Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[N+:30]([O-])=O)=[CH:9][CH:8]=1.[Cl-].[NH4+].O1CCCC1.O>C(O)C.[Fe]>[Cl:35][C:2]([Cl:1])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 95 %

Procedure:
A solution of the product of Example 60B (1.23 g, 2.0 mmol), iron powder (0.56 g, 10.0 mmol) and ammonium chloride (0.16 g, 3.0) in an ethanol (30 mL), tetrahydrofuran (30 mL), and water (10 mL) solution was heated to reflux for 6 hours. The resultant mixture was diluted with ethanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as a yellow powder (1.12 g, 95%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][NH2:31])=[O:29])=[CH:24][CH:23]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:33](Cl)Cl>C(OC)(OC)OC.C(O)(=O)C>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[O:29][CH:33]=[N:31][N:30]=4)=[CH:24][CH:23]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(C(=O)NN)cc3)ncnc21
Reactant: ClCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(-c4nnco4)cc3)ncnc21
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of N-Cyclopropyl-3-[6-(4-hydrazinocarbonyl-phenyl)-purin-9-yl]-4-methyl-benzamide (8.0 mg, 0.019 mmol) in 0.5 mL of trimethyl orthoformate was added three drop of acetic acid. The reaction mixture was stirred at 120° C. in microwave for 10 minutes. Then 0.5 mL of methylene chloride and 3 mL of hexanes were added. The product was collected by filtration to give a colorless solid (6.0 mg, 73%). HPLC tR=2.12 min; MS m/z 438 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]=[C:12]1[CH2:21][OH:22].C(N(CC)CC)C.Cl>ClCCl>[O:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]=[C:12]1[CH:21]=[O:22]
Reactant: OCC1=COc2ccccc2O1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC1=COc2ccccc2O1
Reaction time: 0.08 h

Procedure:
A solution of 1.2 ml (14 mmol) of oxalyl chloride in 30 ml of anhydrous dichloromethane is cooled to −60° C. under an inert atmosphere; 2 ml (28 mmol) of anhydrous dimethyl sulphoxide are then added to the medium. After 5 minutes of stirring, 1.53 g (9.33 mmol) of the alcohol obtained in Step A in 15 ml of dichloromethane are slowly added to the solution. 15 minutes later, 6.5 ml (47 mmol) of triethylamine are added to the medium. After returning to ambient temperature, the solution is acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. The organic phases, dried over magnesium sulphate and then filtered, are concentrated in vacuo. The title aldehyde is obtained pure in the form of a white solid after passage over a silica column (eluant: AcOEt/PE: 10/90).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][C:10]#[C:11][CH2:12][NH:13]C(OC(C)(C)C)=O)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].Cl>C(O)(=O)C.O1CCOCC1>[C:1]([NH:4][CH:5]([CH2:9][C:10]#[C:11][CH2:12][NH2:13])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CC#CCNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=O)NC(CC#CCN)C(=O)O

Procedure:
Ex-8g) 10 g of 2-Acetylamino-6-t-butyloxycarbonylamino-4-hexynoic acid is taken up in 50 mL of acetic acid and 25 mL of 4N HCl in dioxane and stirred for 2 h at 25° C. The reaction mixture is stripped to dryness to give 2-Acetylamino-6-amino-4-hexynoic acid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:8]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C#N)C.[OH-].[K+]>C(O)CO.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([CH2:5][C:4]([OH:21])=[O:3])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C#N)C1(c2ccc(Cl)cc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)CC1(c2ccc(Cl)cc2)CCOCC1
Yield: 125.2 %

