Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[CH3:30][O-:31].[Na+]>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:21]1[C:7]2[N:8]=[C:9]([O:31][CH3:30])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]1=[O:29]
Reactant: C[O-]
Reactant: COC(=O)/C=C/c1c(Nc2ccccc2Cl)nc(SC)nc1-c1ccccc1F
Agent: [Na+]
Product: COc1nc(-c2ccccc2F)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2-chloro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 8-(2-chloro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.70 (s, 3H), 6.59 (d, 1H, J=9.7 Hz), 7.01-7.20 (m, 3H), 7.40 (m, 2H), 7.56 (m, 4H); LC MS (m/e)=382 (MH+). Rt=2.24 min
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>C(OCC)(=O)C.CCCCCC>[C:13]([O:17][C:18](=[O:21])[C:19](=[CH2:20])[CH:9]([OH:10])[C:8]1[CH:11]=[CH:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C1CN2CCN1CC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
4-(methoxycarbonyl)benzaldehyde (3.3 g, 20 mM), t-butylacrylate (3.5 ml, 24 mM) and 1,4-diazabicyclo[2,2,2]octane (449 mg, 4 mM) were mixed and stirred in a vessel at room temperature for 5 days. The resulting mixture was extracted with ethyl ether. The organic layer was separated, washed with 2N hydrochloric acid, water and an aqueous sodium bicarbonate solution in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/19), to obtain 4.1 g of the title compound as a white solid (yield 73%).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4]>O.C(O)(=O)C.O1CCCC1.CO.[C].[Pd]>[F:47][C:2]([F:1])([F:48])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4]
Reactant: O=C(NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)C(=NOCc1ccc(F)cc1)c1csc(NC(=O)C(F)(F)F)n1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=CCS[C@@H]2C(NC(=O)C(=NOCc3ccc(F)cc3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Yield: 83.7 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(4-fluorobenzyloxyimino)acetamido]-3-cephem-4-carboxylate (syn isomer, 4.65 g.), 10% palladium carbon (2.3 g) in water (9.3 ml.), acetic acid (0.93 ml.), tetrahydrofuran (93 ml.) and methanol (93 ml.) were treated in a similar manner to that of Example 7-(2) to give 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(4-fluorobenzyloxyimino)-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 3.15 g.).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:16](Cl)(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>ClCCl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Fc1cccc2ccccc12
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.3 %

Procedure:
To an ice/salt cooled solution of 1-fluoronaphthalene (5.1 g) in anhydrous dichloromethane (20 ml) was added aluminium chloride (5.6 g). After 5 minutes, a solution of isovaleryl chloride (4.2 g) in anhydrous dichloromethane (5 ml) was added dropwise over 20 minutes. The mixture was allowed to warm to room temperature overnight, then added cautiously to a vigorously stirred mixture of ice water and dichloromethane. The organic layer was separated, clarified with methanol, washed with brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (7 g) was obtained following silica gel column chromatography of the residue in 20-40% dichloromethane in petroleum ether.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]([C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=2[CH:13]=O)[CH2:3]1.[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CO>[CH3:1][C@H:2]1[C@@H:3]2[C:28]3([CH2:13][C:12]4[C:11]([N:4]2[CH2:5][C@@H:6]([CH2:8][CH2:9][CH3:10])[O:7]1)=[CH:18][CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=4)[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]3=[O:30]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CCC[C@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@@H](C)O1
Solvent: CO
Product: CCC[C@@H]1CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 80 °C

