Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCNS(C)(=O)=O)CCCC3
Temperature: 0 °C
Yield: 31.5 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.00 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.84 mL, 6.00 mmol) and methanesulfonyl chloride (232 μL, 3.00 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et2O and a few drops of MeOH. The resulting white powder was isolated by filtration and further purified by column chromatography (SiO2, 3% MeOH/CHCl3 saturated with aqueous NH4OH) to give 389 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide as a white powder. m.p. 151.0-153.0° C.;
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.Br[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CC(OC)(C)C>[F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)[CH3:15])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2o1
Reactant: CC(Br)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CC(c1cccc([N+](=O)[O-])c1)n1c(=O)oc2cc(F)c(F)cc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
500 mg (2.9 mmol) of 5,6-difluoro-3H-benzoxazol-2-one, 672 mg (2.9 mmol) of (1-bromoethyl)-3-nitrobenzene and 1.58 g (11.4 mmol) of potassium carbonate are suspended in 6 ml of acetonitrile, and the mixture is stirred at 60° C. for 6 h. The mixture is subsequently diluted with 30 ml of MTBE, washed with 3×20 ml of H2O, dried over sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography on silica gel.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[CH3:10][NH:11][S:12]([C:15]1[CH:16]=[C:17]([C:25](Cl)=[O:26])[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=1)(=[O:14])=[O:13]>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:25]([C:17]1[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=[C:15]([S:12](=[O:14])(=[O:13])[NH:11][CH3:10])[CH:16]=1)=[O:26])[CH3:2]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 62 %

Procedure:
In a similar manner to that of the above example, 82 g of levorotatory 1-ethyl-2-aminomethyl-pyrrolidine was reacted with 195 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 151 g of levorotatory-N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 136°-137° C.; yield: 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:12][OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 25 g (0.18 mol) of 4-methoxybenzaldehyde in 100 ml of ethanol was added dropwise under ice cooling to a solution of 15.3 g (0.22 mol) of hydroxylamine hydrochloride and 11.0 g (0.28 mol) of sodium hydroxide in 100 ml of water. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 30 minutes and ethanol was distilled off under reduced pressure. An insoluble solid was then collected by filtration. The solid was washed with water and hexane. The washings were combined with the filtrate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, whereby 4-methoxybenzaldoxime was obtained as a colorless liquid. Its yield was 23.7 g (85%). It was then provided for the next reaction without further purification.
Reaction SMILES: [C:1](=O)([O:17]N1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH2:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH:36][C:1]([O:2][CH2:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:17])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(OCc1cccc2c1Cc1ccccc1-2)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=O)OCc1cccc2c1Cc1ccccc1-2

Procedure:
A solution of fluorenylmethyl succinimidyl carbonate (31.0 g, 0.092 mol) in acetonitrile (300.0 ml) was slowly added to mono tert-butyloxycarbonylethylenediamine (10.0 g, 0.063 mol) dissolved in 10% aq. Na2CO3 (250 ml). Acetonitrile was evaporated and the product was extracted with ethyl acetate, organic phase was dried over Na2CO3, concentrated and the product was allowed to crystallize by adding petroleum ether. The product was collected on filter, washed with petroleum ether. Yield 20.0 g (84%). TLC petroleum ether-diethylether 88:12 Rf 0.64. NMR (300 MHz, DMSO-d6, 25° C.) d: 1.37 (s, 9H, tBu), 2.99 (m, 4H, CH2CH2), 4.20-4.29 (m, 3H, Fmoc OCH2CH--), 6.76 (t, 1H, NH), 7.25 (t, 1H, NH), 7.33-7.89 (m, 8H, Fmoc). M.p. 146-148° C.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH2:12][C:13]2([OH:16])[CH2:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH2:11][CH2:12][C:13]2([O:16][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[CH2:14][CH2:15]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(O)CC2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2(OC3CCCCO3)CC2)cc1
Reaction time: 5 h

