Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:22][CH3:23])=[C:19]([O:20][CH3:21])[C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:74][O:75][C:76]1[CH:77]=[C:78]([CH:80]=[CH:81][C:82]=1[O:83][CH3:84])[NH2:79]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:19]1[C:13]2[CH:12]=[C:11]([C:8]3[N:6]4[N:7]=[C:2]([NH:79][C:78]5[CH:80]=[CH:81][C:82]([O:83][CH3:84])=[C:76]([O:75][CH3:74])[CH:77]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[S:15][C:14]=2[CH:16]=[C:17]([O:24][CH3:25])[C:18]=1[O:22][CH3:23]
Reactant: COc1ccc(N)cc1OC
Reactant: COc1cc2sc(-c3cnc4ccc(Cl)nn34)cc2c(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3ncc(-c4cc5c(OC)c(OC)c(OC)cc5s4)n3n2)cc1OC
Temperature: 110 °C

Procedure:
To a solution of 6-chloro-3-(4,5,6-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.133 mmol, 1.0 equiv), xantphos (15 mg, 0.0266 mmol, 0.2 equiv), palladium acetate (2 mg, 0.0133 mmol, 0.1 equiv), and potassium carbonate (367 mg, 2.66 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (20 mg, 0.133 mmol, 1.0 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave the product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:26]([C:23]3([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)=[O:27])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C1(c2ccccc2)CC1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 1-phenylcyclopropanecarboxylic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.46-7.37 (m, 4H), 7.33 (dt, J=7.5, 11.5, 4H), 7.28-7.22 (m, 2H), 6.22 (d, J=7.3, 1H), 4.31 (dd, J=6.7, 12.7, 1H), 3.56 (d, J=13.2, 1H), 3.40 (d, J=13.2, 1H), 2.81 (dd, J=2.1, 8.9, 1H), 2.39-2.18 (m, J=7.3, 12.5, 18.1, 4H), 2.13 (dd, J=7.3, 8.9, 1H), 1.99 (dt, J=5.6, 11.0, 1H), 1.75 (q, J=3.6, 2H), 1.67-1.58 (m, J=8.3, 16.6, 1H), 1.38-1.22 (m, 2H), 1.01 (q, J=3.6, 2H); MS (ESI+) m/z 361 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH3:30]>C(#N)C>[CH2:29]([O:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21])[CH3:30]
Reactant: CCBr
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of methyl 2-hydroxy-2′-(trifluoromethyl)biphenyl-4-carboxylate (5.03 g), anhydrous potassium carbonate (7.05 g, 51 mmol) and bromoethane (6.35 mL, 85 mmol) was prepared in anhydrous ACN (75 mL) and heated at 50° C. for 15 hours. The reaction mixture was cooled at RT, filtered and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc/heptane), the title was obtained as a colorless oil (4.45 g, 79% over 2 steps). HPLC (Method A), Rt 5.3 min (purity: 99.0%). LC/MS (Method B): 325.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[C:27]([CH3:29])[C:7]([O:8][C:9]2[C:10]3[NH:26][CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:14]=2)=[C:6]([CH3:30])[CH:5]=1)(=[O:3])[CH3:2].C1C(=O)N([Cl:38])C(=O)C1>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH3:30])[C:7]([O:8][C:9]2[C:10]3[NH:26][CH:25]=[C:24]([Cl:38])[C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)[N:14]=2)=[C:27]([CH3:29])[CH:28]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3c(Cl)c[nH]c23)c(C)c1
Yield: 32.4 %

Procedure:
To a solution of 4-(4-(4-acetyl-2,6-dimethylphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (13 mg, 0.03 mmol) in CH2Cl2 (1 mL) was added NCS (4.4 mg, 0.03 mmol) and the mixture refluxed for 16 h. After the completion of the reaction, the solvent was concentrated and purified by preparative TLC eluting with hexanes:ethyl acetate (2:1) to give the product (4.2 mg, 30%).
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][CH2:18][CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:11][C:10]=1[O:27][CH3:28])C1C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[OH:8][C:9]1[C:10]([O:27][CH3:28])=[CH:11][C:12]([CH2:17][CH2:18][CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1cc(CCCC2SC(=O)NC2=O)cc(OC)c1OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cc(CCCC2SC(=O)NC2=O)cc(OC)c1O
Yield: 82 %

