Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]3([C:27]4[N:28]=[N:29][N:30]([CH:32]([F:34])[F:33])[N:31]=4)[CH2:24][O:23]C(C)(C)[O:21][CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.FC1C=CC=C(F)C=1COC1C2N(C(C(NC3(C4N(C(F)F)N=NN=4)COC(C)(C)OC3)=O)=C(C)N=2)C=CC=1.Cl.C(OC(C)C)(C)C>C(OCC)(=O)C.CO>[F:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:27]3[N:28]=[N:29][N:30]([CH:32]([F:34])[F:33])[N:31]=3)([CH2:20][OH:21])[CH2:24][OH:23])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(c2nnn(C(F)F)n2)COC(C)(C)OC1
Agent: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(c2nnnn2C(F)F)COC(C)(C)OC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)(CO)c1nnn(C(F)F)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
23.6 g of a mixture of 8-[(2,6-difluorobenzyl)oxy]-N-{5-[2-(difluoromethyl)-2H-tetrazol-5-yl]-2,2-dimethyl-1,3-dioxan-5-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide and 8-[(2,6-difluorobenzyl)oxy]-N-{5-[1-(difluoromethyl)-1H-tetrazol-5-yl]-2,2-dimethyl-1,3-dioxan-5-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide, a mixture of 220 ml of methanol and 220 ml of 1 M hydrochloric acid was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform/methanol=9:1. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 15.1 g of a crude product. To this crude product were added 30 ml of ethyl acetate and 150 ml of diisopropyl ether, followed by stirring at room temperature for 1 hour. The insoluble materials were separated by filtration, and the solid was washed with 100 ml of diisopropyl ether and dried under reduced pressure to obtain 12.9 g of 8-[(2,6-difluorobenzyl)oxy]-N-{2-[2-(difluoromethyl)-2H-tetrazol-5-yl]-1,3-dihydroxypropan-2-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Li]CCCC.[F:15]/C(/OC)=C/C(OC)=O.Cl.S(=O)(=O)(O)O.[CH2:30]1C[O:33][CH2:32][CH2:31]1>CCCCCC.O.CCOCC>[F:15][C:31]1[C:32](=[O:33])[NH:6][C:5]2[C:7]([CH:30]=1)=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2
Reactant: COC(=O)/C=C(/F)OC
Reactant: COc1cccc(N)c1
Reactant: C1CCOC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccc2cc(F)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.19 %

