Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:18]([S:21][CH2:22][CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](Cl)=[O:25])(=[O:20])[CH3:19].Cl>C(Cl)(Cl)Cl.O>[C:18]([S:21][CH2:22][CH:23]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:25])(=[O:20])[CH3:19]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 41.3 %

Procedure:
3-Aminobenzoic acid (1.4 g) is suspended in chloroform (50 ml), and thereto is added triethylamine (2.06 g), and to the mixture is added 2-acetylthiomethyl-3-phenylpropionyl chloride (2.61 g) with stirring under ice cooling, and the mixture is stirred for 30 minutes and further at room temperature three nights. To the reaction mixture is added water, and the mixture is acidified with hydrochloric acid and extracted with chloroform. The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure. The precipitates are separated by filtration and recrystallized from 50% aqueous ethanol to give the title compound (1.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[CH3:26])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[CH:23]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc2c(c1)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.CO[C:12]([C:14]1[CH:19]=[C:18]([NH2:20])[N:17]2[N:21]=[C:22]([C:24]3[O:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[N:23]=[C:16]2[CH:15]=1)=[O:13].Cl>O1CCOCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12]([C:14]1[CH:19]=[C:18]([NH2:20])[N:17]2[N:21]=[C:22]([C:24]3[O:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[N:23]=[C:16]2[CH:15]=1)=[O:13])[CH3:2]
Reactant: CCNCC
Reactant: COC(=O)c1cc(N)n2nc(-c3ccc(C)o3)nc2c1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1cc(N)n2nc(-c3ccc(C)o3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 35 mg (0.44 mmol) diethylamine in 0.5 ml dioxane was added 0.5 ml methylaluminoxane (10% in toluene) (in a variant trimethylaluminium was used instead of methylaluminoxane which proofed to give comparable results) and stirred for 1 h at room temperature. 31 mg (0.11 mmol) 5-Amino-2-(5-methyl-furan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid methyl ester in 1 ml dioxane was added and the mixture was heated to 80° C. for 72 h. After addition of 0.4 ml 1N HCl the mixture was evaporated to dryness and the residue was taken up in 1.5 ml DMSO, filtered, and the title compound was isolated by reversed phase HPLC eluting with a water/acetonitrile gradient to yield 8.6 mg (25%).
Reaction SMILES: C=O.C(O[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][C:19]=2[O:29][CH3:30])[CH2:12][CH2:11]1)=O)(C)(C)C.Cl.CCOCC>C(O)=O>[CH3:30][O:29][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:18]=1[O:17][CH2:16][CH:13]1[CH2:12][CH2:11][N:10]([CH3:8])[CH2:15][CH2:14]1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Agent: C=O
Agent: Cl
Solvent: CCOCC
Solvent: O=CO
Product: CCOC(=O)c1ccc(OCC2CCN(C)CC2)c(OC)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 111.9 %

Procedure:
Formaldehyde (12M, 37% in water, 35 ml, 420 mmol) was added to a solution of ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-3-methoxybenzoate (35 g, 89 mmol) in formic acid (35 ml). After stirring at 95° C. for 3 hours, the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and 3M hydrogen chloride in ether (40 ml, 120 mmol) was added. After dilution with ether, the mixture was triturated until a solid was formed. The solid was collected by filtration, washed with ether and dried under vacuum overnight at 50° C. to give ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, quant.).
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH3:24]>O1CCCC1.CN(C)C=O>[F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:24])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a suspension of 5.70 g (20.8 mmol) 3-(4-pentafluorosulfanyl-phenyl)-acrylic acid in 30 ml tetrahydrofuran and 0.21 ml N,N-dimethyl formamide a solution of 3.47 ml (27.4 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to mixture of 300 ml ice and 120 ml of a 25% aqueous ammonia solution. The precipitated amide was collected, washed with water and n-heptane and dried at 40° C. in vacuo. Yield 5.17 g (91%) 3-(4-pentafluorosulfanyl-phenyl)-acrylamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]#N)=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+].C[OH:28]>>[CH2:1]([O:8][C:9]1[C:10]([C:23]([OH:28])=[O:25])=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ncc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CO
Agent: [Na+]
Product: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carbonitrile, 1, (26.0 g, 82.3 mmol) in MeOH (217 mL) is added 30% w/v sodium hydroxide (320 mL) and the reaction mixture is refluxed for 16 hours. The solvent is removed under reduced pressure and the resulting suspension is acidified with conc. HCl until the pH is between 1 and 2. The precipitate that results is collected by filtration, washed with H2O (10 mL) and dried overnight in a vacuum oven to afford 30 g (quantitative) of the desired product as the hydrochloride salt. 1H NMR (250 MHz, DMSO-d6) δ ppm 8.02 (1H, d, J=2.4 Hz), 7.29-7.53 (11H, m), 5.96 (1H, br s), 5.28 (4H, s). HPLC-MS: m/z 336 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:7]=1.[B:14]1(B2OCC(C)(C)CO2)[O:19]CC(C)(C)C[O:15]1>>[F:13][C:5]1[CH:4]=[CH:3][C:2]([B:14]([OH:19])[OH:15])=[CH:7][C:6]=1[N:8]1[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(Br)cc1-n1cncn1
Product: OB(O)c1ccc(F)c(-n2cncn2)c1

