Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][N:21]=[C:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO.O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][NH:21][CH:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1=NCCn2c1cc1c2-c2ccc(OC3CCCC3)cc2CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CC1NCCn2c1cc1c2-c2ccc(OC3CCCC3)cc2CC1
Yield: 31 %

Procedure:
3-Cyclopentyloxy-5,6,10,11-tetrahydro-8-methylbenzo[g]pyrazino[1,2-a]indole (0.8 g) was dissolved in a mixture of 50 ml of methanol and 5 ml of water under argon. The solution was treated portionwise with 0.3 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 30 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 30 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 0.8 g of amorphous, brown solid, was chromatographed on 30 g of silica gel with methylene chloride/methanol mixtures (50:1 to 20:1). The isolated crude product was dissolved in a 25-fold amount of hot ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.34 g (31 %) of 3-cyclopentyloxy-5,6,8,9,10,11-hexahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 187°-189° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].C([Sn](CCCC)(CCCC)[C:31]#[C:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])CCC.[Cl-].[Li+]>CN(C)C=O.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>[CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([C:31]#[C:32][CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: CCCC[Sn](C#CC1CCCN1C(=O)OC(C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#CC2CCCN2C(=O)OC(C)(C)C)cccc1NC(=O)C(C)(C)C
Temperature: 95 °C
Yield: 86.7 %

Procedure:
A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-trifluoromethanesulfonyloxybenzoate (Intermediate 39, 3.83 g), tert-butyl 2-tributylstannanylethynyl-pyrrolidine-1-carboxylate (Intermediate 41, 5.81 g), bis(triphenylphosphine)palladium(II) dichloride (0.702 g) and lithium chloride (1.28 g) in dimethylformamide (50 mL) was stirred and heated at 95° C. under nitrogen for 1 hour. After cooling, the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give tert-butyl 2-[3-(2,2-dimethylpropionylamino)-2-methoxycarbonyl-phenylethynyl]-pyrrolidine-1-carboxylate (3.71 g) as a viscous gum.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)=[O:21])[CH3:18]>>[CH:1]1([N:6]2[C:10]3=[N:11][C:27]([C:26]4[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH2:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH:25]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)COc1cccc(C=O)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Product: CCOC(=O)COc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1
Temperature: 160 °C
Yield: 37.9 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.54 g, 15.95 mmol), 3-(ethoxycarbonylmethoxy) benzaldehyde (4.3 g) and xylenes (20 ml) was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, a solid formed which was collected by filtration and washed with methanol and then ether. The product was recrystallized from acetonitrile to afford 2.48 g of 1-cyclopentyl-3-ethyl-6-[3-(ethoxycarbonylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one. An additional 0.3 g of product was also obtained from the recrystallization of the filtrate for a total of 2.78 g.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][NH:32][CH3:33].[ClH:34]>O1CCCC1.ClCCl>[ClH:34].[CH3:31][N:32]([CH3:33])[CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CNC
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C[C@H](O)Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Temperature: 45 °C
Yield: 71 %

Procedure:
To (R)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)-phenyl)pyridin-2(1H)-one (230 mg, 0.56 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (892 mg, 8.38 mmol) followed by dimethylamine (2.8 ml of a 2 M solution in tetrahydrofuran, 5.6 mmol). The reaction mixture was heated in a 45° C. oil bath for 3.75 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (198 mg, 0.43 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.38 mL, 0.47 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (198 mg, 71%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.42 (br s, 1H), 8.20 (s, 1H), 8.02-8.00 (m, 2H), 7.88-7.80 (m, 5H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0, 2.0 Hz, 1H), 5.60 (br s, 1H), 4.56-4.52 (m, 1H), 4.48-4.44 (m, 1H), 4.27 (br s, 1H), 2.92-2.88 (br m, 2H), 2.58 (br s, 6H); ESI MS m/z 457 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.5 min; [α]23D −9.5° (c 0.14, Methanol).
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.CCCCC.[CH3:23][S:24]SC>O1CCCC1>[CH3:23][S:24][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: CSSC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CSc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A mixture of potassium hydride in mineral oil (35 wt. %, 3.04 g, 26.52 mmol) in tetrahydrofuran (53 mL) was cooled to 0° C. then was treated with a solution of 6-bromo-1H-indole (5.20 g, 26.52 mmol) in tetrahydrofuran (53 mL). The reaction was stirred at 0° C. for 30 min. At this time, the reaction was cooled to −78° C. and then was treated with 1.7M solution of tert-butyllithium in pentane (31.2 mL, 53.04 mmol). The reaction mixture was stirred at −78° C. for 20 min. At this time, the reaction was added to a solution of methyl disulfide (4.78 mL, 53.04 mmol) in tetrahydrofuran (15 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 18 h. At this time, the reaction was quenched by the addition of a saturated aqueous ammonium chloride solution (300 mL) and was extracted with ethyl acetate (1×500 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×300 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9:1 hexanes/ethyl acetate) afforded 6-methylsulfanyl-1H-indole (2.3 g, 53%) as an off-white solid: mp 88-90° C.; EI-HRMS m/e calcd for C9H9N5 (M+) 163.0456, found 163.0457.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:8]=2/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[CH2:3]1.[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:8](/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[C:7]=1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:28]([C:24]2[N:23]([CH3:22])[CH:27]=[CH:26][N:25]=2)=[O:29])[CH2:3]1
Reactant: Cn1ccnc1C(=O)O
Reactant: N[C@H]1CCN(c2c(Cl)cccc2/C=C2\SC(=O)NC2=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccnc1C(=O)N[C@H]1CCN(c2c(Cl)cccc2/C=C2\SC(=O)NC2=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.1 %

