Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.CC(C)=[O:19]>>[C:13]([C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([CH3:10])([CH3:12])[CH3:11])[N:6]=1)[C:2]([OH:19])=[O:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)n1
Reactant: CC(C)=O
Product: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)n1

Procedure:
Jone's reagent was added dropwise to a solution of 4-hydroxymethyl-2,6-di-t-butylpyridine (Compound B, 302 mg, 1.37 mmol) in 5 ml of acetone until the solution changed color from light yellow to orange (55 drops of Jone's reagent were consumed). After 5 minutes 2 ml of isopropanol were added to the reaction mixture, and a green precipitate of Cr3+ salt was formed. The precipitate was removed by filtration and the solution was diluted with ethyl acetate, then washed with brine, water and dried over MgSO4. After filtration, the solvent was removed to give the desired product as a white solid (227 mg). 1H NMR δ 7.71 (s, 2H), 1.34 (s, 18H).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1(C)C=CC(S([O:39][CH2:40][CH2:41][CH2:42][Cl:43])(=O)=O)=CC=1>C(#N)C.C1C=CC=CC=1>[Cl:43][CH2:42][CH2:41][CH2:40][O:39][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH3:2]
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CC#N
Product: CC(=O)c1ccccc1OCCCCl
Temperature: 80 °C

Procedure:
2 ml of 2-hydroxy-acetophenone were added with stirring to a mixture of 2.31 g of tetrabutylammonium acid sulfate, 20 ml of 50% sodium hydroxide solution, 40 ml of benzene and 20 ml of acetonitrile and after adding 8.26 of 3-chloro-propyl p-toluene sulfonate, the mixture was heated under an inert atmosphere at 80° C. for 17 hours. The decanted aqueous phase was extracted with benzene and the organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 95-5 benzene-ethyl acetate mixture. Evaporation ofthe solvents yielded 3.38 g of 1-[2-{3-chloropropoxy}-phenyl]-ethanone.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:27][CH2:26][C:13]2[N:14]([CH:22]([CH3:25])[CH:23]=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1>C1COCC1.CCOC(C)=O.O>[CH3:9][N:10]1[CH2:27][CH2:26][C:13]2[N:14]([CH:22]([CH3:25])[CH:23]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:24])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1
Reactant: Cc1ccc2c(c1)c1c(n2C(C)C=O)CCN(C)C1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2C(C)C(O)c2ccccc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyl magnesium bromide (1M solution in THF) (6.24 mL, 6.24 mmol) was added dropwise at −70° C. to a stirred solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-propionaldehyde (400 mg, 1.56 mmol) in THF (40 mL), the reaction mixture stirred at RT for 16 h, diluted with EtOAc (75 mL) and water (60 mL). The two layers were separated, the aq. layer extracted with EtOAc (2×75 mL), and the combined organic layers dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude (500 mg) was purified by prep. HPLC to afford 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)1-phenyl-propan-1-ol yielded as the TFA salt (65 mg). 1H NMR (CDCl3, Free base) δ (ppm): 7.37 (d, 1H), 7.17 (t, 3H), 7.12 (s, 1H), 7.06 (m, 2H), 6.95 (d, 1H), 5.11 (t, 1H), 4.37 (t, 1H), 3.57 (dd, 1H), 3.46 (d, 1H), 2.67 (m, 2H), 2.51 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.68 (d, 3H). Separation by chiral HPLC provides diastereomers II-95a-d.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[CH2:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(N(CC)CC)C>[Pd].CO>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH:5]2[CH2:4][C:3](=[O:14])[CH2:2]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(C2=C(Cl)C(=O)C2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C2CC(=O)C2)cc1