Procedure:
A stirred solution of (4-{4-chloro-phenyl}-tetrahydro-pyran-4-yl)-cyano-acetic acid ethyl ester (3.3 g, Reference Example 22) in ethylene glycol (50 mL) was treated with a solution of potassium hydroxide (5 g) in water (10 mL) in one portion and then heated at reflux temperature for 23 hours. The resultant pale amber solution was evaporated and the oily residue was treated with water (50 mL). The mixture was washed with diethyl ether (20 mL), then ice-cooled, then acidified to pH 1 by addition of concentrated hydrochloric acid (3 mL) and then extracted with diethyl ether (50 mL). The organic extract was washed with water (25 mL) then dried over magnesium sulfate and then evaporated to give the title compound (3.42 g) as a colourless oil, which slowly crystallised on standing. LC-MS: RT=2.92 minutes, MS(ES+): 253 and 255(M+H)+.
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28]([OH:35])(=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[C:31]([CH2:30][CH2:29][C:28]([O-:35])=[O:34])([OH:33])=[O:32].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)CCC(=O)O
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: O=C([O-])CCC(=O)O
Yield: 72.3 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and succinic acid (0.41 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 3-carboxypropanoate as a crystalline white solid (0.95 g, 72% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10]([O-:12])=[O:11].[H-].[Na+].Br[C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([F:28])[F:27])=[CH:22][CH:21]=1.[CH3:31]N(C)C=O>>[F:29][CH:19]([F:30])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[N:6]2[CH2:5][CH2:4][N:3]([C:7]3[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=3)[C:10]([O:12][CH3:31])=[O:11])[C:2]2=[O:1])=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])c1ccnc(N2CCNC2=O)c1
Reactant: FC(F)c1ccc(C(F)(F)Br)cc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccnc(N2CCN(C(F)(F)c3ccc(C(F)F)cc3)C2=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a solution of 2-(2-oxoimidazolidin-1-yl)isonicotinate (0.50 g, 2.26 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (0.10 g, 60% dispersion in mineral oil, 2.5 mmol) at 0° C. The resulting solution was stirred at 0° C. for 30 minutes, followed by the addition of 1-(bromodifluoromethyl)-4-(difluoromethyl)benzene (0.58 g, 2.26 mmol). The mixture was warmed to ambient temperature and stirred for 55 hours. 1-(Bromodifluoromethyl)-4-(difluoromethyl)benzene (0.13 g, 0.5 mmol) was again added and the reaction was stirred at 60° C. for 5 hours then concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with hexanes and ethyl acetate (from 10:1 to 1:1) to give methyl 2-(3-((4-(difluoromethyl)phenyl)-difluoromethyl)-2-oxoimidazolidin-1-yl)isonicotinate as a colorless solid (0.09 g, 13%): MS (ES+) m/z 397.8 (M+1).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:25]=[CH:26][CH:27]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2cccc(Cl)c2)nc1
Yield: 60.3 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)nicotinamide (Intermediate 4, 905 mg, 3.00 mmol), 2-(3-chlorophenyl)ethylamine (560 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (738 mg) as a white solid. Mass spectrum (ion spray): m/z=408 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.15 (d, 1H), 7.31 (d, 1H), 7.25-7.18 (m, 3H), 7.11 (d, 1H), 6.98-6.93 (m, 3H), 5.89 (br. s, 2H), 4.26 (t, 1H), 3.03-2.96 (m, 3H), 2.87-2.78 (m, 3H), 2.44 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]5[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=[O:32])[CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1.Cl.[CH2:40](N(CC)CC)C.C(Cl)(=O)C>CO.O1CCOCC1>[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:23]2[N:12]3[C@@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:14][O:15][C:16]4=[C:11]3[C:10](=[CH:9][CH:8]=[C:7]4[C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:38])[N:24]=2)[CH2:26][CH2:27]1)(=[O:32])[CH3:40]
Reactant: Cc1noc(C)c1-c1ccc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(=O)Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1CCC(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To the solution of tert-butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate (8.8 mg, 0.017 mmol) in methanol (1 mL) was added 4.0 M hydrogen chloride in dioxane (1 ml) at room temperature. The resulting mixture was stirred at room temperature for 10 min. The solvents were then evaporated under a steam of nitrogen. Triethylamine (0.23 mL, 1.7 mmol) was added to the resulting residue, followed by acetyl chloride (0.029 mL, 0.41 mmol). The mixture was then stirred under a stream of nitrogen for 5 min at room temperature, followed by removal of solvents and residual reagents. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound (6.3 mg, 81%). LCMS for C26H28O3N5 (M+H)+: calculated m/z=458.2. found 458.2.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([O:13][C:14]2[C:15]3[C:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[O:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8]1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:21]1[O:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([O:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])[CH2:8]3)[C:15]=2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: COC(=O)CCCN1CCC[C@@H](Oc2ncnc3oc(-c4ccccc4F)c(-c4ccc(OC)cc4)c23)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(CCCC(=O)O)C4)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 113 mg (0.20 mmol) of 4-[(3R)-3-{[6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]-pyrimidin-4-yl]oxy}piperidin-1-yl]butyric acid methyl ester in 3 ml of dioxane and add 0.8 ml of a 1 N sodium hydroxide solution. Stir at room temperature for 16 hours, then add 0.8 ml of 1 N hydrochloric acid and 10 ml of ethyl acetate. Remove the organic phase, dry over sodium sulphate, filter and concentrate. 95 mg (90% of theory) of the target compound are obtained.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]1(=[O:19])[CH2:17][C:16](=[O:18])[CH2:15]1>C(OCC)(=O)C>[CH:8]1([NH2+:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1.[OH:19][C:14]1[CH2:17][C:16](=[O:18])[CH:15]=1
Reactant: O=C1CC(=O)C1
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CCOC(C)=O
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: O=C1C=C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
A solution of 7.1 g of dicyclohexylamine (98 percent; 38.3 mmol) in 15 ml of ethyl acetate was instilled in a suspension of 3.0 g of 1,3-cyclobutanedione (97 percent; 34.6 mmol) in ethyl acetate (52.2 ml) at 20° C. in 15 minutes. After 1 hour of stirring at room temperature, the suspension was washed four times with ethyl acetate and dried under vacuum. 9.4 g of the title product with a content of 94.7 percent (according to HPLC), corresponding to a yield of 96.7 percent, relative to cyclobutanedione, was obtained. Data for the title compound was:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:18])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CCCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCCC#Cc1cnc2ccccc2c1
Yield: 88.7 %

