccc2)C1
Reactant: Sc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN2CCC(Sc3ccccc3)C2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 727.5 %

Procedure:
A solution of 55 g (0.5 mole) of thiophenol in 50 ml of dimethylsulfoxide was added dropwise with stirring to 250 ml of dimethylsulfoxide containing 21.5 g (0.55 mole) of sodamide. After stirring the mixture at 40° C. for 1 hr, 120 g (0.05 mole) of 3-bromo-1-benzyl-pyrrolidine (slightly exothermic) was added dropwise. The solution was stirred at 60° C. for 1 hr, diluted with 500 ml of water and extracted with isopropyl ether. The ether phase was dried over sodium sulfate and concentrated, and the residue distilled, b.p. 170°-170° C./5 mm. to give 98 g (73%) of product.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[OH:7])=[O:5].[OH-].[Na+].Cl[C:20](OCC)=[O:21]>O1CCOCC1>[CH3:14][C:10]1[CH:9]=[C:8]([N:6]2[C:4](=[O:5])[N:3]([C:2]([F:15])([F:16])[F:1])[C:20](=[O:21])[O:7]2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(N(O)C(=O)NC(F)(F)F)c1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cccc(-n2oc(=O)n(C(F)(F)F)c2=O)c1

Procedure:
1-Trifluoromethyl-3-(3'-methylphenyl)-3-hydroxyurea (11.7 grams; 0.05 mol) is dissolved in dioxane (75 ml) and mixed with 2N aqueous sodium hydroxide (30 ml). Ethyl chloroformate (5.7 ml; 0.06 mol) is then added dropwise to the mixture with stirring, resulting in the formation of a precipitate. The precipitate is recovered by filtration, is washed and dried to yield 2-(3'-methylphenyl)-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([F:27])[CH:24]=[C:25]([F:26])[C:20]=2[O:19][CH2:18][C:17]1=[O:28].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[CH:22]=[C:23]([F:27])[CH:24]=[C:25]([F:26])[C:20]=4[O:19][CH2:18][C:17]3=[O:28])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C1COc2c(F)cc(F)cc2N1CCCCl
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)cc(F)cc2N1CCCN1CCC(OCC2CC2)CC1
Yield: 50.4 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.076 g, 0.49 mmol), 4-(3-chloropropyl)-6,8-difluoro-4H-benzo[1,4]oxazin-3-one (0.143 g, 0.55 mmol), K2CO3 (0.136 g, 0.98 mmol) and KI (0.147 g, 0.98 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; heptanes/EtOAc 1:1) to give the title compound (0.094 g, 50%). 1H NMR (CDCl3) δ 6.83-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.60 (s, 1H), 3.92 (t, J=6.8 Hz, 2H), 3.36-3.24 (m, 3H), 2.77-2.68 (m, 2H), 2.34 (t, J=6.8 Hz, 2H), 2.09 (t, J=9.6 Hz, 2H), 1.93-1.76 (m, 4H), 1.66-1.56 (m, 2H), 1.08-0.97 (m, 1H), 0.53-0.48 (m, 2H), 0.19-0.15 (m, 2H); 13C NMR (CDCl3) δ 163.9, 157.4 (dd, J=241.4 Hz, J=12.7 Hz), 151.4 (dd, J=247.6 Hz, J=14.3 Hz), 131.4 (dd, J=12.5 Hz, J=4.7 Hz), 130.2 (dd, J=14.6 Hz, J=3.9 Hz), 99.3 (dd, J=26.9 Hz, J=22.3 Hz), 98.6 (dd, J=28.4 Hz, J=3.5 Hz), 74.8, 72.8, 67.8, 55.1, 51.5, 40.3, 31.5, 24.8, 11.1, 3.2.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1COCC1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 92.3 %

Procedure:
4-Chlorobenzonitrile (140 mg, 1.02 mmol) reacted with p-methoxyphenylboronic acid (200 mg, 1.32 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (182 mg, 3.00 mmol) in THF solvent to give the title compound (197 mg, 94%) as white solid after recrystallization from hexane: 1H-NMR (400 MHz, CDCl3): δ 7.70 (d, 2H, J=8.41 Hz), 7.65 (d, 2H, J=8.40 Hz), 7.55 (d, 2H, J=8.80 Hz), 7.02 (d, 2H, J=8.79 Hz), 3.88 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 160.18, 145.17, 132.52, 131.45, 128.31, 127.06, 119.04, 114.52, 110.07, 55.35. GC/MS(EI): m/z (M+).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:21])[C:6](O)([CH3:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]2>O.CO>[CH:16]([CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:6]([CH3:19])[C:5]([OH:21])=[O:4])[CH:8]=2)[CH2:12]1)([CH3:18])[CH3:17]
Reactant: COC(=O)C(C)(O)c1ccc2c(c1)CC(C(C)C)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc2c(c1)CC(C(C)C)C2