Procedure:
2-(cis-2-methyl-6-propylmorpholin-4-yl)-5-nitrobenzaldehyde (446 mg, 1.53 mol) is combined with barbituric acid (217 mg, 1.53 mmol, Aldrich) in a vial with MeOH (6 mL). The sealed reaction is heated to 80° C. on a shaker block for 19 hours and then the solvent is removed by rotary evaporation. The product is purified 2× on a Biotage Flash 75M using 10% MTBE in CH2Cl2 eluent. The product is dried under vacuum at 100° C. yielding a yellow-orange solid. 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 0.95, 1.00, 1.47, 3.04, 3.34, 3.56, 3.95, 4.14, 6.85, 7.77, 8.02, 9.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][N:11]=[C:10]1[S:22][CH2:23][CH2:24][CH3:25].[OH-].[K+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][N:11]=[C:10]1[S:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCSc1ncc(CCCC(=O)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCSc1ncc(CCCC(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of ethyl 4-[1 (2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]butyrate (244 mg) was dissolved in ethanol (5 mL) and a solution of potassium hydroxide (950 mg) in water (5 mL) was added. After being stirred at room temperature for 2 hours, the solution was diluted with water, acidified to pH 3.5 to 4.0 with 10% hydrochloric acid solution and the precipitated product was filtered, washed well with water and recrystallized from acetonitrile to afford 0.144 g (64%) of 4-[1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]butyric acid; mp 98°-99° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([O:19]C)=[O:18].O[Li].O.Cl>C1COCC1.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a stirring solution of methyl 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetate (4.8 g, 16.8 mmol) in THF/water (25 mL/5 mL, 5:1) was added LiOH.H2O (3.52 g, 84.2 mmol). The resulting mixture was stirred overnight. The crude mixture was slowly acidified with 1N HCl and then extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated under vacuum to give 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (4.3 g). Retention time (min)=3.005, method [7], MS (ESI) 272.1 (M+H).
Reaction SMILES: [N:1]([C:4]1[N:5]=[C:6]([CH:17]2[CH2:19][CH2:18]2)[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[N:9]([CH2:11][CH3:12])[CH:10]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[N:5]=[C:6]([CH:17]2[CH2:19][CH2:18]2)[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[N:9]([CH2:11][CH3:12])[CH:10]=1
Reactant: CCN1C=C(N=[N+]=[N-])N=C(C2CC2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN1C=C(N)N=C(C2CC2)c2ccccc21

