Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N+:14]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O>[Ni].CO>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[NH2:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1C2CN(Cc3ccccc3)CC21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: NC1C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.3 %

Procedure:
To a mixture of 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane (4.00 g) and a catalytic amount of Raney nickel in MeOH was added slowly a solution of 98% H2NNH2—H2O (70 mL) at rt. The mixture was stirred for 5 h at room temperature and filtered. The filtrate was concentrated in vacuo to give the title compound as brown oil (3.60 g) and the crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.3 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([NH:6][C:5]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:4]=1[C:1](=[O:3])[CH3:2])=[O:21]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: O=C(Cl)c1ccco1
Product: COc1cc(NC(=O)c2ccco2)c(C(C)=O)cc1OC
Yield: 99 %

Procedure:
2-Acetyl-4,5-dimethoxyaniline (300 mg) and 2-furoyl chloride (260 mg) were reacted in the same manner as in the preparation of compound 95 to obtain N-(2-furoyl)-2-acetyl-4,5-dimethoxyaniline (440 mg). The compound (380 mg) and potassium t-butoxide (740 mg) were reacted in the same manner as in the preparation of compound 95 to obtain 6,7-dimethoxy-2-(2-furyl)-4(1H)-quinolone (compound 94, 30 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1>CCO>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:1][C:2]3[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1cccc(O)c1
Solvent: CCO
Product: Oc1cccc(Nc2ccnc3cc(Cl)ccc23)c1
Yield: 180.2 %

Procedure:
3-aminophenol (5.00 g, 25.25 mmol) and 4,7-dichloroquinoline (2.76 g, 1 eq) were refluxed overnight in 5 mL of EtOH. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 9:1:0.1) to yield expected compound as a pale yellow solid (6.8 g, 99% yield). LC-MS: m/z (ESI) 271.2 [M+H]+;
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21](N)=[O:22].S(=O)(=O)(O)[OH:25]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:22])=[O:25]
Reactant: NC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: O=S(=O)(O)O
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl

Procedure:
2.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide and 10 g of 63 % sulfuric acid are heated for 1.5 hours at 100° C. and prepared in accordance with example 2. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained: F 179.5°-181°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][C:29]([CH3:31])=[CH:30][C:26]=2[CH:25]=1)=[O:23]>C(Cl)Cl>[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][C:29]([CH3:31])=[C:30]([C:15](=[O:16])[C:14]3[CH:18]=[CH:19][C:11]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:12][CH:13]=3)[C:26]=2[CH:25]=1)=[O:23]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc2oc(C)cc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(C)c(C(=O)c3ccc(-c4ccccc4)cc3)c2c1
Yield: 118.7 %

Procedure:
Aluminum chloride (0.80 g) was stirred in methylene chloride (10 ml) at room temperature. Thereto was added 4-phenylbenzoyl chloride (0.67 g), and then a solution of 5-(methoxycarbonyl)-2-methylbenzo[b]furan (0.67 g) in methylene chloride (5 ml), and the mixture was stirred for 4 hr. Ice was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and saturated brine (once), dried over sodium sulfate and concentrated to give the objective compound (1.36 g).
Reaction SMILES: O=[C:2]1[CH:7]([C:8](OCC)=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.Cl.[CH:21]([NH2:23])=[NH:22].CC[O-].[Na+]>CCO>[OH:9][C:8]1[C:7]2[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3][C:2]=2[N:22]=[CH:21][N:23]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(O)ncnc2C1
Yield: 53.5 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.00 g, 7.39 mmol) in EtOH (37 mL) was added formamidine hydrochloride (910 mg, 11.08 mmol) followed by NaOEt (6.89 mL, 2.68 M in EtOH) dropwise. The mixture was then heated to reflux overnight. The mixture was concentrated in vacuo and then dissolved in a minimum amount of water. The pH was adjusted to pH 7 with 1 N HCl. The aqueous layer was then saturated with solid NaCl and extracted with a combination of EtOAc and DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 eluting with IPA/EtOAc afforded the desired product as a white solid (993 mg, 53%). MS (ESI) mass calcd. C12H12N3O3, 251.13. m/z found 252.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.05 (s, 1H), 4.42 (s, 2H), 3.69-3.61 (m, 2H), 2.63 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH2:25][O:26][CH3:27])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:28][CH2:29][CH2:30][CH3:31])[CH:13]=2)[CH:8]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)(=O)=O.[C-:41]#[N:42].[Na+]>CN(C=O)C>[C:41]([CH2:6][CH:7]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH2:25][O:26][CH3:27])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:28][CH2:29][CH2:30][CH3:31])[CH:13]=2)[CH:8]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)#[N:42]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(COS(C)(=O)=O)C2c1ccc2c(c1)OCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(CC#N)C2c1ccc2c(c1)OCO2
Yield: 85.5 %