Procedure:
1-(5-Bromo-2-fluorophenyl)-1H-[1,2,4]triazole (1.1 g, 4.5 mmol) was reacted with bis(neopentyl glycolato)diboron (1.13 g, 5.0 mmol) using the method in Example 49 to give 4-fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid as a white solid: MS (ES+) m/z 208 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:32][C:33]([F:56])([F:55])[CH2:34][CH2:35][C@@H:36](OS(C(F)(F)F)(=O)=O)[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C1COCC1>[C:1]1([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:36]([CH2:35][CH2:34][C:33]([F:32])([F:55])[F:56])[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Cc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](c1ccccc1)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
A solution of tert-butyl 2-phenylacetate (8.5 g, 44.2 mmol) in THF (400 mL) in a 1 L round-bottomed flask was cooled in −78° C. bath and treated with a solution of KHMDS, 0.5M in toluene (97 mL, 48.6 mmol) via cannula over 10 minutes. After 10 minutes the mixture was removed from the bath and placed in a room temperature water bath and stirred for 15 minutes and then again cooled in −78° C. bath. After 15 minutes a solution of Preparation 4D (R)-benzyl 5,5,5-trifluoro-2-(((trifluoromethyl)sulfonyl)oxy)pentanoate (19.18 g, 48.6 mmol) in THF (50 mL) in a 100 ml, round bottom flask was added over 10 min via cannula with a 20 mL THF rinse. The reaction mixture turned cloudy. The reaction mixture was stirred at −78° C. for 1 hour and then quenched with saturated aqueous NH4Cl. The mixture was removed from −78° C. bath, diluted with 10% LiCl aq and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated. The resulting light brown residue was dissolved in 100 mL CH2Cl2 and treated with charcoal and MgSO4. The mixture was filtered to give an almost colorless solution. The CH2Cl2 solution was concentrated and diluted with hexane and cooled in −20° C. freezer. The resulting solids were filtered and rinsed with cold hexane (containing 5% MTBE) and dried on a fitted filter funnel under a stream of nitrogen to give 8.16 g. The solid was triturated with 40 mL hexane and 4 mL MTBE stirring the white suspension at room temperature for 1 hour and then cooling at −20° C. for 3 hours before filtering the white solid and washing with cold solvent (10:1 hexane:MTBE) to give (2R,3R)-1-benzyl 4-tert-butyl 3-phenyl-2-(3,3,3-trifluoropropyl)succinate (7.16 g, 37% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.32-7.23 (m, 8H), 7.05-6.97 (m, 2H), 4.89-4.76 (m, 2H), 3.69 (d, J=11.4 Hz, 1H), 3.23 (ddd, J=11.2, 9.9, 3.9 Hz, 1H), 2.19-2.04 (m, 2H), 2.03-1.88 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[H-].[Na+].[CH3:39]I.Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][N:26]([CH3:39])[S:27]([CH3:30])(=[O:29])=[O:28])[C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C(O)c2ccccc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1csc2c1S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)(C)C)C1=O)N2)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of Example 187 (124 mg, 0.22 mmol) in 2 mL of N,N-dimethyl formamide was cooled to 0° C., treated with sodium hydride (24 mg, 60% in oil, 0.5 mmol), stirred at 0° C. for 1 h, stirred at room temp for 30 min, treated with methyl iodide (9 μL, 0.14 mmol), stirred for 2 h, treated with methyl iodide (7 μL, 0.11 mmol), and stirred at room temp over night. The mixture was diluted with water and ethyl acetate, treated with 1N HCl, and extracted with ethyl acetate. The organic phase was washed with 2×10 mL of H2O and concentrated in vacuo. The crude material was chromatographed on silica gel with a gradient of methanol in dichloromethane (0-5%) to afford the title compound (48 mg, 39% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.40 (td, J=12.8, 3.7 Hz, 1 H), 0.72 (s, 9 H), 0.81 (td, J=12.9, 4.4 Hz, 1 H), 1.56 (s, 3 H), 2.01 (m, 1 H), 2.21 (td, J=12.8, 4.6 Hz, 1 H), 2.85 (s, 3 H), 3.02 (s, 3 H), 4.39 (s, 2 H), 7.32 (s, 1 H), 7.50 (m, 1 H), 7.71 (m, 2 H), 8.12 (d, J=7.8 Hz, 1 H), 14.21 (s, 1 H); MS (APCI−) m/z 564 (M−H)−.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC)CC)C.O>CN(C=O)C>[C:1]([O:11][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@H](O)c1ccccc1
Yield: 68.2 %