Procedure:
To a solution of 1-(2-p-toluenesulphonyloxyethyl)cyclopropanol (an intermediate in Preparation 2) (1.30 g) in dichloromethane (15 ml) at room temperature was added dihydropyran (0.88 g, 95%) and pyridinium p-toluenesulfonate (0.1 g). After 5 hours, the reaction solution was diluted with ether (70 ml) and extracted consecutively with water, 5% sodium hydrogen carbonate solution, and brine. After drying and removal of the solvent in vacuo, the product was purified by chromatography (50 g silica gel; 30% ether in petroleum ether as solvent) followed by recrystallisation from hexane to give the title compound as plates, m.p. 56°-57° C. (Found C, 59.99; H, 7.13; S 9.37. C17H24O5S requires C, 59.98; H, 7.11; S 9.42%), δ (100 MHz) 0.5 (2H, m), 0.85 (2H, m), 1.2-2.4 (8H, m), 3.1-3.9 (4H, m), 4.55 (1H, m), 7.6 (3H, m), 7.9 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]([F:69])([F:68])[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([NH2:67])[CH:61]=[CH:60]2>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH:67][C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:56]([F:68])([F:55])[F:69])[CH:58]=4)[N:63]=3)=[O:21])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:24])([F:23])[F:25])([O-:3])=[O:2]
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Nc1ccc2cc(C(F)(F)F)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)Nc1ccc2cc(C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (30 ml) was added EDAC.HCl (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and triethylamine (85 mg, 0.84 mmol). After 15 minutes 6-(trifluoromethyl)quinolin-2-amine (68 mg, 0.32 mmol) was added and the resulting solution was stirred overnight at room temperature. The contents were then quenched with water (100 ml) and extracted with dichloromethane (3×50 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 3% methanol in dichloromethane to afford 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]-oxy]-N-[6-(trifluoromethyl)quinolin-2-yl]acetamide as a yellow solid (80.6 mg, 52%). (ES, m/z): [M+H]+ 557.20; 1H NMR (300 MHz, CD3OD): δ 8.51-8.47 (m, 2H), 8.29 (s, 1H), 8.05-7.99 (m, 2H), 7.93 (dd, J=1.8, 9.0 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.83 (dd, J=2.4, 9.0 Hz, 1H), 4.27 (s, 2H), 3.63-3.45 (m, 2H), 2.27-2.14 (m, 4H), 1.70-1.56 (m, 2H), 1.46-1.34 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:15])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].CN([CH:24]=[O:25])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>>[C:1]([NH:4][C:5]1[S:6][C:7]([CH:24]=[O:25])=[C:8]([CH3:15])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CN(C=O)c1ccccc1
Reactant: CCOC(=O)c1c(C)csc1NC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(NC(C)=O)sc(C=O)c1C
Reaction time: 1.5 h

Procedure:
A mixture of 22.7 parts of 2-acetylamino-3-ethoxycarbonyl-4-methylthiophene, 261 parts of N-methylformanilide and 28.4 parts of phosphoryl chloride is stirred for 90 minutes at 90° - 95° C. 300 Parts of a 4N aqueous solution of sodium acetate are added and the mixture stirred for 10 minutes at 90° C. The oily solid is separated from the liquid and crystallised from ethanol to give 2-acetylamino-3-ethoxycarbonyl-4-methyl-5-formylthiophene (m.pt 174° - 176° C).
Reaction SMILES: [C:1]1([N:7]2[CH2:13][C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Br:16][CH2:17][CH2:18]Br.[I-].[K+]>C(O)C>[C:1]1([N:7]2[CH2:13][C:11](=[O:12])[N:10]([CH2:18][CH2:17][Br:16])[C:8]2=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: BrCCBr
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN(c2ccccc2)C(=O)N1CCBr

Procedure:
A mixture of 1-phenylhydantoin (5 g, 28.3 mmoles), 85% potassium hydroxide (2.06 g, 31.2 mmoles), 1,2-dibromoethane (11.72 g, 62.4 mmoles) and potassium iodide (catalytic amounts) in 100 ml of ethanol was refluxed for 67 hours. The solid was filtered, the mother liquors were evaporated and the crude product was purified by silica gel column chromatography eluting with increasing mixtures of ethyl acetate in hexane. By crystallization from acetone/hexane 1.56 g of the title compound were obtained, m.p. 146°-147° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([CH3:17])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1C#N
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1CN
Reaction time: 88 h