Procedure:
(1RS,2RS,3RS)-2-Methanesulfonyloxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (1.5 g, 2.96 mmol) was stirred in DMF (10 ml) under argon with NaCN (1.45 g, 29.6 mmol) at 60° C. for 20 h then cooled and partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to afford the title compound as an oil (1.27 g, 86%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1cccc(F)c1
Product: CCOC(=NC(=O)c1cccc(F)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and m-fluorobenzoyl chloride, there is obtained ethyl N-(m-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 388 (3), 359 (13), 194 (100), 123 (46), 95 (36);
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[C:14]([N:21]([CH3:33])[C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>O1CCCC1>[C:17]([O:16][C:14]([N:21]([CH3:33])[C@@H:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]([O:32][CH2:2][C:3]#[N:4])=[O:31])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: N#CCCl
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)OCC#N
Reaction time: 12 h
Yield: 89 %

Procedure:
Chloroacetonitrile (1.1 mL) and DIPEA (258 mg, 0.341 mL, 1.99 mmol) were added to Boc-MePhe-OH (497 mg, 1.78 mmol) in tetrahydrofuran (5 mL) and stirred for 12 h. The solvent was removed under reduced pressure and SiO2 flash chromatography (20-35% ethyl acetate in hexanes) afforded 505 mg of a pale yellow oil in 89% yield. Rf 0.3 in 20% ethyl acetate in hexanes; 1H NMR (500 MHz, CDCl3): δ 7.28-7.25 (m, 2H), 7.20-7.16 (m, 3H), 4.72-4.68 (m, 2H), 4.53-4.52 (m, 1H), 3.27 (m, 1H), 3.11-3.02 (m, 1H), 2.67 (d, J=17 Hz, 3H), 1.36 (d, J=12 Hz, 9H); 13C NMR (125 MHz, CDCl3): δ 169.9, 155.5, 136.8, 128.9, 128.6, 128.4, 126.8, 126.7, 114.2, 80.8, 61.5, 48.7, 35.4, 33.0, 28.1; HRMS (ESI) m/z calcd for C17H22N2O4Na [M+Na]+ 341.147. found 341.149.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6](=[O:18])[C:5]2=[O:19].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>C1COCC1>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:6](=[O:18])[C:5]([C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:8]=1[NH:7][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(=O)c2cc(I)ccc21
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1C(=O)C(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
62.41 g of tert-butyl 5-iodo-2,3-dioxo-2,3-dihydroindole-1-carboxylate are dissolved in dried THF, and 18.98 ml of isoindoline are added. The mixture is stirred at 25° C. for 30 min, evaporated to dryness in vacuo, and the residue is triturated with petroleum ether, filtration gives 82.3 g of tert-butyl {2-[2-(1,3-dihydroisoindol-2-yl)-2-oxoacetyl]-4-iodophenyl}carbamate (beige solid);
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH3:20][NH:21][C:22]1[C:26]([CH:27]=O)=[CH:25][N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]=1.O>CN(C)C=O>[CH3:20][NH:21][C:22]1[C:26](/[CH:27]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:25][N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CNc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC)OCC
Reaction time: 0.25 h

Procedure:
To a solution (5 mL) of tetraethyl methylenediphosphonate in N,N-dimethylformamide was added sodium hydride (60% in oil, 8.8 mg) at room temperature, and the mixture was stirred for 15 min. 3-(Methylamino)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.00 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was stirred at room temperature for 2 hrs, and stood still for 16 hrs. The precipitated pale-yellow needle crystals were collected by filtration. The obtained crystals were recrystallized from ethyl acetate-hexane to give diethyl {(E)-2-[3-(methylamino)-1-phenyl-1H-pyrazol-4-yl]ethenyl}phosphonate as pale-yellow needle crystals (1.45 g, yield 87%). melting point: 132-133° C.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)=[CH:23][C:22]=1[C:39]([F:42])([F:41])[F:40]>CCO.CC(O)=O.[Zn]>[F:1][C:2]([F:43])([F:44])[C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[CH:23][C:22]=1[C:39]([F:42])([F:41])[F:40]
Reactant: O=C(Nc1ccc(-c2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2C(F)(F)F)c(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccc(-c3ccc(NC(=O)c4ccc(N)cc4)cc3C(F)(F)F)c(C(F)(F)F)c2)cc1