Procedure:
To a stirred solution of 3-azido-5-cyclopropyl-1-ethyl-1H-benzo[e][1,4]diazepine (5.8 g, 21.5 mmol) in ethanol (500 mL) under argon was added 10% palladium on charcoal (1.0 gm). The argon was displaced with hydrogen and the mixture was vigorously stirred for 45 min (1 atm hydrogen). The reaction was filtered and the filtrate concentrated in vacuo to an oil (5.3 gm, 100%) which solidified upon standing. MP 93-95° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl.CCOCC>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(CC2CCCCC2N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(CC2CCCCC2NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
Obtained by operating as in example 1c from 6.1 g (22 mmoles) of ethyl 4-[(2-aminocyclohexyl)methyl]benzeneacetate, 2.7 g (26.5 mmoles) of triethylamine in 150 ml of dichloromethane and 4.6 g (22 mmoles) of 4-chlorobenzenesulfonyl chloride in 50 ml of ether. The colorless oil obtained (yield=quantitative) is used without any other purification.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:62]2[CH2:67][CH2:66][N:65]([CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=3)[CH2:64][CH2:63]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:61]=[CH:60][C:45]([CH2:46][N:47]4[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49][CH2:48]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:62]2[CH2:67][CH2:66][N:65]([CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=3)[CH2:64][CH2:63]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:61]=[CH:60][C:45]([CH2:46][N:47]4[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCNCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Yield: 73.1 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (10 mg, 0.015 mmol), TFA (0.25 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (6 mg, 71%) as a yellow solid; δH (500 MHz, DMSO-d6 2.46-2.49 (m, 1H, piperazine NCH2), 2.62 (s, br, 4H, piperazine N(CH2)2), 2.93 (s, br, 2H, piperazine NCH2), 3.30 (hidden by DMSO peak, 2H, piperazine NCH2), 3.34-3.38 (m, 2H, piperazine NCH2), 3.56 (s, 2H, NCH2), 3.61 (s, 2H, NCH2), 3.67 (s, br, 4H, piperazine N(CH2)2), 7.39 (dd, J=7.5, 4.5 Hz, 1H, pyridine H-5), 7.68 (d, J=7.8 Hz, 2H, phenyl H-3 & H-5), 7.78 (d, br, J=7.6 Hz, 1H, pyridine H-4), 8.13 (d, J=7.4 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (d, br, J=4.6 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2);
Reaction SMILES: [BH4-].[Na+].[Si]([O:10][C:11]1[CH:20]=[CH:19][C:14]2[C:15](=O)[CH2:16][O:17][C:13]=2[CH:12]=1)(C(C)(C)C)(C)C.CC(C)=O.Cl>CO.O>[O:17]1[C:13]2[CH:12]=[C:11]([OH:10])[CH:20]=[CH:19][C:14]=2[CH:15]=[CH:16]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: Oc1ccc2ccoc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
NaBH4 (6.0 g, 160 mmol) was added to a solution of 6-(tert-butyldimethylsilyloxy)benzofuran-3(2H)-one (40.0 g, 151 mmol) in MeOH (800 mL) at room temperature. After stirring at room temperature for 2 h, the reaction mixture was treated with acetone. Subsequently 4N HCl were added to the mixture and the stirring was continued for 3 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×1000 mL). The extract was washed with brine, dried, concentrated in vacuo and purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford the pure product (17.0 g, 85.5% yield). 1H NMR (300 MHz, CDCl3) δ: 7.51 (d, J=2.1, 1H), 7.41 (d, J=8.4, 1H), 7.02 (d, J=1.8, 1H), 6.81 (dd, J=8.4, 2.1, 1H), 6.68 (dd, J=2.1, 0.9, 1H), 5.5 (br s, 1H).
Reaction SMILES: C([O:8][C:9]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:12]([CH2:13][N:14]2[C:22]3[C:21](=[O:23])[NH:20][C:19]([CH2:24][CH3:25])=[N:18][C:17]=3[N:16]=[CH:15]2)=[CH:11][C:10]=1[C:32]([CH3:35])([CH3:34])[CH3:33])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH2:24]([C:19]1[NH:20][C:21](=[O:23])[C:22]2[N:14]([CH2:13][C:12]3[CH:26]=[C:27]([C:28]([CH3:29])([CH3:31])[CH3:30])[C:9]([OH:8])=[C:10]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:11]=3)[CH:15]=[N:16][C:17]=2[N:18]=1)[CH3:25]
Reactant: CCc1nc2ncn(Cc3cc(C(C)(C)C)c(OCc4ccccc4)c(C(C)(C)C)c3)c2c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1nc2ncn(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c2c(=O)[nH]1
Yield: 88.1 %

Procedure:
0.2 g of 10% palladium carbon was added to a solution of 0.9 g (1.90 mmol) of the resulting hypoxanthine compound in 50 ml of methanol and the mixture was stirred overnight in a hydrogen atmosphere. Palladium carbon was removed by filtration and the residue was concentrated under vacuum to obtain 0.64 g of 2-ethyl-7-(4-hydroxy-3,5-di-t-butylbenzyl)hypoxanthine (yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][NH:6][C:7](=[O:36])[CH:8](C)[C:9]([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=[O:10].FC1C=C(C=C(F)C=1)CNC(=O)CC(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][NH:6][C:7](=[O:36])[CH2:8][C:9]([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=[O:10]
Reactant: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Agent: O=C(O)CC(=O)NCc1cc(F)cc(F)c1
Product: O=C(CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoguinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-malonamide, MS: m/e=531.3 (M+H+), was prepared in analogy to N-(3,5-difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-malonamide (example 16) from N-(3,5-difluoro-benzyl)-malonamic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.CN(C)[CH:19]=[O:20].O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:19]=[O:20]
Reactant: FC(F)(F)c1ccccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cccc(C(F)(F)F)c1Cl