Procedure:
To a 50 mL vial charged with a magnetic stir bar was added (S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-3-chlorobenzylidene)thiazolidine-2,4-dione (75 mg, 0.23 mmol) (Example 86), 1-methyl-1H-imidazole-2-carboxylic acid (87 mg, 0.69 mmol), HATU (220 mg, 0.58 mmol) and dichloromethane (5 mL). Hunig's base (0.202 mL, 1.16 mmol) was then added and the mixture was stirred at rt for 4 h. The reaction was then diluted with dichloromethane and washed with water. The mixture was separated with a phase separator tube and the organic phase was evaporated to dryness. The residue was purified by reverse phase chromatography to afford the title compound as a yellow solid (21 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (s, 1 H) 7.51 (dd, 1 H) 7.41 (dd, 1 H) 7.18-7.27 (m, 2 H) 7.01 (s, 1 H) 4.67-4.77 (m, 1 H) 4.00 (s, 3 H) 3.63-3.75 (m, 2 H) 3.47-3.54 (m, 1 H) 3.36-3.47 (m, 1 H) 2.39-2.51 (m, 1 H) 2.14 (dd, 1 H); m/z 432.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:11]([OH:13])=[O:12].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CC#N>[N:22]1([CH2:21][CH2:20][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:20][CH2:21][N:22]3[CH2:27][CH2:1][O:4][CH2:24][CH2:23]3)[CH:16]=2)[C:11]([O:13][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:12])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: O=C(OCCN1CCOCC1)c1cc(OCCN2CCOCC2)cc(OCCN2CCOCC2)c1
Yield: 50.3 %

Procedure:
To a suspension of K2CO3 (82.88 g, 0.6 mol) in CH3CN (300 ml) was added 3,5-dihydroxybenzoic acid (4.62 g, 0.03 mol), followed 10 minutes later by N-(2-chloroethyl)morpholine hydrochloride (18.42 g, 0.099 mol). The reaction mixture was refluxed overnight, cooled, filtered and the filtrate was concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with acetone, followed by Kugelrohr distillation at>195° C. and 0.2 mm Hg to afford 7.45 g of 4-morpholinylethyl 3,5-di-[2-(4-morpholinyl)ethoxy]benzoate.
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCC1OC(=O)C(O)=C1c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Reaction time: 8 h

Procedure:
3-(4-Hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)-propionic acid (100 mg) was dissolved in pyridine (2 ml), and acetic anhydride (1 ml) was added. The mixture was allowed to stand overnight. The excess reagent and solvent were removed by distillation under reduced pressure, and the residue was dried to give 3-(4-acetoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (116 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([F:14])[CH:7]=1.[C:19](Cl)(Cl)=[O:20].CCO>C1(C)C=CC=CC=1>[F:14][C:8]1[CH:7]=[C:6]([N:5]2[CH2:4][C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:1][C:19]2=[O:20])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1ccc(NCc2ccccc2N)cc1F
Reactant: O=C(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(N2Cc3ccccc3NC2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
To a stirred suspension of crude N-(2-aminobenzyl)-3-fluoro-4-methoxyaniline (246 mg, 1 mmol) in 10 mL toluene at 0° C. under a drying tube was added phosgene solution (20% in toluene, 683 μL, 1.30 mmol). The cooling bath was removed and the reaction allowed to warm to room temperature over 30 minutes. The solution was then warmed to reflux. After 1 hour, the reaction was concentrated to dryness and the residue dissolved in a minimum of hot 95% EtOH. A precipitate formed which was isolated by filtration with 95% EtOH and dried to give a tan solid (65 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 7.14 (m, 1H), 7.08 (m, 2H), 7.01 (m, 2H), 6.81 (d, 1H), 4.80 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:15]([C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[CH:11]=1)=[O:17]
Reactant: Nc1nccs1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)Nc3nccs3)c2)cc1
Yield: 78.3 %