Procedure:
The prepared precursor, DA167, i.e., N,N′-(2,2′-bis(trifluoromethyl)-[1,1′-biphenyl]-4,4′-diyl)bis(4-nitrobenzamide) (6.18 g, 0.01 mol) is dissolved in the mixture of solvents EtOH/AcOH (100/20 mL) at mild reflux. Zinc (Zn) powder (6.54 g, 0.1 mol) is carefully added in 1 portion, which is extremely exothermic, thus 2 liter (L) high-beaker is recommended to be used. The mixture is immediately bubbled up within several seconds, and then clear colorless solution is formed. The mixture is refluxed for additional 10 minutes or more and filtered hot to remove unreacted zinc. The solution is poured into H2O (300 mL), resulting in white precipitate. Precipitate is filtered and thoroughly washed with H2O (2×300 mL) by suspension-filtration procedure to remove traces of mother liquor and zinc salts. Filtration of solid and drying under vacuum at 90° C. for 12 hours yields white powder of N,N′-(2,2′-bis(trifluoromethyl)-[1,1′-biphenyl]-4,4′-diyl)bis(4-aminobenzamide), DA168 4.1 g (yield 73.5%). 1H NMR 300 MHz of DA168 are as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([NH:44][CH2:45][CH2:46][F:47])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][NH:44][CH2:45][CH2:46][F:47])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: O=C(CCl)NCCF
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCNCCF)c(F)c2)C(C)C)c1
Yield: 22.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 2-chloro-N-(2-fluoroethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (5.8 mg) was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Br:6][C:7]1[C:8]([Cl:17])=[N:9][CH:10]=[C:11]([S:13](Cl)(=[O:15])=[O:14])[CH:12]=1>C(Cl)Cl.N1C=CC=CC=1>[N:2]1([S:13]([C:11]2[CH:12]=[C:7]([Br:6])[C:8]([Cl:17])=[N:9][CH:10]=2)(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: C1CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1cnc(Cl)c(Br)c1)N1CCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 37.3 %

Procedure:
Azetidine hydrochloride (0.32 g, 3.44 mmol) was added to a solution of 3-bromo-2-chloropyridine-5-sulfonyl chloride (1 g, 3.44 mmol) in DCM (4 mL) and pyridine (10 mL) and stirred at RT for 22 hours. The solvent was removed in vacuo and ethyl acetate (30 mL) added. The organic phase was washed with 1M hydrochloric acid (20 mL), water (20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound (0.4 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[CH:24]=[N:23]2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=4)[C:25]=3[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 64 %

Procedure:
The compound was prepared from 4-trifluoromethylphenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 77 mg (64%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.45 (s, 0.8H), 7.62 (d, J=7.8 Hz, 2H), 7.55 (s, 0.2H), 7.40-7.49 (m, 4H), 7.15 (m, 2H), 4.08 (s, 0.3H), 3.96 (m, 2H), 3.75 (m, 1.7H), 2.80-2.86 (m, 2H), 2.00 (m, 2H); MS: (ES) m/z calculated for C21H18F4N3O [M+H]+ 404.1, found 404.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccs1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccs4)nc23)CC1
Yield: 35.5 %

Procedure:
Beginning with 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.056 mL (0.52 mMol) 2-thiophenecarbonyl chloride, 0.052 gm (34%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16](O)=[O:17])=[C:9]([Cl:13])[C:10]=2[Cl:12])[CH2:5][CH2:4][CH:3]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.S(Cl)(Cl)=O.Cl.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>C1C=CC=CC=1>[CH2:29]([N:31]([CH2:32][CH3:33])[C:16](=[O:17])[CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[C:10]([Cl:12])[C:9]=1[Cl:13])[C:2](=[O:1])[CH:3]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:4][CH2:5]2)[CH3:30]
Reactant: CCNCC
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Agent: Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Reaction time: 1 h