Procedure:
6-(3-Quinolinyl)-5-hexyn-1-ol was prepared in the manner described above in Example 105 starting with 15.0 g of 3-bromoquinoline, 8.5 g of 5-hexyn-1-ol, 1.05 g of bis(triphenylphosphine)palladium dichloride and 0.10 g of cuprous iodide in 115 ml of dichloromethane and 28.5 ml of triethylamine. The crude product was chromatographed on a preparative high pressure liquid chromatograph eluting with 2.5% methanol-dichloromethane to give 14.4 g (89%) of 6-(3-quinolinyl)-5-hexyn-1-ol as a colorless oil. A portion was purified further on a silica thick layer plate eluting with 10% methanol-dichloromethane and solidified on drying, mp 47°-48° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=1[OH:44]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=1[OH:44]
Reactant: CN1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NCC4CCN(C)CC4)c3c2)cc(Cl)c1O
Yield: 44.1 %

Procedure:
Following general procedure F, {6-bromo-4-[(1-methylpiperidin-4-yl)methylamino]quinolin-3-yl}(cyclopropyl)methanone (63 mg, 0.156 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (53 mg, 0.187 mmol) to afford the desired product (33 mg, 44%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.12 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 7.99 (dd, J=8.7, 1.9 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 3.98 (s, 3H), 3.84 (d, J=6.7 Hz, 2H), 3.20-3.13 (m, 2H), 2.87-2.80 (m, 1H), 2.51 (s, J=10.3 Hz, 3H), 2.46 (t, J=11.6 Hz, 2H), 1.97 (d, J=13.2 Hz, 2H), 1.90 (s, 1H), 1.53-1.40 (m, 2H), 1.24-1.17 (m, 2H), 1.14-1.07 (m, 2H); ESI MS m/z [C27H30ClN3O3+H]+; HPLC>99% (AUC), tR=8.32 min.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:12][CH2:11][C:8]2([O:10][CH2:9]2)[CH2:7][CH2:6]1.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CCO>C(O)C.C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:12][CH2:11][C:8]([CH2:9][N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[O:17])([OH:10])[CH2:7][CH2:6]1
Reactant: Oc1ccccn1
Reactant: Fc1ccccc1CN1CCC2(CC1)CO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccccn1CC1(O)CCN(Cc2ccccc2F)CC1
Yield: 60.8 %