Procedure:
2-Chloro-3-(p-methoxyphenyl)-2-cyclobuten-1-one (17.4 g., 0.084 mole), triethylamine (11.7 ml., 0.084 mole), and 2.1 g. of 10% Pd/C in 300 ml. of 10% aqueous methanol is shaken under H2 (50 psi) until reduction is complete (30 min). The mixture is filtered and the filtrate evaporated. An ether solution of the residue is washed (water), dried (MgSO4), and evaporated to give 15.4 g. of an oil which is chromatographed on alumina using benzene.
Reaction SMILES: CC([C@]1(O)[C@@]2(C)[C@]3(O)[C@]45O[C@@]2(O)C[C@@](C)([C@@]4(O)CCC([C@H]5[OH:19])=C)[C@]3(O)[C@@H]1OC(C1NC=CC=1)=O)C.C(OC1C=CC(C(NCCC(O)=O)=O)=CC=1)CCC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:69]1([N:75]=[C:76]=[N:77][CH:78]2[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]2)[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O1CCCC1.O>[C:76]([NH:75][CH:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74]1)([NH:77][CH:78]1[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]1)=[O:19]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=C1CC[C@]2(O)[C@]3(C)C[C@]4(O)O[C@@]2([C@@H]1O)[C@]1(O)[C@@]3(O)[C@H](OC(=O)c2ccc[nH]2)[C@](O)(C(C)C)[C@@]14C
Agent: CCCCOc1ccc(C(=O)NCCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dehydro-ryanodine (60 mg., 0.125 mmol), N-(p-n-butoxybenzoyl)-β-alanine (40 mg. 0.15 mmol) and DMAP (2 mg., 0.02 mmol), dried over P2O5, were dissolved in a solvent mixture of CH2Cl2 (10 ml.) and tetrahydrofuran (0.1 ml) dried over Molecular Sieve. To the stirred solution dicyclohexylcarbodiimide (35 mg., 0.15 mmol) was added at once and the reaction mixture maintained at room temperature for 6 hours. Water (0.1 ml) was added and stirring continued for 30 minutes. The solids formed (dicyclohexylurea) were filtered and washed twice with CH2Cl2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[H][H]>[Ru].O1CCOCC1>[F:9][C:8]([F:10])([F:11])[CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ru]
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC1CCCC(C(F)(F)F)C1
Temperature: 175 °C

Procedure:
A mixture of 200 parts of 3-aminobenzotrifluoride, 4 parts of sodium methoxide, 15 parts of 5% ruthenium on alumina, and 200 parts of dioxane is heated in an autoclave at 175°C. under 5,000 p.s.i. of hydrogen for 4 hours. The reaction mixture is cooled and filtered and the solvent is evaporated in a rotary evaporator. The residue is distilled to give 159 parts of 3-trifluoromethylcyclohexylamine, b.p. 69°-70°/27 mm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]([N:13]1[C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-])=O)=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH2:26]([O:28][C:29](=[O:50])[CH:30]=[C:31]([N:38]1[C:42]2[CH:43]=[C:44]([N+:47]([O-])=O)[CH:45]=[CH:46][C:41]=2[N:40]=[CH:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:27].C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:47][C:44]1[CH:45]=[CH:46][C:41]2[N:40]=[CH:39][N:38]([CH:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:50])[C:42]=2[CH:43]=1.[NH2:22][C:20]1[CH:19]=[CH:18][C:17]2[N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH:14]=[N:15][C:16]=2[CH:21]=1
Reactant: CCOC(=O)C=C(c1ccccc1)n1cnc2ccc([N+](=O)[O-])cc21
Reactant: CCOC(=O)C=C(c1ccccc1)n1cnc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of ethyl-3-(5-nitro-1H-benzimidazol-1-yl)-3-phenyl-2-propenoate and ethyl-3-(6-nitro-1H-benzimidazol-1-yl)-3-phenyl-2-propenoate (5.34 g, 15.8 mmol) in a mixture of ethanol and water (10:1, 66 mL) was added palladium on carbon (801 mg, 10% w/w Pd) and ammonium formate (6.0 g, 95 mmol). The suspension was heated to reflux, and was stirred at this temperature for 1.5 hours. The reaction mixture was allowed to cool to room temperature, then filtered through Celite®, and the filter pad washed several times with ethanol. The combined filtrates were evaporated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (99:1) to give, in order of elution, ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate, [LCMS (Method A, Mobile Phase I) RT=3.33 min, MH+ 310] and ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (1.96 g), [LCMS (Method A, Mobile Phase I) RT=3.35 min, MH+ 310].
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][C:19]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[C:15]([C:14]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=2[Cl:12])[C:16]=1[C:17]#[N:18]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: CCOC(=O)c1cnn2c(N)c(C#N)c(-c3ccc(Cl)cc3Cl)nc12

Procedure:
Commercial 3-amino-4-carbethoxypyrazole and (2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reacted according to the procedure of Example 1, Step A, and the crude product was purified by preparative HPLC(C18 reverse phase column, gradient elution with 30-80% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the title compound as a reddish-orange solid. LC-MS 376 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Oc1ccc(C2COC(c3c(F)cccc3F)=N2)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(F)c1C1=NC(c2ccc(OCc3ccc4ccccc4c3)cc2)CO1
Yield: 50 %

