Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[N:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[C:9]([CH3:17])[C:8]([F:18])=[C:7](F)[C:6]=2[F:20])C.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[F:18][C:8]1[C:9]([CH3:17])=[C:10]2[C:5](=[C:6]([F:20])[C:7]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[N:4]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[CH:3]=[C:12]([C:13]([OH:15])=[O:14])[C:11]2=[O:16]
Reactant: CCc1c(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c2n1-c1ccc(F)cc1F
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of 0.43 g (1.08 mmol) of ethyl 6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.37 g (4.30 mmol) of anhydrous piperazine, and 20 ml of acetonitrile was refluxed overnight, cooled to room temperature, and concentrated. The residue was taken up in 10 ml of 6N hydrochloric acid and refluxed for two hours. The mixture was cooled and the solids were filtered. The crude product was suspended in water which was made basic (pH 12), filtered through a fiberglass pad, and neutralized (pH 6.5). The solids were filtered and washed with water and ether to give 0.37 g of the title compound, mp 283°-284° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)(=O)=O)N=2)CC1.[NH:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]([OH:61])=[O:60])=[CH:58][C:53]=2[N:52]=[CH:51]1>C(O)(C)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4\[NH:19][C:18](=[O:20])[NH:17][C:16]\4=[O:21])=[C:9]3[N:8]=[C:7]([N:50]3[C:54]4[CH:55]=[CH:56][C:57]([C:59]([OH:61])=[O:60])=[CH:58][C:53]=4[N:52]=[CH:51]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CC(C)O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(-n4cnc5cc(C(=O)O)ccc54)nc23)N1
Temperature: 150 °C

Procedure:
A mixture of (Z)-5((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (10 mg, 0.028 mmol) was mixed with 1H-benzo[d]imidazole-5-carboxylic acid (20 mg, 0.140 mmol) in isopropanol (1 mL). The mixture was stirred under microwave heating at 150° C. for 20 minutes. The solvent was removed to provide (Z)-1-(4-(cyclopropylamino)-8-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a][1,3,5]triazin-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid as a crude mixture which was taken on to the next step without further purification. LCMS (ES):>95% pure, m/z 446 [M+H]+
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 6 %

Procedure:
Using cyclohexyl{3-ethyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanol (0.90 g) synthesized in Example 39(4) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.75 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (85 mg, 6%) was obtained as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13]C(C)(C)C(C)(C)[O:10]2)=[CH:5][C:4]=1[O:18][CH:19]([F:21])[F:20].O.C(OCC)(=O)C>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:13])[OH:10])=[CH:5][C:4]=1[O:18][CH:19]([F:20])[F:21]
Reactant: CC1(C)OB(c2ccc(Cl)c(OC(F)F)c2)OC1(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OB(O)c1ccc(Cl)c(OC(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.2 %

Procedure:
2 M hydrochloric acid (10 mL) was added to the crude product of 2-(4-chloro-3-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.14 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for four hours. Water and ethyl acetate were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was extracted with a 2 M sodium hydroxide solution. The resulting solution was made acidic with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1→50:50) to give the title compound (93 mg).
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]([CH3:13])=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.C(O)(=O)C>O>[C:10]([O:9][CH2:8]/[CH:7]=[C:6](\[CH3:13])/[CH:5]=[O:4])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC=C(C)C(OC(C)=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC/C=C(\C)C=O
Yield: 81.6 %