Procedure:
A mixture of 2-t-butoxycarbonylamino-5-cyano-6-methylpyridine (14.68 g, 62.9 mmol) and 10% Pd/C (1.5 g) in glacial acetic acid (150 ml) was shaken on a Parr apparatus at 60 psi for 88 h. The reaction was filtered through celite and was evaporated in vacuo. The residue was dissolved in water and the solution was washed with methylene chloride (2 times), then was basified with sodium carbonate and extracted with ethyl acetate (2 times). The combined ethyl acetate layers were dried (Na2SO4) and evaporated in vacuo to a solid. The crude product was recrystallized (ethyl acetate/hexanes) to give the title compound:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[NH:16][NH2:17]
Reactant: Fc1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
470 g of 3,5-dichloro-2,4-difluorobenzotrifluoride in 1000 ml of ethanol are initially introduced, and 142 g of hydrazine hydrate are metered in, and the mixture is then heated under reflux for 3 hours. Thereafter, the solvent is distilled off under reduced pressure and the residue is stirred into 1 l of cold water. After 30 minutes, the mixture is filtered under suction and the solid product is dried in a through-circulation oven. 445 g of 2,6-dichloro-3-fluoro-4-trifluoromethyl-phenylhydrazine having a melting point of 50° to 51° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>>[CH2:17]([O:16][C:10](=[O:15])[C:11](=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:12](=[O:13])[CH3:14])[CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(Cl)cc1
Product: CCOC(=O)C(C(C)=O)=C(N)c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-chlorobenzonitrile and ethyl acetoacetate: MS (m/z) 268.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:22])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Reaction time: 72 h
Yield: 40.7 %

Procedure:
2'-Methyl-4'-(1-methylimidazol-2-yl)biphenyl-4-carboxylic acid (D90, 310 mg, 1.06 mmol) was heated at reflux in thionyl chloride (10 ml) for 30 minutes, cooled, evaporated in vacuo and the orange residue redissolved in dry THF (10 ml). 1'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 260 mg, 1.06 mmol) and triethylamine (0.15 ml, 1.06 mmol) were added and the mixture stirred for 72 hours. The mixture was evaporated in vacuo, the residue partitioned between H2O and CHCl3 (4 times) and the organics combined, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash silica-gel chromatography with 2% MeOH/CHCl3 as eluant to yield the title compound as a pale yellow gum (224 mg, 41%) which was converted to the hydrochloride salt.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:12])[O:7][CH:8]([CH3:11])[C:9]=1O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:5]1[C:6](=[O:12])[N:14]=[N:15][C:9]=1[CH:8]([OH:7])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1OC(=O)C(C(C)(C)C)=C1O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(O)C1=C(C(C)(C)C)C(=O)N=N1
Reaction time: 48 h

Procedure:
3-tert-Butyl-4-hydroxy-5-methyl-5H-furan-2-one (3 g, 17.7 mmol) was dissolved in ethanol (40 ml) with hydrazine hydrate (2.73 ml, 88.5 mmol) and heated under reflux for 14 h. The volume was reduced by evaporation to ˜15 ml and heating continued for a further 48 h. The solvents were removed under high vacuum and the residue was triturated with diethyl ether to leave a white solid (crude 4-tert-butyl-5-(1-hydroxyethyl)pyrazol-3-one, 2.6 g). This white solid (2.6 g, 14 mmol) was dissolved in dichloromethane (70 ml) with tosyl chloride (3.24 g, 16.8 mmol) then cooled to 0° C. and triethylamine (2.56 ml, 18.2 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature then diluted with more dichloromethane (50 ml) and washed with saturated brine (1×100 ml). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum to leave a residue which was purified on silica gel using 20-50% ethyl acetate in isohexane as eluent to give 4-tert-butyl-5-(1-hydroxyethyl)-3-(4-methylphenyl)sulfonyloxypyrazole (3.8 g) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.34 (9H, s), 1.50 (3H, d, J=6.7 Hz), 2.45 (3H, s), 5.26 (1H, q, J=6.7 Hz), 7.35 (2H, d, J=8.2 Hz), 7.95 (2H, d, J=8.2 Hz), 10.72 (1H, br s); MS (ES+) m/e 339 [MH]+.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[NH:3]1.N.C(O)CO>>[CH3:16][N:13]1[CH2:14][CH2:15][CH:10]([C:8]([C:4]2[N:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: CN1CCC(C(=O)C2CCCC(Br)N2)CC1
Agent: N
Solvent: OCCO
Product: CN1CCC(C(=O)c2ccccn2)CC1
Temperature: 85 °C
Yield: 128.2 %