Procedure:
1-(Toluene-4-sulfonyl)-1H-pyrrole-3-carboxylic acid thiazol-2-ylamide (68 mg) was prepared from 1-(toluene-4-sulfonyl)-1H-pyrrole-3-carboxylic acid (66 mg, 0.25 mmol) and 2-aminothiazole (25 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Br:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[Br-:9].[C:12]1([CH2:11][CH2:10][N+:1]2[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccncc1
Reactant: BrCCc1ccccc1
Solvent: CN(C)C=O
Product: OCc1cc[n+](CCc2ccccc2)cc1
Product: [Br-]
Reaction time: 3 h
Yield: 79.6 %

Procedure:
A mixture of 10.9 g of 4-pyridinemethanol, 25 g of 2-bromoethylbenzene an 30 mL of dimethylformamide was stirred in a 90° oil bath for 3 hours. Removal of the solvent and crystallization of the residue from 30 mL of ethanol gave 23.4 g (80%) of 1-(2-phenylethyl)-4-hydroxymethylpyridinium bromide, mp 132°-134°. NMR (DMSO) δ8.9 (d, 2H): 8.0 (d, 2H); 7.2-7.4 (m, 5H); 6.0 (t, 1H), 4.8-4.9 (d+t, 4H); 3.3 (t, 2H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:14](=[O:21])[NH:13][C:12]1=[O:22])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[C:14](=[O:21])[NH:13][C:12]1=[O:22]
Reactant: CC(C)(C)[Si](C)(C)OCCCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(=O)n(CCCCO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A solution of 1-[4-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-trifluoromethyl-1H-pyrimidine-2,4-dione (Prep22, 260 mg, 0.71 mmol) in DCM (15 mL) was cooled at 0° C. and then TFA (820 μl, 1.1 mmol) was added. The mixture was stirred for 1 hour at room temperature and the solvent was evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (7-3) to afford the title compound (132 mg, 74% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:6][C:7]=1[NH2:8].N1C=CC=CC=1.[CH3:21][CH:22]([CH2:26][S:27][CH3:28])[C:23](Cl)=[O:24].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:6][C:7]=1[NH:8][C:23](=[O:24])[CH:22]([CH3:21])[CH2:26][S:27][CH3:28]
Reactant: CSCC(C)C(=O)Cl
Reactant: Nc1sc(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1Cl
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, addition funnel, and nitrogen inlet was charged 7.5 g (30.2 mmoles) of 4-chloro-2-(pyridine-3-yl)-1,3-thiazol-5-amine hydrochloride and 200 mLs of anhydrous methylene chloride. The resulting suspension was cooled to 15° C., and 5.98 g (76 mmoles) of pyridine was added at a rate that maintained the temperature below 20° C. 1.85 g (15.11 mmoles) of N,N-dimethylpyridin-4-amine was added in one portion and the resulting yellow solution was stirred at 5° C. for 10 minutes. A solution of 2-methyl-3-(methylthio)propanoyl chloride (5.54 g 36.3 mmoles) in 25 mLs of methylene chloride was added dropwise at a rate that maintained the temperature below 15° C. The reaction was stirred at ambient temperature for 12 hours, than poured into 200 mLs of water. The target was extracted with methylene chloride (3×100 mLs) and the combined methylene chloride extracts were washed with 0.5 N aqueous hydrochloric acid (100 mLs), water (100 mLs) and saturated aqueous sodium chloride solution (100 mLs). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 30 minutes to yield a yellow oil (5.4 g, 55%): 1H NMR (400 MHz, CDCl3) δ 9.12 (dd, J=2.3, 0.8 Hz, 1H), 9.00 (s, 1H), 8.64 (dd, J=4.8, 1.6 Hz, 1H), 8.17 (ddd, J=8.0, 2.3, 1.6 Hz, 1H), 7.37 (ddd, J=8.0, 4.9, 0.8 Hz, 1H), 3.00-2.57 (m, 3H), 2.17 (s, 3H), 1.38 (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.68, 155.24, 150.55, 146.75, 132.81, 129.26, 127.62, 124.99, 123.80, 40.85, 37.98, 17.46, 16.45.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=O)C.[Na+].[Cl:24]Cl>C(O)(=O)C>[F:1][C:2]1[C:3]([C:9]2[C:13]([Cl:24])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: ClCl
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2ncc(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 60 °C