Procedure:
According to the same manner as that described in Reference Example 37, 5-[3-(4-benzyloxy-3,5-dimethoxyphenyl)-propyl]-2,4-thiazolidinedione was treated with titanium tetrachloride to give 5-[3-(4-hydroxy-3,5-dimethoxyphenyl)-propyl]-2,4-thiazolidinedione as an oil (yield: 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7]1.[NH3:16].CO>[Ni]>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:16])=[CH:7]1
Reactant: O=Cc1ccn(Cc2cccc(F)c2)c1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1ccn(Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
7N Ammonia/methanol (40 mL) and Raney nickel (2 g) were added to 1-(3-fluoro-benzyl)-1H-pyrrole-3-carbaldehyde described in Preparation Example 58 (1.0 g, 4.9 mmol), and the solution was stirred for 18 hours under hydrogen atmosphere at room temperature. The catalyst was removed by filtering through Celite pad, then, NH silica gel was added to the filtrate, the solvent was evaporated in vacuo for adsorption, purification by NH silica gel column chromatography (hexane:ethyl acetate=2:1, then 1:1, then ethyl acetate) was carried out, and the title compound (530 mg, 2.5 mmol, 53.0%) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:23].Cl>O1CCOCC1>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:31])=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(Cl)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: CCCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCOC(=O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reaction time: 5 h
Yield: 80.5 %

Procedure:
On the other hand, 0.8 g of n-butanol and 2.0 g of triethylamine were dissolved in 20 ml of dioxane. To this solution, a solution prepared by dissolving above 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetyl chloride in 5 ml of dioxane, was dropwise added over a period of 5 minutes at room temperature under stirring. After completion of the dropwise addition, the stirring was continued at room temperature for further 5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of a 2% hydrochloric acid aqueous solution. The precipitates were collected by filtration, washed with a dilute alkaline aqueous solution and water, and dried. Then, the precipitates were recrystallized from toluene to obtain 3.3 g of n-butyl 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetate. Yield: 80.5% as calculated on the basis of 4-(2,3-dichlorophenyl)carbamoylacetic acid) Melting point: 132°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)/C=C/c1cnc2ccccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cnc2ccccc2c1
Yield: 76.3 %

Procedure:
A mixture of (E)-3-(3-quinolinyl)-2-propenoic acid methyl ester (3.6 g, 16.9 mmol) and 5% Pd/C (0.4 g) in EtOAc (300 mL) was hydrogenated at atmospheric pressure. Upon sessation of hydrogen uptake, the catalyst was separated by filtration through a pad of Celite and the filtrate was evacuated to dryness to give the crude product (3.48 g) which was purified via flash chromatography eluting with a mixture of CH2Cl2 and ether (1:1) to give 3-quinolinepropanoic acid methyl ester (2.77 g, 12.9 mmol) in 76% yield as a glass.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[C:15]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:27][C:28]1[C:33]([N:34]=[C:35]=[O:36])=[C:32]([Cl:37])[C:31]([O:38][CH3:39])=[CH:30][C:29]=1[O:40][CH3:41].O>C1COCC1>[Cl:27][C:28]1[C:29]([O:40][CH3:41])=[CH:30][C:31]([O:38][CH3:39])=[C:32]([Cl:37])[C:33]=1[NH:34][C:35](=[O:36])[N:17]([C:15]1[CH:16]=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:12]=[CH:13][N:14]=1)[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Reactant: O=[N+]([O-])c1ccccc1Nc1cc(NCc2cccnc2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c(Cl)c(NC(=O)N(Cc2cccnc2)c2cc(Nc3ccccc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of N-(2-nitro-phenyl)-N′-pyridin-3-ylmethyl-pyrimidine-4,6-diamine (150 g, 0.467 mmol) in THF (15 mL) was added NaH (60%, 48 g, 1.2 mmol) at 0° C., and the mixture was stirred for 30 minutes at room temperature. A solution of 2,4-dichloro-3-isocyanato-1,5-dimethoxy-benzene (procedure 2A, steps a-d; 180 g, 0.73 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 2 hours. Water (2 mL) was added to quench the reaction. The mixture was concentrated, and the residue was purified by flash chromatography on silica to obtain the title compound (85 mg, yield: 32%). MS (ESI): 570 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C1C[O:16][CH2:15]C1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH:15]=[O:16])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
2-tert-Butyl-4-methylphenol 9.68 g (58.93 mmol) and THF 100 ml were charged in a sufficiently dried 1 liter reactor purged with nitrogen, ethylmagnesium bromide 23.00 ml (an ether solution, 3.0N, 69.00 mmol) was added dropwise to the reactor at 0° C. in 30 minutes and after that, the resultant mixture was gradually heated to a room temperature and stirred for 1 hour at a room temperature. Toluene 100 ml was added, the resultant mixture was heated to 95° C., and the mixed solvents of the ether/THF were evaporated off to obtain a slightly opaque slurry. After the slurry was cooled to a room temperature, toluene 100 ml, p-formaldehyde 4.50 g (149.90 mmol) and triethylamine 12.50 ml (89.93 mmol) were added and the resultant mixture was stirred at 95° C. for 2 hour. After being cooled to a room temperature, the mixture was quenched with 300 ml of 1N hydrochloric acid and an organic layer was concentrated and purified by a silica gel column to obtain 3-tert-butyl-5-methylsalicylaldehyde 7.36 g (yield 65%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:11]#[N:12].C(N(CC)CC)C.[SH2:30].C(OCC)(=O)C>N1C=CC=CC=1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:11]([NH2:12])=[S:30]
Reactant: S
Reactant: COCCOCOc1ccc(C#N)cc1OCOCCOC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOCOc1ccc(C(N)=S)cc1OCOCCOC
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
15.0 g (50.7 mmol) of 3,4-di(2-methoxyethoxymethoxy)benzonitrile was dissolved in 15.0 ml of pyridine, and 7.5 ml (50 mmol) of triethylamine was added thereto. To this solution, hydrogen sulfide gas was introduced and stirred at room temperature for 6 hours. To the reaction solution, ethyl acetate and water were added. The organic layer was separated and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 18.8 g (yield: 100%) of crude 3,4-di(2-methoxyethoxymethoxy)thiobenzamide. The product was used for the subsequent reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([OH:14])=[O:13]>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:11]([C:10]([OH:16])=[O:15])[C:12]([OH:14])=[O:13]
Reactant: Cc1ccccc1C=O
Reactant: O=C(O)CC(=O)O
Product: Cc1ccccc1C=C(C(=O)O)C(=O)O
Temperature: 90 °C