Procedure:
To a solution of 3-methoxyaniline (1.718 mL, 15.29 mmol) in THF (12 mL) was added 2.5 N n-BuLi (5.965 mL, 14.91 mmol) in hexane at 0 C. The reaction mixture was stirred at 0 C for 5 minutes. (E)-methyl 3-fluoro-3-methoxyacrylate (1.00 g, 7.457 mmol) in THF (10 mL) was added. The mixture was stirred at 0° C. for one hour. 1 N HCl (20 mL) and ether (30 mL) were added. The organic layer was separated, washed with water, saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give an oil. Sulfuric acid (70%; 8 mL) was added. The mixture was stirred at 56° C. (bath) for 2 hours. After cooling to ambient temperature, ice (20 g) and water (50 mL) were added. The mixture was stirred at ambient temperature for 10 minutes. The solid was collected by filtration and washed with water to give 3-fluoro-7-methoxyquinolin-2(1H)-one (1.40 g, 7.247 mmol, 97.19% yield) as a solid.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[C:18]([CH:20]1[CH2:22][CH2:21]1)#[CH:19]>C1(C)C=CC=CC=1.C(N(CC)CC)C.CO.[Cu]I.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>[CH:20]1([C:18]#[C:19][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ccc(Br)c(OCC2CC2)c1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1ccc(C#CC2CC2)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
Ethyl 4-bromo-3-(cyclopropylmethoxy)benzoate (0.77 g, 2.57 mmol), ethynylcyclopropane (0.45 mL of a 70% w/v solution in toluene, 3.86 mmol), copper(I) iodide (49 mg, 0.26 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.36 g, 0.51 mmol) were placed in 50 mL triethylamine and stirred in a sealed tube at room temperature for 20 h. The reaction was diluted with MeOH and filtered through Celite®., then the filtrate was concentrated to an oil. Purification by column chromatography on silica gel using 25% EtOAc/hexane gave the product (0.47 g, 61%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:18]([O-])=O)[C:14]=1[S:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[Cl-].[NH4+].C>C(O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:18])[C:14]=1[S:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Temperature: 60 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A 50 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-ethylsulfanyl-8-nitro-9H-β-carboline (85.0 mg, 0.28 mmol) in 10 ml anhydrous ethanol. To the resulting orange mixture at RT was added 0.33 M aqueous ammonium chloride (2.0 ml, 0.66 mmol) and iron powder (680 mg, 12.2 mmol). The reaction mixture was heated to 60° C. and stirred vigorously for 20 hr. Next, the mixture was cooled to RT, diluted with ethyl acetate (15 ml), and activated charcoal (˜180 mg) was added. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated to afford 77.8 mg of 6-chloro-7-ethylsulfanyl-9H-β-carbolin-8-ylamine as a yellow solid (>99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.N1C=CC=CC=1.[CH:42]1([C:45](Cl)=[O:46])[CH2:44][CH2:43]1>ClCCl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([CH3:28])[C:5]2[C:4]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:3][C:2]([NH:1][C:45]([CH:42]3[CH2:44][CH2:43]3)=[O:46])=[N:7][CH:6]=2)=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1-c1cc(NC(=O)C2CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.1 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 2 ml pyridine and 23 mg (0.22 mmol) cyclopropanecarboxylic acid chloride at 0° C. After stirring for 2 days at room temperature, the solvent was removed in vacuo and the residue was purified by flash-chromatography to give 61 mg (54%) of the title compound as white solid. MS m/e (%): 586 (M+Na+, 25), 564 (M+H+, 100).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:15][C@@H:16]([OH:23])[CH2:17][NH:18][C:19](=[O:22])[CH2:20][OH:21])=[C:9]([CH2:24][CH3:25])[CH:8]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:24]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH3:13])[C:10]=1[O:14][CH2:15][C@@H:16]([OH:23])[CH2:17][NH:18][C:19](=[O:22])[CH2:20][OH:21])[C:6]([OH:26])=[O:5])[CH3:25]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1OC[C@@H](O)CNC(=O)CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C(=O)O)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To a cooled (0° C.) solution of 3-ethyl-4-[(S)-2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid tert-butyl ester (5.94 g, 16.2 mmol) in DCM (100 mL), TFA (5 mL) is added. The mixture is warmed to rt and stirred for 2 h. The mixture is concentrated, dissolved in acetonitrile/water (6 mL) and separated by prep. HPLC to give the title compound (2.20 g) as a white powder; LC-MS: tR=0.41 min; [M+H]+=312.18.
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]C)=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[SH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([SH:36])=[CH:34][CH:35]=2)=[CH:7][CH:8]=1
Reactant: CSc1ccc(CNCCCCNCCCCCCCNCCCCNCc2ccc(SC)cc2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Sc1ccc(CNCCCCNCCCCCCCNCCCCNCc2ccc(S)cc2)cc1

Procedure:
Dissolve 1,19-bis[(4-methylmercaptophenyl)methyl]-1,6,14,19-tetraazanonadecane (2.94 g, 5 mmol) in chloroform (20 mL) and treat with meta-chloroperbenzoic acid (863 mg, 5 mmol). Add calcium hydroxide (556 mg, 7.5 mmol) and stir for 15 minutes. Filter and evaporate the solvent in vacuo. Dissolve the residue in trifluoroacetic anhydride (10 mL) and heat at reflux for 30 minutes. Evaporate the volatiles in vacuo and dissolve the residue in a mixture of methanol-triethylamine (1:1, 100 mL) and evaporate the solvent in vacuo. Dissolve the residue in chloroform, wash with saturated ammonium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give the crude title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C@H:3]1[OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:1][C@@H:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C@H:3]1[O:9][S:18]([CH3:17])(=[O:20])=[O:19])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COC1C[C@@H](O)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1C[C@@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
(1R*,2R*)-1,2-Dihydroxy-4-methoxycyclopentane (1.21 g) and triethylamine (7.66 ml) were dissolved in dichloromethane (20 ml), and methanesulfonyl chloride (2.13 ml) was added dropwise over 20 minutes at −78° C. After completion of drop addition, the mixture was warmed to 0° C. and stirred for 80 minutes to obtain crude (1R*,2R*)-1,2-bis(methanesulfonyloxy)-4-methoxy-cyclopentane. This product was dissolved in N,N-dimethylformamide (20 ml), and sodium azide (3.57 g) was added. The mixture was stirred at 65° C. for 22 hours. Sodium azide (3.57 g) was additionally added to stir the mixture at 70° C. for 2 days. The reaction mixture was allowed to cool, and water and diethyl ether was added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate 2:1) to obtain the title compound (584 mg) as a colorless liquid.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[S:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]=1)=[O:20])=[O:7])(=O)C.CO.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:29][C:27]1[S:26][C:24]2[NH:25][C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][C:6](=[O:7])[CH2:5][OH:4])=[O:20])=[CH:22][C:23]=2[CH:28]=1
Reactant: CC(=O)OCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CO)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
N-{(1R,2R)-1-[(2-Acetoxyacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 39; 393 mg, 0.92 mmol) was dissolved in THF (5 mL), MeOH (5 mL) and K2CO3 (50 mg) were then added and the suspension stirred at ambient temperature for 4 hours. Water (10 mL) was added and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by evaporation under reduced pressure, the crude product was triturated (EtOAc:isohexane, 1:5), filtered, washed with isohexane (5 mL) and dried to give the title compound (257 mg, 72%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=O)[N:8]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>CO>[OH:26][CH2:25][CH2:27][NH:28][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][S:13][C:9]1[N:8]=[C:7]([NH:6][C:5]([NH2:22])=[N:4][CH2:3][C:2]([F:1])([F:23])[F:24])[CH:12]=[CH:11][N:10]=1
Reactant: NCCO
Reactant: CCOC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCC(=O)NCCO)n1