Procedure:
23.00 g (0.104 mol) of N-(2-fluorobenzyl)-1-oxa-6-azaspiro[2,5]-octane and 10.30 g (0.108 mol) of 2-hydroxy-pyridine were weighed and added into 80 mL N,N-dimethylformamide, and then 1.00 g (0.007 mol) potassium carbonate was added. The reaction was stirred and reacted at a bath temperature of about 80° C. for 1 day, and the solvent was recovered. Potassium carbonate aqueous solution was added into the residue The mixture was extracted with dichloromethane twice, combined, washed with water, and dried. The solvent was recovered, crystallized with petroleum ether-ethyl acetate to obtain colorless flake-like crystal, 22.80 g, yield 69.3%. 1H-NMR (CDCl3, ppm) δ: 7.372 (2H, m), 7.228 (2H, m), 7.092 (1H, t, J=7.56 Hz), 7.020 (1H, t, J=8.96 9.24 Hz), 6.639 (1H, d, J=9.24 Hz), 6.228 (1H, t×d, J1=6.72 Hz, J2=1.12 Hz), 4.720 (1H, s), 4.036 (2H, s), 3.603 (2H, s), 2.69 (2H, dd, J1=7.84 Hz, J2=3.64 Hz), 2.46 (2H, t×d, J1=8.40 Hz, J2=2.80 Hz), 1.55-1.74 (4H, m). The product was heated and dissolved in ethanol-ethyl acetate, salified with HCl-EtOH while warm and naturally cooled to obtain a colorless fine granular crystal, which was dried under vacuum to obtain 20.00 g product. Melting point: 249-251° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O)(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:25])(=[O:18])=[O:19]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 64 hours. The compound was purified by two silica gel chromatographies on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (30%). MS (ESI): m/z=449.11 [M+H]+.
Reaction SMILES: O[Li].O.O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:18]([O:20]C)=[O:19])[OH:17]>C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:18]([OH:20])=[O:19])[OH:17]
Reactant: COC(=O)C1(O)CCOc2c(Cl)cc(Cl)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(O)CCOc2c(Cl)cc(Cl)cc21

Procedure:
LiOH.H2O (0.15 g; 3.6 mmol) and water (2 mL) were added to a solution of 6,8-dichloro-4-hydroxychroman-4-yl-carboxylic acid, methyl ester (0.50 g; 1.8 mmol; from step (i) above) in THF (5 mL). The resultant mixture was stirred at room temperature for 30 min., THF was evaporated and the water phase was washed with methylene chloride. The reaction mixture was made acidic with HCl (2M) and extracted with methylene chloride. The organic layer was dried (Na2SO4) and evaporated, yielding the sub-title compound. Yield: 390 mg (83%).
Reaction SMILES: CS(C)=O.[CH2:5]([OH:8])[CH2:6][OH:7].CC([O-])(C)C.[K+].Cl[C:16]1[CH:25]=[C:24]2[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]2[CH:26]2[CH2:28][CH2:27]2)=[CH:18][C:17]=1[F:33]>O>[CH:26]1([N:23]2[C:24]3[C:19](=[CH:18][C:17]([F:33])=[C:16]([O:7][CH2:6][CH2:5][OH:8])[CH:25]=3)[C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22]2)[CH2:27][CH2:28]1
Reactant: OCCO
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(OCCO)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a mixture of DMSO (5 mL) and ethyleneglycol (6 mL), KOtBu (1.6 g, 14.23 mmol) was added portion-wise over 10 min, and then heated to 90° C. To the mixture, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105° C. and the mixture was stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2:1 mixture of Intermediate 25A and Intermediate 25B (1.0 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CC(C)=O.CN(C=O)C>[CH3:19][N:20]([C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:17]=1)[C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: N#C[S-]
Reactant: O=C(O)c1cccnc1Cl
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CN(c1ccc([N+](=O)[O-])cc1)c1nc(=O)c2cccnc2s1
Yield: 81 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.757 g (11.2 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 891 mg of ammonium thiocyanate, 15 ml of acetone, 1.78 g of N-methyl-4-nitroaniline and 10 ml of acetone were used. The product was then recrystallized from ethanol to obtain 2.85 g of 2-[N-methyl-N-(4-nitrophenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](=O)[NH:19][CH2:20][C:21]2[C:26]([Cl:27])=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C=O>C(#N)C>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([Cl:27])[C:21]3=[CH:20][N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(NC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To benzyl((trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl)methylcarbamate (8.79 g, 18.98 mmol) in acetonitrile (anhydrous) (90 ml) were added phosphorus oxychloride (5.31 ml, 56.9 mmol) and N,N-dimethylformamide (a drop) and the mixture was stirred at 60° C. overnight. Then the mixture was concentrated, the residue was dissolved in dichloromethane and quenched with an excess of 7M ammonia in methanol. This mixture was concentrated again and the residue was purified by column chromatography (silica gel, dichloromethane with gradient 0 to 5% of methanol) to yield benzyl((trans)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (6.58 g).