Procedure:
48.8 parts of 1,1,4-triacetoxy-2-methyl-but-2-ene, consisting, according to NMR analysis, of 46.4% of (E)-isomer and 53.6% of (Z)-isomer, are boiled with 500 parts of glacial acetic acid and 18 parts of water for 2.5 hours. After stripping off the acid and water on a rotary evaporator at from 40° to 50° C. under a waterpump vacuum, fractional distillation of the residue gives 23.2 parts of 4-acetoxy-2-methylcrotonaldehyde (81.6% of theory) of boiling point 102°-103° C./23.9 mbar (nD20 =1.4641). According to NMR analysis (aldehyde protons), the aldehyde obtained consists of 98.0% (E)- and 2.0% (Z)-4-acetoxy-2-methylcrotonaldehyde.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH2:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N+]=[N-].[CH:27]([O-])=[O:28].[NH4+]>C(O)C>[CH:27]([NH:1][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH2:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:28]
Reactant: O=C[O-]
Reactant: [N-]=[N+]=NCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: [NH4+]
Solvent: CCO
Product: O=CNCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
Reduction of this azide to the corresponding amine was carried out according to a published procedure of Gartiser et al., Tetrahedron Lett., 1983, 24:1609. A suspension of 3-azidomethyl-9-(2,5-dichlorobenzyl)-9H-β-carboline (4.60 g, 12 mmol), ammonium formate (3.90 g, 61.7 mmol), and 10% Pd-on-carbon (2.0 g, 20mol %) in ethanol (200 mL) was stirred at room temperature under nitrogen for 15 hours. The reaction mixture was filtered to remove the solids, and the filtrate concentrated and diluted with CH2Cl2 (100 mL). The resulting solution was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was recrystallized from ethyl acetate, affording 3.0 grams (65%) of N-formyl-[9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methylamine as a pale-yellow solid. 1H NMR (CDCl3) 6 8.65 (s, 1H), 8.30 (s, 1H), 8.24 (d, 1H), 7.95 (s, 1H), 7.58 (t, 7.40 (m, 3H), 7.20 (dd, 1H), 6.51 (s, 1H), 5.60 (s, 2H), 4.78 (d, 1H); MS monoisotopic mass (calculated) 383.1, MH+ (observed) 384.9.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:46])[CH:22]=2)(OC(C)(C)C)=O.[CH3:47][O:48][CH2:49][CH2:50]O>>[Br:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:50][CH2:49][O:48][CH3:47])=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: c1ccc2[nH]ccc2c1
Product: COCCOc1c2[nH]c3ccc(Br)cc3c2cc2c1[nH]c1ccc(Br)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dibromo-6-hydroxyindolo[2,3-b]carbazole and the reagent is 2-methoxyethanol. 1H-NMR (400 MHz, CDCl3) δ ppm 8.75 (s, 1H), 8.21 (s, 2H), 7.45 (d, J=6.8 Hz, 2H), 7.32-7.24 (m, 2H), 4.43 (t, J=4.4 Hz, 2H), 3.85 (t, J=4.4 Hz, 2H), 3.65 (s, 3H); MS (ESI) m/z 487.0 (M−H)−
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1(=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:7]1([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=C1CCc2ccccc21
Reactant: C1CNCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: c1ccc2c(c1)CCC2N1CCNCC1
Yield: 37.1 %

Procedure:
Piperazine (17.2 g, 0.2 mol), indan-1-one (2.6 g, 20 mmol), titanium(IV) isopropoxide (13.3 ml, 40 mmol) and sodium borohydride (3.6 g, 95 mmol) were reacted by Method A to give the product (1.5 g, 37.1%). The crude product was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:19][C:5]1[C:6]([O:7][C:8]2[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:18][C:2]([NH:1][C:30](=[O:31])[CH2:29][Cl:28])=[C:3]([F:20])[CH:4]=1
Reactant: Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Temperature: 25 °C

Procedure:
A solution of 2-(5-amino-2-chloro-4-fluorophenoxy)-3-trifluoromethylpyridine (1.32 g) and triethylamine (0.8 ml) in toluene (20 ml) was stirred at 0° C. while a solution of chloroacetyl chloride (0.4 ml) in toluene (10 ml) was added. The mixture was stirred over night at room temperature and processed. Column chromatography on silica gel using methylene chloride as eluent gave a white solid (1.4 g), mp 146-9° C. 1H NMR (CDCl3, TMS): 4.20(2H, s), 7.12(1H, dd, J=5,8 Hz), 7.30(1H, d, J=9 Hz), 8.01(1H, m), 8.22(1H, m), 8.34(1H, d, J=7 Hz).
Reaction SMILES: [F:1][C:2]1([CH2:6][NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>CN(C)C=O>[F:1][C:2]1([CH2:6][NH:7][C:8]([C:10]2[N:11]([CH2:35][CH:32]3[CH2:34][CH2:33]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:3][O:4][CH2:5]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)NCC4(F)COC4)cc3c2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)NCC2(F)COC2)n3CC2CC2)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 51, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide, sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2.[OH-].[Na+:28]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:21])[F:22])[C:6]([C:24]([O-:26])=[O:25])=[CH:5]2.[Na+:28]
Reactant: CCc1ccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)O)=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)[O-])=C3)cc1