Procedure:
17.92 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example H15) are initially introduced into 60 ml of glacial acetic acid together with 10.6 g of sodium acetate. The mixture is heated up to 60° C., while stirring, and a saturated solution of chlorine in glacial acetic acid is added until TLC analysis of a worked-up sample shows a complete conversion (silica gel 60 F254; eluting agent: n-hexane/ethyl acetate 2/1; UV; Rf value of the starting material 0.34; Rf value of the product 0.48). The mixture is then concentrated to dryness in vacuo and the resulting residue is partitioned between sodium bicarbonate solution and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. 19.8 g of the desired target compound (pure according to TLC) are obtained. Melting point 95-96° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=O.[BH4-].[Na+]>>[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: CC(C)(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)CCNCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 68.2 %

Procedure:
Using a method similar to Example 201, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphtalene-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol), 3,3-dimethylbutyraldehyde (75 mg, 0.750 mmol), and NaBH4 (38 mg, 1.00 mmol) gives the title compound (130 mg) as a white foam. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.55 (s, 1H), 8.14 (d, 1H), 7.22-7.14 (m, 2H), 6.90 (m, 2H), 5.76 (br. s, 2H), 3.03 (m, 1H), 2.92-2.80 (m, 2H), 2.71-2.55 (m, 3H), 2.49-2.41 (m, 1H), 1.85-1.65 (m, 4H), 1.42 (t, 2H), 0.90 (s, 9H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])([O-])=[O:2].[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#C)=CN=1.[C:27]1([N:33]=[C:34]=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1.O>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][C:4]1[CH:25]=[C:22]([C:23]2[CH:27]=[N:33][CH:34]=[C:19]([O:18][CH2:17][C@@H:13]3[CH2:14][CH2:15][CH2:16][N:12]3[CH3:11])[CH:24]=2)[O:2][N:1]=1
Reactant: O=C=Nc1ccccc1
Reactant: C#Cc1ccc(OC[C@@H]2CCCN2C)nc1
Reactant: COC(=O)CCC[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCCN3C)c2)on1
Temperature: 60 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of methyl 4-nitrobutyrate (90 μL, 0.69 mmol, 3.0 equiv.) and 3-[[(1-methyl-2(S)-pyrrolidinyl)methoxy]-5-ethynylpyridine (50 mg, 0.23 mmol) in dry benzene (2.3 mL) were added phenyl isocyanate (80 μL, 0.69 mmol, 3.0 equiv.) and triethylamine (60 μL, 0.46 mmol, 2.0 equiv.). The reaction mixture was stirred at 60° C. for 24 h, then diluted with water and stirred vigorously for 2 h. The mixture was extracted with CH2Cl2, and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by CC on SiO2 with CH2Cl2/MeOH 9:1 to give the isoxazole (80 mg, 98%). 1H NMR (CD3OD, 400 MHz) δ 8.58 (s, 1H), 8.39 (s, 1H), 7.57 (s, 1H), 6.51 (s, 1H), 4.09 (dd, 1H, J=9.2, 5.5 Hz), 4.02 (dd, 1H, J=9.2, 5.5 Hz), 3.73 (s, 3H), 3.15 (t, 1H, J=7.2 Hz), 3.07 (t, 2H, J=7.2 Hz), 2.80 (t, 2H, J=7.2 Hz), 2.73 (m, 1H), 2.51 (s, 3H), 2.36 (m, 1H), 2.07 (m, 1H), 1.85 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:19]=[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:19]=[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[C:16]([Br:20])[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2nc3c(OC)cccn3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C1(c2nc3c(OC)ccc(Br)n3n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
To a stirred solution of 1-(8-methoxy-[1, 2, 4]triazolo[1,5-a]pyridine-2-yl)-cyclopropanecarboxylic acid ethyl ester (25 g, 95.7 mmol) in acetonitrile (300 mL) at RT, N-bromosuccinimide (34 g, 191.5 mmol) was added portion wise. After addition the reaction mixture was stirred at RT for 6 hours. The reaction mixture was diluted with EtOAc (600 mL), washed with water (100 mL×2), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (0 to 10% EtOAc in dichloromethane as eluent) to afford the title compound (25 g, 77%, colorless solid). 1H NMR (400 MHz, DMSO): δ=7.44 (d, J=8.4 Hz; 1H), 7.07 (d, J=8 Hz; 1H), 4.13-4.08 (m, 2H), 3.97 (s, 3H), 1.60-1.57 (m, 2H), 1.48-1.45 (m, 2H), 1.13 (t, J=7.4 Hz; 3H) ppm.