Procedure:
Combine 2-methylbenzaldehyde (39.6 g, 0.33 mol) and malonic acid (34.3 g, 0.33 mol). Heat at 90° C. for one hour, add 3.9 g of the aldehyde, and heat 6 hr. at 90°. Allow to cool, partition between diethyl ether and 1N NaOH, acidify the aqueous layer, filter off the solid, wash and dry to give the title compound as a beige solid, m.p. 197°-200°.
Reaction SMILES: FC(F)(F)C(NCC1C=CC=CC=1C(O)=O)=[O:4].[CH:18]1([N:24]=[C:25]=[N:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[C:25]([NH:24][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccccc1CNC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Weighed into a 10 ml round-bottomed flask were 593 mg (2.4 mmol) of trifluoroacetamidomethyl benzoic acid. This acid was dissolved in 4 ml of anhydrous tetrahydrofuran and 324.4 mg (1.2 mmol) of 1,3-dicyclohexylcarbodiimide were added. It was left stirring, at ambient temperature, for 2 hours. The white precipitate of dicyclohexylurea obtained was filtered over a frit.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH2:23][CH3:24])[CH2:20][O:19]1>>[CH2:23]([CH:21]1[CH2:20][O:19][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:22]1)[CH3:24]
Reactant: COc1ccccc1N
Reactant: CCC1COC(CBr)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1COC(CNc2ccccc2OC)O1

Procedure:
2-Methoxyaniline (0.5 mole) and sodium carbonate (30 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4-ethyl-1,3-dioxolane (0.55 mole) is slowly added and the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and additional sodium carbonate (5 grams) is added to the filtrate. The mixture is then distilled under reduced pressure to yield the desired product N-(4-ethyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:10]1([CH3:22])[CH:15]=[CH:14][C:13]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]([C:20](=[O:21])[NH:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:22])=[CH:11][CH:12]=2)(=[O:17])=[O:18])[C:4](=[O:9])[CH2:3]1
Reactant: CC1CC(=O)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC(C)CC2=O)cc1

Procedure:
Reaction of equimolar amounts of 5-methyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-METHYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 121.5°-122.5° C. (corr.).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](N(OC)C)=[O:14])=[CH:8][CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:14])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CON(C)C(=O)Cc1ccc(Br)cc1
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a round bottom flask contained EtMgCl (10 mL, 2M in THF, 20 mmol) at 0° C., was added a solution of 70A (516 mg, 2 mmol) in 10 mL THF. The solution was stirred at rt for 30 min, then was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-30% EtOAc/hexanes) afforded 70B (288 mg, 65%). MS (ESI) m/z 227.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[O:25][CH2:24]3)=[CH:17][CH:16]=2)[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[S:4]1)#[N:2].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>C(O)C>[C:26]([NH:30][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:3]2([C:1]#[N:2])[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[S:4]2)=[CH:20][CH:19]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: CN1C(=O)C(C#N)(c2ccc(OCC3CO3)cc2)Sc2ccccc21
Solvent: CCO
Product: CN1C(=O)C(C#N)(c2ccc(OCC(O)CNC(C)(C)C)cc2)Sc2ccccc21
Yield: 74.8 %