Procedure:
A solution of 6-chloro-8-(4-ethylphenyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid 51.9 mg (0.136 mmole) in 2.0 mL of ethanol was treated with 1.345 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 1.25 (t, 3H, J=7.6 Hz), 2.67 (q, 2H, J=7.6 Hz), 5.82 (q, 1H, J=7.2 Hz), 7.21-7.25 (m, 4H), 7.38-7.40 (m, 3H).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+:26]>O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[K+:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 85 °C

Procedure:
To a tank (34) containing 1000 ml of pure water kept at 30° C., the foregoing nucleus particles were continuously introduced. Into a tank (35) containing 218.7 g of behenic acid and 4155.3 g of pure water with stirring at 85° C., 387.3 ml of 1.5N aqueous KOH solution was added in 5 min. and reacted further for 60 min. to obtain a potassium behenate solution. Finally, water was added to make the total amount to 5250 ml. To a tank (36), 1050 ml of aqueous solution containing 98.7 g of silver nitrate was added and maintained at 10° C. Further, 525 ml of an aqueous solution containing 43 g of light-sensitive silver halide emulsion A was prepared in a tank (37) and maintained at 30° C. The foregoing potassium behenate solution, aqueous silver nitrate solution and silver halide solution were added by triple jet addition at flow rates of 150 ml/min. 30 ml/min and 15 ml/min, respectively to perform particle growth.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>ClCCCl.CC(O)=O.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: Clc1nccc(-c2ccc(CN3CCOCC3)cc2)n1
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To a solution of 42 (950 mg, 4.35 mmol) and morpholine (455 μL, 5.21 mmol) in dry 1,2-dichloroethane (10 mL) at room temperature was added AcOH (2 drops) followed by NaBH(OAc)3 (1.1 g, 5.21 mmol) and the mixture was stirred for 16 h. A solution of 10% K2CO3 was added to the reaction mixture followed by dichloromethane and the phases were separated. The aqueous phase was extracted with CH2Cl2 and organic layer was dried over anhydrous Na2SO4, filtered to form a residue which was purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 20/80) to afford the title compound 43 (460 mg, 1.59 mmol, 36% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)O.S(=O)(=O)(O)O.[OH-].[Na+]>ClCCl>[Br:15][C:11]1[CH:10]=[C:9]([CH:7]2[C:17]3[C:3](=[C:2]([Cl:1])[CH:20]=[C:19]([Cl:21])[CH:18]=3)[CH2:4][N:5]([CH3:16])[CH2:6]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(Br)c2)C1
Temperature: 2.5 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-bromophenyl)ethanol (25 g, 64.27 mmol, 1.00 equiv) in dichloromethane (100 mL). This was followed by the addition of sulfuric acid (100 mL) dropwise with stirring at 0-5° C. The resulting solution was stirred for 4 h at room temperature. The resulting solution was diluted with of ice water. The pH value of the solution was adjusted to 8 with sodium hydroxide. The resulting solution was extracted with 3×300 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from petroleum ether:ethyl acetate in the ratio of 8:1. This resulted in 15 g (63%) of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:9]([OH:24])[CH:8]=1)[CH3:2].[C:26]([O-])([O-])=O.[K+].[K+].CI.[F-].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[C:9]([O:24][CH3:26])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)c(OC)c1
Reaction time: 3 h