Procedure:
A solution of 26.6 g of potassium hydroxide in 50 cc of water is added to a solution of 41.5 g of crude α-hydroxy-2-isopropyl-α-methyl-5-indanacetic acid methyl ester in 500 cc of methanol, and the mixture is boiled at reflux for 11/2 hours. The solution is concentrated, diluted with water and extracted with ether in order to remove the neutral components. The aqueous phase is then acidified with hydrochloric acid, extracted with ether, the ether extract is washed with water, dried over sodium sulphate and concentrated by evaporation. The resulting α-hydroxy-2-isopropyl-α-methyl-5-indanacetic acid is recrystallized from ether/hexane and has a M.P. of 126°-130°.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]=[C:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2.CN(C)C=O.[H][H]>[Pd].CO>[CH2:3]([CH:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH:2]([CH3:21])[CH3:1]
Reactant: CC(C)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21

Procedure:
2.8 g of a mixture of 10-(2-methyl-1-propenyl)-5H,10H-imidazo[1,2-]indeno[1,2-e]pyrazin-4-one and 10-(2-methylpropylidene)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are hydrogenated in the presence of 180 ml of dimethylformamide, 20 ml of methanol and 0.5 g of 10% palladium on charcoal for 22 hours at 50° C. and at a pressure of 54 bar of hydrogen. After filtration of the catalyst under inert atmosphere, the solvents are evaporated off and the grey solid obtained (2.1 g) is purified by chromatography on a column of silica (180 g partially deactivated with 3 ml of water), using a mixture of dichloromethane and methanol (90/10 by volume) as eluent. After trituration in 20 ml of ethyl ether, filtration and drying at 100° C., 1.2 g of 10-isobutyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, in the form of a cream-coloured solid melting above 260° C. (Analysis % calculated C: 73.10, H: 6.13, N: 15.04, O: 5.73, % found C: 72.9, H: 5.6, N: 14.8).
Reaction SMILES: Br.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[C:16]([O:28][CH3:29])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(Cl)Cl>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:28][CH3:29])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)c2ccnc3ccccc23)ccc1OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccnc3ccccc23)ccc1O
Reaction time: 4.5 h

Procedure:
15 ml of 33 percent hydrobromic acid in glacial acetic acid are added dropwise within 5 minutes at room temperature to 7.5 g of 4-(benzyloxy)-3-methoxyphenyl 4-quinolyl ketone dissolved in 150 ml of methylene chloride. After stirring at 20° for 4.5 hours, the reaction mixture is poured portionwise into 250 ml of saturated sodium bicarbonate solution. The methylene chloride phase is separated; the aqueous phase is extracted twice with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxyphenyl 4-quinolyl ketone of m.p. 190°-192°.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:34]1([NH:39][C:40]2([CH2:45]O)[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.[S:47]1C=C[CH:49]=[C:48]1CC(O)=O>C1COCC1>[CH:34]1([NH:39][C:40]2([CH2:45][C:48](=[S:47])[CH3:49])[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(O)Cc1cccs1
Reactant: OCC1(NC2CCCC2)CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)CC1(NC2CCCC2)CCCC1
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a 0° C. solution of Ph3P (27.9 g, 0.107 mol, 1.3 equiv.) in anh. THF (400 mL) were successively added diisopropyl azodicarboxylate (21.5 g, 0.107 mol, 1.3 equiv.) and 1-cyclopentylamino-1-(hydroxymethyl)cyclopentane (Method B4d; 15.0 g, 0.082 mol). The resulting slurry was stirred for 30 min., then was treated with thiolacetic acid (7.6 mL, 0.107 mol, 1.3 equiv.). The resulting yellow solution was stirred for 15 min. and concentrated under reduced pressure to about 100 mL. The residue was dissolved in EtOAc (200 mL) and the resulting solution was extracted with a 1N HCl solution (5×125 mL). The combined aqueous layers were washed with EtOAc (2×200 mL), neutralized with K2CO3 to pH 7.0-7.5, then extracted with EtOAc (5×200 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The residue was dried in vacuo to afford 1-cyclopentylamino-1-(thioacetylmethyl)cyclopentane as a yellow oil (19.1 g): TLC (10% EtOAc/hexanes) Rf0.16; 1H NMR (CDCl3) δ1.20-1.87 (m, 16H), 2.34 (s, 3H), 2.92-3.02 (m, 1H), 3.15 (s, 2H); 13C NMR (CDCl3) δ23.9, 25.2, 29.3, 36.4, 40.1, 55.8, 73.0, 169.8; CI-LRMS m/z (rel abundance) 242 ((M+H)+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:12].Cl>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (405 mg) and 2-bromo-4'-hydroxyacetophenone (646 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature, giving a clear solution. A precipitate had formed after an hour. After 231/2 hours, 2N-hydrochloric acid (5 ml) was added to the suspension and the solid was collected. This was washed with ethanol to give the title pyrimidinone (679 mg,); m.p. 260° with decomposition; λmaxEtOH 224 nm (ε 17300), 282.5 nm (ε 15660), 353 nm (ε 4900).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([NH2:18])[N:3]=1.C1C(=O)N([I:26])C(=O)C1>C(Cl)Cl.CO>[I:26][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:18])=[N:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N)nc(-c2cccc(C(F)(F)F)c2)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 5.0 g (14 mmol) 4-methyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-ylamine and 3.3 g (15 mmol) NIS. Yield after chromatography on silica gel with DCM/MeOH: 3.8 g (73%).
Reaction SMILES: S(Br)([Br:3])=O.[Cl:5][C:6]1[C:7]([CH:15](O)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1>C1(C)C=CC=CC=1>[Br:3][CH:15]([C:7]1[C:6]([Cl:5])=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(O)c1cc2c(cc1Cl)OCO2
Reactant: O=S(Br)Br
Solvent: Cc1ccccc1
Product: COC(=O)C(Br)c1cc2c(cc1Cl)OCO2