Procedure:
To a stirred suspension of 2-cyano-3,4-dihydro-2-[4-(2,3-epoxypropoxy)phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine (1.2 g, compound No. 23) in ethanol (15 ml), tert-butylamine (3.6 ml) is added. The mixture is refluxed for 1.5 hours, and concentrated in vacuo to give 1.3 g (74.8%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].Cl[C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.C(OCC)(=O)C>CN(C)C=O>[N:17]1[C:18]2[NH:1][C:2]3[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][C:3]=3[S:12][C:19]=2[N:20]=[CH:21][CH:16]=1
Reactant: COC(=O)c1cnc(S)c(N)c1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(c1)Nc1nccnc1S2
Yield: 30.4 %

Procedure:
To a solution of 1.0 g of methyl 5-amino-6-mercaptonicotinate in N,N-dimethylformamide (30 ml) were added 0.52 g of sodium hydride (oily: 60% or more) and 0.97 g of 2,3-dichloropyrazine and the resulting mixture was reacted at 100° C. for 2 hours. Then ethyl acetate was added to the reaction mixture, which was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, diethyl ether was added to the residue and the crystals thus precipitated were taken up by filtration to thereby give 0.43 g of crude methyl 10H-pyrazino[2,3-b]pyrido[3,2-e][1,4]thiazin-8-carboxylate as a brown solid. To a solution of 1.43 g of these crude crystals in N,N-dimethylformamide (50 ml) were added 0.26 g of sodium hydride (60% oily) and 0.5 g of chloromethyl methyl ether and the resulting mixture was reacted under ice-cooling for 1 hour. After adding ethyl acetate, the mixture was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, diethyl ether was added to the residue and the crystals thus precipitated were taken up by filtration to thereby give 1.5 g of the title compound as red crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)=[O:13])[NH:11][C:6]2=[CH:5][CH:4]=1.[C:25](=[O:37])([O:34][CH2:35][CH3:36])[O:26][CH2:27][CH2:28][N:29]([C:31](Cl)=[O:32])[CH3:30].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:25](=[O:37])([O:26][CH2:27][CH2:28][N:29]([C:31]([N:9]1[C:7]2=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[N:11]=[C:10]1[S:12]([CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=1)=[O:13])=[O:32])[CH3:30])[O:34][CH2:35][CH3:36]
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2n1
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine synthesized according to the method described in JP-A-63-146882 was subjected to preparative HPLC for optical resolution to give a (−) enantiomeric form (0.10 g) thereof. To a solution (5 mL) of this form in tetrahydrofuran were added 2-[(chlorocarbonyl) (methyl)amino]ethyl ethyl carbonate (0.081 g) obtained in Reference Example 34, triethylamine (0.080 mL) and 4-dimethylaminopyridine (0.007 g) and the mixture was stirred at 50° C. for 18 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=2:1) to give the title compound (0.053 g) as a colorless oil.
Reaction SMILES: O=C(C1(C(F)(F)F)CC1)CC#[N:5].[C:13](=[N:26][NH:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)([C:20]1[CH:25]=CC=[CH:22][CH:21]=1)[C:14]1[CH:19]=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:25][C:20]1([C:13]2[CH:14]=[C:19]([NH2:5])[N:27]([C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[N:26]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cn1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2N)cn1
Yield: 66.9 %

Procedure:
Heat a mixture of 3-Oxo-3-(1-trifluoromethyl-cyclopropyl)-propionitrile (2.66 g, 15.0 mmol), N-benzhydrylidene-N′-(6-methyl-pyridin-3-yl)-hydrazine (TL, 2002, 43, 2171-2173) (4.31 g, 15.0 mmol), and p-tolylsulfonic acid (14.29 g, 75.0 mmol) in ethanol (85 mL) at 90° C. in a sealed tube for 18 hours. After removal of the solvent, subject residue to silica gel chromatography eluting with 0-5% methanol in dichloromethane to give a brown solid (2.29 g, 54% yield). MS(ES+): m/z=283.2 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])[CH:5]=[C:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:7]=1F.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([S:27]([NH:30][CH3:31])(=[O:28])=[O:29])[CH:5]=[C:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[C:7]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CNS(=O)(=O)c1cc(F)c(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: C1COCCN1
Product: CNS(=O)(=O)c1cc(F)c(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example 202 from 3,4-Difluoro-N-methyl-5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide (example CC) and morpholine to yield the title compound as a colourless foam, MS (m/e): 531.1 (M+H, 100%).