Procedure:
To a vigorously stirred solution of the compound of example 41e (4.5 g; 12.7 mmol) in dry DMF (20 ml) was added sequentially fused K2CO3 (3.5 g; 25.5 mmol), methyl iodide (0.96 ml; 15.3 mmol) and KF (0.45 g). The reaction mixture was stirred for 3 h, diluted with water (200 ml) and the oily residue was extracted with chloroform (3×30 ml). The organic layer was washed with brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform). Yield, 3.25 g (69.5%); mp, 75° C.; MS (ESI+): 390 (M++Na), 368 (M++1); analysis: C18H25NO7 requires C, 58.85; H, 6.85; N, 3.81; found: C, 58.79; H, 7.26; N, 3.81%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:40][CH2:39][CH2:38]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:37]5[CH2:40][CH2:39][CH2:38]5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:35][CH2:36]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(N4CCC4)CC3)cc1F)C2=O

Procedure:
The title compound was synthesized in the same manner as Example 13 by condensing 2-[2-fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) with azetidine (67.8 mg, 1.19 mmol) to obtain 55 mg (85% yield) of the compound.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(#N)C>[CH2:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[CH2:4][C@@H:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Temperature: 60 °C

Procedure:
8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (Japanese Unexamined Patent Publication (Kokai) No. 2004-002470, Example 21f; 25.0 g) and (S)-(+)-camphorsulfonic acid (18.6 g) were dissolved in acetonitrile (100 mL) and concentrated under reduced pressure. To the residue, methyl-tert-butyl ether (250 mL) was added and recrystallization was carried out by being left to stand at room temperature, and the crystal (21.8 g) was filtered (the crystal is the crystal mentioned in Example 23). The resultant crystal was dissolved by heating at 60° C. in a mixed solution of methyl-tert-butyl ether (833 mL) and acetonitrile (167 mL). The solution was recrystallized by being left to stand at room temperature, and the crystal (7.39 g) was filtered. The resultant crystal was diluted with a mixed solution of an aqueous saturated sodium hydrogen carbonate solution and saturated brine, and then extracted five times with ethyl acetate. The organic layer was washed with a mixed solution of an aqueous saturated sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound having the following physical properties (4.11 g, 88% ee). Optical purity was confirmed using a high-performance liquid chromatography (HPLC).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH3:21])[CH:15]=[CH:14][C:13]([S:16]([NH:19][NH2:20])(=[O:18])=[O:17])=[CH:12][CH:11]=1>CO>[S:16]([NH:19][N:20]=[CH:5][C:4]1[CH:3]=[CH:2][CH:9]=[CH:8][C:6]=1[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)([C:13]1[CH:12]=[CH:11][C:10]([CH3:21])=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
4-Fluoro-benzaldehyde (26.6 ml, 31.25 g, 251 mmol) was added all at once to a stirred suspension of 4-tolylsulfonyl hydrazine (43.47 g, 287 mmol) in methanol (200 ml). Within 30 seconds everything dissolved and there was a small exotherm to 32° C., before the temperature dropped. After 30 minutes some of the solvent was evaporated. Crystallisation started after scratching and the solution was left for two hours at room temperature and overnight at ca 5° C. to crystallize. The crystals were filtered off, washed with methanol (2×ca 30 ml), then left in the air to dry, yielding 51.8 g (71%) m.p. 123-125° C.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=O)[CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[N:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=1>C(#N)C>[Cl:19][C:13]1[N:12]=[C:11]2[C:16]([CH:17]=[CH:18][C:9]([NH:8][C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:7])=[N:10]2)=[CH:15][CH:14]=1
Reactant: O=C(O)C1CCC1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1CCC1
Temperature: 20 °C
Yield: 61.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with cyclobutanecarboxylic acid (5 g), N,N'-carbonyldiimidazole (10.5 g) and 2-amino-7chloro-1,8-naphthyridine (7 g). The product produced by filtration (9 g; m.p. 192° C.) is dissolved in boiling acetonitrile (150 cc). After 3 hours' cooling at 20° C., the crystallised solid is separated by filtration, washed with ethyl ether (3×25 cc) and dried at 35° C. under reduced pressure (0.066 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)cyclobutanecarboxamide (6.3 g) is produced, m.p. 192°-194° C. EXAMPLE 6