Procedure:
A solution of 0.6 mole of 2-chlorotrifluoromethylbenzene in 1 l of tetrahydrofuran is cooled to -65° C. and 0.58 mole of butyllithium dissolved in hexane is added. The mixture is maintained at the same temperature for 2 hours and a mixture containing 44 ml of dimethylformamide and 200 ml of tetrahydrofuran is then added dropwise. The reaction medium is allowed to return to ambient temperature, 600 ml of water are added, extraction is then carried out with ethyl ether followed by evaporation to dryness. The product is distilled to purify.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH:5]1[N:10]([N:11]([CH3:24])[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:9](=[O:25])[CH2:8][N:7]([S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])[CH2:6]1.C(N(CC)CC)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(Cl)Cl>[ClH:39].[ClH:1].[Cl:39][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:26]([N:7]1[CH2:8][C:9](=[O:25])[N:10]([N:11]([CH3:24])[CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:5]([CH2:4][NH:3][C:47](=[O:49])[CH3:48])[CH2:6]1)(=[O:27])=[O:28])[CH:38]=[CH:37]2
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CN
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-(aminomethyl)-4-[(6-chloro-2-naphthyl)sulfonyl]-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-2-piperazinone dihydrochloride (0.14 g) obtained in Example 113, triethylamine (0.16 ml) and methylene chloride (3 ml) was combined with acetic anhydride (0.043 ml) with stirring at room temperature and then stirred for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain the title compound (0.12 g) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:35])[CH:11]=[C:12]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:35])[CH:11]=[C:12]([C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(O)c1cc(=O)c(OCc2ccccc2)c2n1CCN(Cc1ccc(Cl)c(Cl)c1)C2=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)c1cc(=O)c(OCc2ccccc2)c2n1CCN(Cc1ccc(Cl)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.9 %

Procedure:
To a solution of the above-mentioned crude 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-(1-hydroxy-2,2-dimethylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (132 mg) in chloroform (4 ml) was added Dess-Martin reagent (65 mg) and the mixture was stirred at room temperature for 20 min. Saturated aqueous sodium hydrogen carbonate solution and sodium sulfite were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate:chloroform=4:1) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (38 mg).
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13](O)=O.CN(C)C=O>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]#[N:5]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of chlorosulphonyl isocyanate (5.35 ml.) in dichloromethane (3 ml.) was added over 45 minutes to a stirred suspension of 3-methoxy-4-methylbenzoic acid (9.97 g.) in dichloromethane (18 ml.) at reflux under an atomosphere of nitrogen. The resulting bright-red homogeneous solution was heated under reflux for 45 minutes, chilled in an ice-bath, and treated dropwise with N,N-dimethylformamide (9.5 ml.), over 15 minutes. After stirring for 30 minutes at 0° C., the orange solution was poured onto ice. The organic layer was separated, washed with water (5×20 ml.), dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (SiO2, 10:90 v/v hexane: toluene) to give 3-methoxy-4-methylbenzonitrile (5.28 g., 60%) as a white solid, m.p. 51°-52.5° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@:13]([C:15]#[C:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([OH:14])[C@@H:12]([CH2:27][OH:28])[O:11][C@H:10]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])(C(C)(C)C)(C)C.Cl.CO>>[CH:18]([Si:17]([C:16]#[C:15][C@@:13]1([OH:14])[C@@H:12]([CH2:27][OH:28])[O:11][C@@H:10]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[C@@H:9]1[OH:8])([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:22])[CH3:23])([CH3:19])[CH3:20]
Reactant: CC(C)[Si](C#C[C@@]1(O)[C@@H](CO)O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H]1O[Si](C)(C)C(C)(C)C)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Product: CC(C)[Si](C#C[C@@]1(O)[C@@H](CO)O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H]1O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
Added to 2.0 g of 1-(2-O-(tert-butyldimethylsilyl)-3-C-triisopropylsilylethynyl-β-D-ribofuranosyl)uracil obtained above were 50 of a 2.6% (w/v) hydrochloric acid/methanol solution, and the mixture was stirred at room temperature. After 180 minutes, the solvent was distilled off under reduced pressure, and the residue was azeotropically distilled with ethanol, purified by column chromatography on covered silica gel (chloroform:methanol=50:1-15:1) and then suspended in hexane. The suspension was filtered to obtain 1.4 g (yield: 89%) of the title compound as a white powdered substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:12]=1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1ccc(F)c(F)c1
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(F)c(F)c3)n2)ccc1-n1cnc(C)c1
Yield: 81 %

Procedure:
The title compound was prepared in analogous manners as described in example 9) from 3,4-difluorophenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 81% yield as a pale-brown solid.