Procedure:
Load 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-piperidine (20 g, 70.67 mmol, 1 eq) in 73.6 ml of 7M NH3/ethylene glycol (530 mmol, 7.5 eq) into a 130 ml pressure autoclave, and add Cu2O (101 mg, 0.706 mmol, 0.01 eq) as a catalyst. Seal the autoclave and heat the reaction mixture to 85° C. at about 50 psi (345 kPa) for 20 hrs. Cool the reaction mixture to room temperature, transfer the organic layer to a 250 ml flask, and place the flask under reduce pressure to remove ammonia. Add water (70 mL) and of 30% NaOH (38 mL) and then extract the mixture with methyl t-butyl ether (MTBE)(5×100 ml). Combine the organic fractions and then dry with MgSO4, filter, and concentrate under reduce pressure to obtain crude 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (18.5 g).
Reaction SMILES: Br[C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[CH:7]([CH3:15])[CH2:6][CH2:5]2.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>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.O1CCOCC1>[CH3:15][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[C:3]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]1[C:12](=[O:14])[CH3:13]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccccc3)c2CCC1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)c(Oc3ccccc3)c2CCC1C
Temperature: 80 °C

Procedure:
A screw-cap vial equipped with a magnetic stir bar was charged with rac-1-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.024 g, 0.067 mmol), 4-(methylsulfonyl)phenylboronic acid (0.020 g, 0.100 mmol), 1,4-dioxane (0.67 mL), 1.0 M aqueous sodium bicarbonate (0.200 mL, 0.200 mmol), and bis(triphenylphosphine)palladium(II) chloride (4.7 mg, 6.7 μmol). The vial was flushed with nitrogen and then capped. The reaction mixture was then heated to 80° C. for 3 h and then cooled to room temperature. The reaction mixture was diluted with 5% aqueous sodium chloride solution (0.5 mL) and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were concentrated under reduced pressure to afford a dark brown residue, which was then purified by preparative thin layer chromatography (1×1000 micron plate; eluting with 3:2 ethyl acetate-hexanes). The major band was isolated (26 mg) and further purified by preparative HPLC to afford rac-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone. 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (d, J=6.60 Hz, 3H), 1.45 (br s, 1H), 2.07-2.24 (m, 1H), 2.27 (s, 3H), 2.29-2.37 (m, 1H), 2.71 (dt, J=16.13, 6.42 Hz, 1H), 3.01 (s, 3H), 4.79 (br s, 1H), 6.59-6.69 (m, 2H), 6.82-6.95 (m, 1H), 7.15 (t, J=7.70 Hz, 2H), 7.32 (br d, J=7.33 Hz, 2H), 7.65 (d, J=8.43 Hz, 2H), 7.84 (d, J=8.43 Hz, 2H). MS (ESI, pos. ion) m/z 436 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[O:9][C:4]=2[CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Reactant: BrCc1ccccc1
Product: CC1(C)OC(=O)c2ccc(OCc3ccccc3)cc2O1

Procedure:
7-Benzyloxy-2,2-dimethyl-benzo[1,3]dioxin-4-one was prepared from 7-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and benzyl bromide under conditions analogous to example 47-a. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.85 (d, J=8.5 Hz, 1H), 7.39 (m, 5H), 6.71 (dd, J=8.7, 2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 5.09 (s, 2H), 1.72 (s, 6H).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29](=O)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][C:23]=3[S:22][C:21]2=[O:37])=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[CH3:38][O:39][NH2:40]>>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29](=[N:40][O:39][CH3:38])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][C:23]=3[S:22][C:21]2=[O:37])=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(C)=O
Reactant: CON
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(C)=O)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.