Procedure:
A mixture of ethyl 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate (0.2 g.), ethanolamine (0.5 ml.) and MeOH (5 ml.) was heated under reflux for 48 hours and then evaporated to dryness. Water was added to the residue, and the mixture extracted with EtOAc. The extract was dried and evaporated to dryness and the residue recrystallised from a small volume of EtOAc to give N-(2-hydroxyethyl)-4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide (0.12 g.), m.p. 148°-150°.
Reaction SMILES: C([Li])(C)(C)C.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.[CH:29](=[O:31])[CH3:30]>O1CCCC1>[OH:31][CH:29]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH3:30]
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Reactant: CC=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1.7M solution of t-butyllithium in hexane (8.03 ml, 13.65 mmol) was added dropwise, under nitrogen, to a stirred solution of 5-bromo-3-(N-methyl-4-piperidyl)-1H-indole (EP-A-0303507, 1.0 g, 3.4 mmol) in dry tetrahydrofuran (35 ml) at about -70° C., ensuring that the temperature of the reaction mixture did not rise above -50° C. during the addition. The resulting mixture was allowed to warm to room temperature over a period of 1 hour, then cooled to about -70° C. and treated, dropwise, with a solution of acetaldehyde (0.15 g, 3.4 mmol) in dry tetrahydrofuran (5 ml). After being stirred for a further 0.5 hour at about -70° C., the reaction mixture was quenched with water and allowed to warm to room temperature. The bulk of the organic solvents was removed by evaporation under reduced pressure and the remaining mixture partitioned between ethyl acetate and 10% aqueous ammonium chloride solution. The organic phase was separated, combined with two further ethyl acetate extracts of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure to give an oil which was purified by column chromatography on silica gel, eluting with 0.880 aqueous ammonia:methanol:dichloromethane (1:20:79), to provide the title compound which was employed in the following Example without further characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:12][N:10]([CH3:11])[CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:13]=[CH:14][C:15]([NH2:16])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(OCCCN(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCCN(C)C)ccc1N
Yield: 98.4 %

Procedure:
A mixture of [3-(3-methoxy-4-nitrophenoxy)propyl]dimethylamine (2.0 g, 7.7 mmol) and 5% Pd—C (0.4 g) in ethyl acetate (75 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 1.7 g of the product as a light grey oil, in 97% yield: 1H NMR (CDCl3) δ 1.86-1.98 (m, 2H), 2.25 (s, 6H), 2.44 (t, J=7.3 Hz, 2H), 3.44 (br, 2H), 3.82 (s, 3H), 3.94 (t, J=6.5 Hz, 2H), 6.35 (dd, J=8.4 Hz, J=2.6 Hz, 1H), 6.46 (d, J=2.6 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]([F:23])[F:22].N1C=CN=N1>>[F:22][CH:21]([F:23])[N:6]1[C:5](=[O:7])[N:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:3]=[C:2]1[CH3:1]
Reactant: Cc1nn(-c2ccccc2)c(=O)[nH]1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]nn1
Product: Cc1nn(-c2ccccc2)c(=O)n1C(F)F
Yield: 89.3 %

Procedure:
This compound was prepared in the manner of Example 1, with 25.0 grams of 4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-1,2,4-triazole (0.110 mole--1.0 equiv.), 30.0 grams (0.217 mole--2.0 equiv.) of potassium carbonate, and 14.3 grams (0.165 mole--1.5 equiv.) of chlorodifluoromethane in 220 mL of polyglyme (% wt/vol. triazole to solvent--11%) as reagents. A yield of 28.7 grams of 91.5% pure 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-1,2,4-triazole (87.8% yield) was obtained. GC analysis of the product indicated the presence of about 5.0% O-isomer by-product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[S:3]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:40][CH3:41])=[C:37]([Pb+3])[CH:38]=1>C(Cl)(Cl)Cl.ClCCl.Cl>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:40][CH3:41])=[C:35]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[S:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:34]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: CC1(C)SC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Temperature: 25 °C