Procedure:
The compound of Example 6 (0.36 g, 1.3 mmol) and 2-bromomethyl naphthalene (0.4 g, 1.7 mmol) were stirred at 23° C. for 18 h with potassium carbonate (0.6 g, 4 mmol) in dimethylformamide (10 mL). The mixture was poured into water (50 mL) and extracted with diethylether (50 mL). The diethylether was washed with water (50 mL) twice, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography using hexanes/ethyl acetate (6:1) as eluent to give the title compound as a solid (0.27 g): m.p. 148°-150° C. 1H NMR (CDCl3, 200 MHz) δ 7.8-7.0 (m,14H), 5.4 (m,1H), 5.2 (m,2H), 4.8 (m,1H), 4.3 (m,1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH3:17])[CH:5]=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>>[CH2:14]([C:12]1[C:11](=[O:16])[NH:10][C:9]([CH3:17])=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][S:28]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:27][CH:26]=3)(=[O:30])=[O:29])[N:7]=2)[CH:13]=1)[CH3:15]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cc(-c2cccc(N)n2)c(C)[nH]c1=O
Product: CCc1cc(-c2cccc(NS(=O)(=O)c3ccc(NC(C)=O)cc3)n2)c(C)[nH]c1=O

Procedure:
Example 277 is substantially repeated except for utilizing 6-amino-5′-ethyl-2′-methyl-1′H-[2,3′]bipyridinyl-6′-one and 4-acetylamino-benzenesulfonyl chloride to afford the title compound. MS: m/e=427 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][C:35]([NH2:37])=[O:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][C:35](=[O:36])[NH2:37])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: NC(=O)CBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC(N)=O)CC4)cn3)nc2n1C1CCCC1
Yield: 44.2 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 2-bromo acetamide (95 mg, 0.690 mmol) gave 2-[5-(4-carbamoylmethyl piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 45%). MS (ESI) m/z 492.4 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].O.S(O)(O)(=O)=O.CS[C:26](=[NH:28])[NH2:27].[OH-].[Na+]>CO>[NH:1]([CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6])[C:26]([NH2:28])=[NH:27]
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(N)NCCNS(=O)(=O)c1cccc2cnccc12
Yield: 84.1 %

Procedure:
In 30 ml of methanol was dissolved 3.3 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide obtained in Referential example 1, and to the solution was added 25 ml of water solution containing 5.0 g of S-methylisothiourea sulfate. And to the mixed solution was added 1N aqueous sodium hydroxide solution, the mixed solution thus obtained was heated at reflux for two hours. After the reflux, the methanol was distilled therefrom under reduced pressure, and the white crystals precipitated were separated by filtration under reduced pressure. The crystalline residue thus obtained was recrystallized from methanol to give 3.24 g of N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, i.e., Compound (2) in a yield of 84%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:13])OCC)[CH:6]=[CH:7][CH:8]=1.[NH3:14]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([NH2:13])=[NH:14]
Reactant: CCOC(=N)c1cccc(Cl)c1
Reactant: N
Agent: Cl
Product: N=C(N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 18-mL vial was charged with ethyl 3-chlorobenzenecarboximidate hydrochloride (450 mg, 2 mmol, 1 eq.) and NH3 (2N in ethanol, 12 ml, 24 mmol, 12 eq.). The resulting mixture was stirred at rt overnight. The volatile material was removed under reduced pressure and the product thus obtained was forwarded to the next step without any further purification.
Reaction SMILES: [Br-].[C:2](=[S:4])=[S:3].Br[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]#[N:8].O>C1COCC1>[CH3:6][C:9]1[CH:14]=[CH:13][C:12]([C:2]([S:4][CH:6]([C:7]#[N:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[S:3])=[CH:11][CH:10]=1
Reactant: N#CC(Br)c1ccccc1
Reactant: S=C=S
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=S)SC(C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml round bottom flask was added 10 ml 4-tolylmagiesium bromide (1.0M solution in ethyl ether) and diluted to 20 ml with anhydrous THF. 0.76 g carbon disulfide was added dropwise to this mixture and stirred for ½ h at room temperature. Then to the dark red solution was added 2 g α-bromobenzeneacetonitrile dropwise and the mixture stirred for another 2 h. Water was added to the mixture and the organic product was extracted with diethyl ether (3×50 ml), dried with magnesium sulfate overnight and filtered. After removal of solvent and column chromatography (5:2 mixture of hexane and ethyl ether), pure α-cyanobenzyl 4-methyldithiobenzoate was obtained as a red odorless solid (48% yield). Proton and carbon NMR spectra were consistent with the expected structure, CTA-CP-6.
Reaction SMILES: Cl.[OH:2][NH2:3].C(=O)([O-])[O-].[Na+].[Na+].[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][C@@H:11]1[CH:20]=O>O.C1COCC1>[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][C@@H:11]1[CH:20]=[N:3][OH:2]
Reactant: NO
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ON=C[C@H]1COC2(CCCCC2)O1
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
In 1000 mL of DI water was added hydroxyl amine hydrochloride (51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodium carbonate (38.1 g, 360 mmol) was added in 3 large portions and the reaction was stirred for 15 minutes. THF (700 mL) was added to the reaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734 mmol) in 800 mL of THF was added in 1 portion. The reaction was stirred for 4 hours, then poured into a 4 L separatory funnel. The layers separated and the aqueous layer was extracted twice with MTBE (about 3000 mL total). The combined organic layers were washed with water (700 mL) and brine (300 mL), dried over MgSO4, and concentrated in vacuo to afford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as a clear viscous oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][NH:13][C:11]=3[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].S(OCC)(O[CH2:31][CH3:32])(=O)=O>C(O)(=O)C>[N:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:31][CH3:32])[C:11]=3[N:12]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)c1c[nH]c2nc(N3CCNCC3)ncc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21