Procedure:
Thionyl bromide (3.7 ml) was added to a stirred solution of methyl 2-(6-chloro-1,3-benzodioxol-5-yl)-2-hydroxyacetate from step (a) (7.8 g, 32 mmol) in toluene (50 ml) at ambient temperature. After 6 hours the reaction mixture was evaporated in vacuo, and the residue was flash chromatographed using dichloromethane as eluant, followed by crystallisation from diisopropylether to give the subtitle compound (7.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:28]O>C(O)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)(=[O:28])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCS(=O)c3ccc([N+](=O)[O-])cc3)ccc2[nH]1
Solvent: O=CO
Product: O=c1ccc2cc(OCCCCS(=O)(=O)c3ccc([N+](=O)[O-])cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 124 from 6-[4-(4-nitro-phenyl-sulfinyl)-butoxy]-carbostyril and hydrogen peroxide in formic acid.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=[C:20]3[NH:28][CH:29]=[CH:30][C:19]=23)[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=[C:20]3[NH:28][CH:29]=[CH:30][C:19]=23)[CH2:16][CH2:17]1)=[O:11]
Reactant: COC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
(R)-Methyl 4-(4-(2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.025 g, 0.046 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour and then concentrated. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid (R)-methyl 4-(4-(2-amino-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.015 g, 74% yield) was collected and dried as the dihydrochloride salt. MS ESI (+) m/z 442 detected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:54])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:54])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (374 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown solid (500 mg, 70%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 118–120° C.; 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 1 H), 6.71 (s, 2 H), 4.34–4.24 (m, 2 H), 4.09–4.01 (m, 1 H), 3.76 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.93–1.74 (m, 2 H), 1.06–0.98 (m, 1 H), 0.95–0.81 (m, 3 H), 0.79–0.72 (m, 1 H), 0.54–0.44 (m, 2 H), 0.34–0.22 (m, 1 H); HRMS (ESI) calcd for C19H22N3O2Cl2 (M+H)+: 394.1089; found m/z 394.1099.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(-c2nc3ccccc3[nH]2)ccn1)c1ccccc1
Temperature: 25 °C
Yield: 12 %

Procedure:
To a solution of N-(2-aminophenyl)-2-benzamidoisonicotinamide (0.18 g, 0.53 mmol) in toluene (10 mL) was added phosphorus oxychloride (0.14 mL, 1.57 mmol) at ambient temperature. The resulting solution was refluxed for 5 hours, cooled to ambient temperature and concentrated in vacuo. The residue was taken up in 1 M aqueous sodium hydroxide solution (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with 20-100% ethyl acetate in hexanes to give N-(4-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)benzamide as a pale yellow solid (0.02 g, 9%): mp 145-146° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.01 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.12-8.07 (m, 2H), 7.91 (dd, J=5.2, 1.4 Hz, 1H), 7.69 (dd, J=6.0, 3.2 Hz, 2H), 7.66-7.51 (m, 4H), 7.30 (dd, J=6.0, 3.2 Hz, 2H); MS (ES+) m/z 315.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cccc(C)c1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1c(C)cccc1C

Procedure:
The title compound is prepared using essentially the same procedure used in example 42 except using 2,6-dimethylphenol in place of 4-chloro-2,6-dimethylphenol and ethyl bromoacetate in place of bromoacetonitrile.