Procedure:
The product of Example I, Step 5 (4.0 g., 0.02 mole) is added to thionyl chloride (11 g.) and the mixture is refluxed until HCl and SO2 are no longer evolved (about 1 hour). The excess thionyl chloride is evaporated. The residue is dissolved in benzene and a solution of diethylamine (3.6 g., 0.05 mole) in benzene is added. The mixture is kept for 1 hour and then evaporated to dryness. The residue is washed with water, 10% sodium bicarbonate and with water and airdried to obtain N,N-diethyl-(1-oxo-2-cyclopentyl-7,8-dichloro-1,2,3,4-tetrahydro-6-naphthyloxy)acetamide.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Cl-].[NH4+]>C(O)C>[CH3:14][CH2:13][O:12][C:5]([C:6]([CH2:1][C:2]([CH3:4])=[O:3])=[O:8])=[O:11]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(C)=O

Procedure:
Ethyl acetopyruvate was prepared from acetone and diethyl oxalate as described in Org. Synthesis, Coll. Vol. 1, 238 (1958). Further reaction with triethylorthofcrmate and ammonium chloride in ethanol. afforded the known enol ether 1. See L. Claisen, Chem. Ber., 40, 3903 (1907).
Reaction SMILES: C([C:5]1[N:6]([CH2:17][C@@H:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][CH:8]=2)(C)(C)C.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[CH3:23][C:20]1([CH3:24])[O:19][CH:18]([CH2:17][N:6]2[C:7]3[C:12](=[CH:11][C:10]([NH2:14])=[CH:9][CH:8]=3)[CH:13]=[CH:5]2)[CH2:22][O:21]1
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)C)cc3cc([N+](=O)[O-])ccc32)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1(C)OCC(Cn2ccc3cc(N)ccc32)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.4 %

Procedure:
To a stirred solution of (R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-nitro-1H-indole (1.0 g, 3.0 mmol) in ethanol (20 mL) and water (5 mL) was added ammonium formate (0.76 g, 12 mmol) followed by slow addition of 10% palladium on carbon (0.4 g). The mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a plug of celite and rinsed with ethyl acetate. The filtrate was evaporated under reduced pressure and the crude product was dissolved in ethyl acetate. The organic layer was washed with water (2×5 mL) and brine (2×5 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give (R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl-1H-indol-5-amine (0.89 g, 98%). 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J=4 Hz, 1H), 6.70 (d, J=2.2 Hz, 1H), 6.48 (dd, J=2.2, 8.6 Hz, 1H), 6.05 (s, 1H), 4.38-4.1 (m, 2H), 4.21 (dd, J=7.5, 16.5 Hz, 1H), 3.87 (dd, J=6.0, 8.6 Hz, 1H), 3.66 (dd, J=6.0, 8.6 Hz, 1H), 3.33 (br s, 2H), 1.40 (s, 3H), 1.34 (s, 9H), 1.25 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C=O)C.S(Cl)([Cl:22])=O>>[Cl:22][C:8]1[C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1

Procedure:
To a solution of 7-nitroquinazolin-4(3H)-one (2.0 g, 10.5 mmol) in 40 ml thionyl chloride was added 0.8 ml of DMF and the mixture was heated at reflux overnight then evaporated to dryness to provide crude 4-chloro-7-nitroquinazoline.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[N:15]=[CH:14][C:13](B(O)O)=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[OH2:19].OO>C1COCC1.[Cl-].[Na+].O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[N:15]=[CH:14][C:13]([OH:19])=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: OB(O)c1cnc(CCCCn2ccnn2)nc1
Reactant: O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnc(CCCCn2ccnn2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-[1,2,3]Triazol-1-yl-butyl)-pyrimidine-5-boronic acid (0.099 g, 0.40 mmol) is dissolved in THF (0.5 ml) and water (0.5 ml) and hydrogen peroxide (30 wt %) (0.054 g, 0.48 mmol) is added. After stirring the solution at r.t. for 2 h, brine (3 ml) is added and the mixture is extracted with THF (2×10 ml). The combined organic phases are dried over MgSO4 and concentrated in vacuo yielding 2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidin-5-ol as a off-white solid. Yield 85 mg (97%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH3:13]O.S(=O)(=O)(O)O>O>[CH3:13][O:11][C:10]([C:2]1[CH:3]=[CH:4][C:5]([C:7]([OH:9])=[O:8])=[CH:6][N:1]=1)=[O:12]
Reactant: CO
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cn1

Procedure:
A mixture of pyridine-2,5-dicarboxylic acid (8.4 g), methanol (100 ml) and concentrated sulphuric acid (1.7 ml) was heated at reflux for 2 hours, cooled and poured into water (11). The resultant precipitate was collected and recrystallised from ethanol to give the title compound as a white solid, m.p. 222-223° C.