Procedure:
To a solution of 2,2,6,6-tetramethylthiopyran-3,5-dione (prepared according to the procedure of E. Er and P. Margaretha, Helvetica Chimica Acta (1992), 75(7), 2265-69) (1.8 g, 9.9 mmol) and N,N-dimethylaminopyridine (5.3 g, 4.34 mmol) in chloroform (60 ml), is added toluene (18 ml) then 5-bromo-2-ethylphenyllead triacetate (6.2 g, 1.09 mmol) in one portion. The resulting mixture is heated at reflux for 2 hours, then allowed to cool to ambient temperature, diluted with dichloromethane and 1M aqueous hydrochloric acid, and the organic phase is separated. The organic phase is concentrated under reduced pressure, and the residue is purified by flash chromatography on silica gel (hexane/ethyl acetate 95:5 to 7:3 ratio), giving 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylthiopyran-3,5-dione (2.42 g) as an orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH:22]=O)=[CH:9][CH:8]=1.[CH:25]([OH:27])=O.[OH-].[Na+].[CH:30]([NH2:32])=O>O>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][N:32]([CH3:30])[CH:25]=[O:27])=[CH:9][CH:8]=1
Reactant: CN(C)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Reactant: O=CO
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCCNc1ccc(CN(C)C=O)c2sc3ccccc3c(=O)c12
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of [[3-(dimethylamino)propyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.6 g; 10.57 mmol) in 50 mL of formamide containing 3.6 g of formic acid was refluxed for 1.5 h and then was allowed to stand at room temperature overnight. the reaction mixture was diluted with water (400 mL), basified with 3 mL of 5N NaOH solution, stirred rapidly for 30 min, and the precipitated solid was filtered, washed with water, and dried, yielding 3.1 g (79%) of N-[[1-[[3-(dimethylamino)propyl]amino]-9-oxothioxanthen-4-yl]methyl]-N-methyl formamide (Formula I: R1 =R2 =Me; Q=CH2NHCHO; R8 =H; n=3), as a yellow powder.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NC1CCOCC1
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NC2CCOCC2)cn1
Yield: 46 %

Procedure:
As described in example 9, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (100 mg, 0.28 mmol), and 4-aminotetrahydropyran instead of tetrahydrofuran-3-amine, was converted to the title compound (56 mg, 46%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 96.5:3.5) and trituration with isopropyl ether. MS: m/e=328.4 [M+H]+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([OH:25])=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:23]([OH:25])=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Yield: 89.1 %

Procedure:
A solution of Z-Leu-Lys(Boc)-OH 41.5 g, 0.084 mol) in methanol (210 mL) was hydrogenated in a Vibromixer apparatus using 10% Pd/C (5.0 g) for 3.5 h. The precipitated product dissolved on addition of H2O (120 mL). The catalyst was removed by filtration (celite); washed twice with H2O and the combined filtrate evaporated to near dryness. The residue was reevaporated from MeOH (2×) and Et2O (2×). The solid product was collected, washed with Et2O and dried to afford 26.9 g of white solid. Recrystallization from warm iPrOH (420 ml) and MeOH (350 mL) afforded, after drying, 24.6 g of white crystalline product (81.5%); mp 142°-143°; Rf 0.63 (n-BuOH:AcOH:EtOAc:H2O; 1-1-1-1); [α]D25 +20.76° (c 1, MeOH). Anal: calcd. for C17H33N3O5 (359.47): C, 56.80; H, 9.25; N, 11.69. Found: C, 56.72; H, 9.55; N, 11.57.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([CH3:10])[O:7][N:6]=1)=O.O.[NH2:12][NH2:13]>C(O)CCC>[CH3:10][C:8]1[O:7][N:6]=[C:5]([C:3]([NH:12][NH2:13])=[O:2])[CH:9]=1
Reactant: NN
Reactant: COC(=O)c1cc(C)on1
Solvent: O
Solvent: CCCCO
Product: Cc1cc(C(=O)NN)no1
Yield: 64 %

Procedure:
As described for example 112a, 5-methyl-isoxazole-3-carboxylic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) at 100° C. for 2 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 64%). 1H-NMR (300 MHz, DMSO): δ=2.44 (d, J=1 Hz, 3H), 4.57 (s, 2H), 6.52 (d, J=1 Hz, 1H), 9.94 (s, 1H).