Procedure:
A solution of 15.2 g (100 mmol) of D-mandelic acid, 21.6 g (100 mmol) of 4-nitrobenzyl bromide, and 14.0 ml (100 mmol) of triethylamine in 300 ml of DMF was stirred for 8 hours at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid and water and recrystallized from ether-petroleum ether to give 19.6 g of the aimed product D-4 in 68% yield.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34].O>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:33]([O:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:34])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (250.2 mg) and triethylamine (186 μL) in THF (5 mL) was added 4-nitrophenyl chloroformate (161 mg) at 0° C., and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (295 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:10](=[O:20])[CH2:9][CH2:8]2.CN(C=O)C.[CH3:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=O.C(N(C(C)C)CC)(C)C>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:34][C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[CH3:37])[CH2:18][CH2:19]1)[C:10](=[O:20])[CH2:9][CH2:8]2
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC1CCNCC1)C(=O)CC2
Reactant: Cc1ccccc1C=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC1CCN(Cc3ccccc3C)CC1)C(=O)CC2
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To 5-(8-methoxy-1-piperidin-4-ylmethyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione (20 μmol, 1.0 eq.) was added a DMF (200 μl) solution of 2-methylbenzaldehyde (24 μmol, 1.2 eq) and acetic acid (10 μl). Si-sodium cyanoborohydride was added further thereto. The solution was shaken for several minutes, diisopropylethylamine (30 μl) was added, and a reaction was carried out at room temperature overnight. The resin was removed by filtration and washed with dichloromethane. The solvent was distilled off from the filtrate in a nitrogen gas stream, and the residue was purified by HPLC (UV-trigger, column: CAPCELL PAK C18, UG 120 S-5, 20 mm×50 mm, 0.05% trifluoroacetic acid-H2O, 0.05% trifluoroacetic acid-CH3CN). The structure was confirmed by LC-MS, and freeze-drying was conducted, giving 5-{8-methoxy-1-[1-(2-methylbenzyl)piperidin-4-yl]methyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione in 50.5% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)=[O:22]>C(O)C.O.O>[C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
3-(4-formyl-phenyl)-acrylic acid tert-butyl ester (150 mg, 0.64 mmol) and KOH (72 mg, 1.28 mmol)) were dissolved in ethanol/water (1:1, 5 ml) and 3,4-difluoroacetophenone (83.2 μl, 0.64 mmol) was added to the resulting solution. The resulting mixture was stirred at room temperature overnight and then diluted with H2O. The precipitate was filtered and dried under vacuo to give 210 mg of 3-{4-[3-(3,4-difluoro-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid tert-butyl ester.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(C)C2=O)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), methyl iodide and sodium hydride, to give the desired product as a light yellow oil (19%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([N:11]([C:13](=[O:18])C(C)(C)C)[NH2:12])=[C:9]([F:19])[CH:8]=[C:7]([Cl:20])[C:5]=2[N:6]=1.[C:21](Cl)(Cl)=[O:22].[C:25]1([CH3:31])[CH:30]=CC=C[CH:26]=1>>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[N:12]=[C:21]([C:25]([CH3:31])([CH3:30])[CH3:26])[O:22][C:13]3=[O:18])=[C:9]([F:19])[CH:8]=[C:7]([Cl:20])[C:5]=2[N:6]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)C(=O)N(N)c1c(F)cc(Cl)c2nc(Cl)sc12
Reactant: O=C(Cl)Cl
Product: CC(C)(C)c1nn(-c2c(F)cc(Cl)c3nc(Cl)sc23)c(=O)o1