Procedure:
To a solution of 1.5 g of 5,8-dihydro-2-(1-piperazinyl)- 5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in 60 ml of a 10% aqueous solution of sodium carbonate was added three 10 ml portions of diethyl sulfate. After completion of the reaction, the resulting mixture was neutralized with acetic acid. The precipitate was collected and recrystallized from dimethylformamide to give 0.8 g of 2-(1-piperazinyl)-5,8-dihydro-8-ethyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (compound 1) m.p. 253° - 255°C. Concentration of the mother liquor to about a half volume gave another solid which was further recrystallized from the same solvent to give 0.6 g of 2-(4-ethyl-1-piperazinyl)-5,8-dihydro-8-ethyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (compound 21), m.p. 228° - 230°C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:20]([NH2:28])=[O:27])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Yield: 93.6 %

Procedure:
4-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridin-2-ylamine (193 mg, 0.73 mmol) is dissolved in DCM (7 mL) and benzoyl isocynate (215 mg, 1.46 mmol) is added. The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (7 mL) and potassium carbonate (151 mg, 1.10 mmol). The mixture is heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (45 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 210 mg of the desired product.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C:11](=[O:16])[CH2:10][CH2:9]2)(=[O:4])[CH3:3].[C:17]1([C:26]2[CH:31]=[CH:30]C=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20](C(Cl)=O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[O:16]=[C:11]1[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:5][C:2]([C:3]3[CH:28]=[CH:27][C:26]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:31][CH:30]=3)=[O:4])[CH:15]=[CH:14][C:13]=2[CH2:12]1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=O)C2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
Concentrated hydrochloric acid (1.5 ml) was added to 6-acetamido-2-tetralone (20 mg. 0.098 mmol) obtained in Reference Example 71, which was stirred at 100° C. for 1 hour, and the solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. [1,1′-Biphenyl]-4-carbonyl chloride (21.3 mg, 0.098 mmol) was added to a dimethylformamide solution (0.5 ml) of the obtained oily substance and triethylamine (0.014 ml, 0.098 mmol) under ice-cooling, which was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with 1N hydrochloric acid, aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), to give the titled compound (10 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[OH:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][NH:39][CH2:38][CH2:37][NH:36]2)=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:39]4[CH2:38][CH2:37][NH:36][CH:35]([C:32]5[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][OH:25])=[CH:34][CH:33]=5)[CH2:40]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: OCCOc1ccc(C2CNCCN2)cc1
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccc(OCCO)cc5)C4)c(F)cc3cc2c1=O

Procedure:
(RS)-3-Ethoxycarbonyl-7,9-difluoro-8-{3-[4-(2-hydroxyethoxy)phenyl]-1-piperazinyl}-1 -methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.9 g) and (RS)-2-[4-(2-hydroxyethoxy)phenyl]piperazine (1.6 g). The expected product (2.2 g) is obtained in the form of a yellow solid, m.p. 183° C.