Procedure:
A solution of 1,4 g 2,4-dichloro-6-fluoro-7-[N-(2,2-dimethylpropanoyl)hydrazino]benzothiazole in 8 ml of a 20% solution of phosgene in toluene was heated for 8 hours at 100° C. After cooling, the toluene was removed in vacuo and the residue taken up in dichloromethane. The extract was shaken with aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate and concentrated. The residue was recrystallised from isopropanol/diisopropyl ether. Yield: 0.5 g=40% of theory. m.p.: 157°-158° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19]>[Pt](=O)=O.FC(F)(F)C(O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Yield: 57.6 %

Procedure:
A mixture of 1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (3 g, prepared as described in Example 19), platinum (IV) oxide (3 g), and trifluoroacetic acid (50 mL) was placed under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr shaker for 2 days. The reaction mixture was filtered through a layer of CELITE filter agent and the filter cake was rinsed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was made basic (p H 14) by the addition of 50% sodium hydroxide and then extracted with chloroform. The extract was dried over sodium sulfate and then purified by chromatography on a HORIZON HPFC system (eluting with chloroform/CMA in a gradient from 100:0 to 70:30) to provide 1.75 g of 1-(4-chlorobutyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as a light yellow solid.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1>>[OH:30][CH:27]1[CH2:28][CH2:29][N:25]([C:3]([C:4]2[CH:5]=[N:6][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])=[CH:8][CH:9]=2)=[O:24])[CH2:26]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reactant: OC1CCNC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(O)C2)cn1
Yield: 87 %

Procedure:
As described for example 220, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using 3-pyrrolidinol instead of 3-amino-1-propanol, to the title compound (122 mg, 87%) which was obtained as a colourless oil. MS: m/e=380.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[S:15]([C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)(=[O:16])=[O:17])[CH3:2]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 91.2 %

Procedure:
Diethylamine (0.815 mL, 576 mg, 7.86 mmol) was added in one portion to a solution of 4-nitrobenzenesulfonyl chloride (582 mg, 2.62 mmol) in dichloromethane (10 mL). The resultant solution was stirred at 23° C. for 14 hours and then washed twice with 1N HCl (15 mL). The organics were dried over magnesium sulfate and concentrated to provide N,N-Diethyl-4-nitro-benzenesulfonamide as an off-white solid (617 mg).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)=[S:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH:8]([Cl:1])[CH2:7][N:6]1[C:25]([C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)=[S:26]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: S=C(Cl)c1ccc(Cl)cc1
Reactant: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CC(Cl)CN1C(=S)c1ccccc1
Reaction time: 3 h
Yield: 126.9 %

Procedure:
In this example, L-proline methyl ester hydrochloride (16.6 g; 0.1 mole) is dissolved in 100 ml chloroform, and the resulting solution is admixed with triethylamine (13.9 ml; 0.1 mole) under ice cooling (5°-10° C.) for 5 minutes. Then, 4-chlorophenylthiocarbonyl chloride (10.4 g; 0.05 moles) is added in drops at 2°-5° C. for 30 minutes. After stirring for three hours, the reaction solution is washed respectively with about 100 ml water, about 100 ml 2N hydrochloric acid and about 100 ml water, and then dried over anhydrous sodium sulfate (30 g). The solvent is distilled off under reduced pressure, and the resulting crystals are recrystallized from ethyl acetate (about 50 ml) and n-hexane (150 ml), whereby 4-chlorophenylthiocarbonyl-L-proline methyl ester (compound number 22; 18.0 g; m.p.: 90°-91° C.) is obtained. Yield: 60%.