Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:18][O:17]C(C)(C)[O:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:21])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[S:29]1(=[O:41])(=[O:40])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH2:33][NH:32][CH2:31][CH2:30]1.Cl>CN(C)C=O.CO>[O:41]=[S:29]1(=[O:40])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH2:33][N:32]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH:14]([OH:15])[CH2:18][OH:17])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:21])[CH:8]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: Cc1ccc2nc(Cl)nc(NCC3COC(C)(C)O3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC(O)CO)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
A solution of 2-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-methylquinazolin-4-amine (431.2 mg, 1.4 mmol) and triethylamine (0.8 mL), 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (296.1 mg, 1.5 mmol) in N,N-dimethyl-formamide (1.0 mL) was stirred at 160° C. for 4 hours. After being cooled to room temperature, the reaction mixture was dissolved in methanol (2.0 mL). To the above mixture, concentrated hydrochloric acid (0.5 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 59.2 mg of the product as a white solid (yield was 10%). MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.01 Hz, 1 H), 7.90 (d, J=7.58 Hz, 1 H), 7.66-7.55 (m, 2 H), 7.50-7.35 (m, 2 H), 7.35-7.28 (m, 1 H), 5.21 (brs, 2 H), 4.56 (brs, 2 H), 4.05-3.95 (m, 1 H), 3.86 (dd, J=13.26, 4.42 Hz, 1 H), 3.73-3.56 (m, 3 H), 3.53 (t, J=5.05 Hz, 2 H), 2.39 (s, 3 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CCCCC(F)(F)C(O)CC[C@@H]1[C@@H:20](CCCCCCC(O)=O)[C:18](=[O:19])[CH2:17][C@H:16]1[OH:30].C1CCC(NC2CCCCC2)CC1.[NH:47]([CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>C(Cl)Cl.CN1CCOCC1>[C:60]([O:59][C:57]([CH2:56][N:47]([CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:16](=[O:30])[C@@H:17]1[O:19][C@@H:18]1[CH3:20])=[O:58])([CH3:62])([CH3:63])[CH3:61]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Reactant: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H]1O[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
A solution of 11.6 g of oxalyl chloride in 25 ml of methylene chloride is added dropwise, in the course of 15 minutes, to a mixture, cooled to -25°, of 20 g of dimethylforinaniide and 115 ml of methylene chloride. The white suspension is stirred for a further 20 minutes at -25°, and a solution of 28.5 g of the dicyclohexylammonium salt of (2R,3R,)-2,3-epoxybutyric acid in 115 ml of methylene chloride is then added in the course of 10 minutes. The reaction mixture is stirred for a further 20 minutes at the same temperature, and a solution of 17.87 g of di-tert-butyl iminodiacetate in 90 ml of methylene chloride and 9.22 ml of N-methylmorpholine are then added dropwise simultaneously in the course of 15 minutes. The cooling bath is removed and the reaction mixture is stirred for 3 hours at room temperature. The white suspension is then filtered through a sintered glass suction filer, the residue is washed with methylene chloride, and the filtrate is diluted with methylene chloride and washed successively with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate solution and water. The aqueous phases are subsequently extracted twice with methylene chloride, and the combined organic phases are dried and evaporated under a water pump vacuum. The yellow-brown crude product is purified by flash chromatography over silica gel (Merck 9385) using a 9:1 mixture of methylene chloride and ethyl acetate as the mobile phase. (2R,3R)-N,N-Bis-(tert-butoxy-carbonylmethyl)-2,3-epoxybutyramide is obtained in the form of a pale yellow oil, [α]D =+52° (c=1.250% in chloroform).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23]>O1CCOCC1.C(OCC)(=O)C>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]1[CH:16]=[CH:17][N:18]=[C:3]1[C:2]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[N:11]2
Reactant: FC(F)(F)c1ccc2c(c1)nc(Cl)c1nccn12
Reactant: NCCCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2ccnc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.9 %

Procedure:
To a solution of 4-chloro-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline (2.00 g; 7.36 mmol; 1 eq) in anhydrous dioxane (250 mL), 3-aminopropanol (6.2 mL; 81.0 mmol; 11 eq) is added, under argon atmosphere. Complete conversion was achieved after 17 hours of stirring under reflux. The initially cloudy yellow solution turns first orange and then becomes translucid. The reaction mixture is cooled to room temperature and diluted in ethyl acetate (500 mL). The organic phase is washed three times with a solution of saturated sodium hydrogenocarbonate (3×330 mL). The organic phases are combined, dried over sodium sulfate and concentrated under vacuum to provide pure title compound (1.94 g; 6.25 mmol; 85%) as a grey powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.F[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([C:25]3[C:26]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:22]=[CH:23][CH:24]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: Fc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1cccc2ccccc12
Temperature: 145 °C
Reaction time: 36 h

Procedure:
Into a flask, 10.00 g of 3,6-dibromo-9H-carbazole, 4.1 ml of 1-fluoronaphthalene, 12.06 g of cesium carbonate, and 300 ml of dimethylsulfoxide were put, and the solution was stirred at 145° C. for 36 hours under nitrogen atmosphere. After heating, the reaction liquid was cooled to room temperature and then filtrated, and the filtrates were concentrated by a vacuum pump. The concentrates were purified by silica gel column chromatography, and then washed by methanol, and thus 5.5 g of 3,6-dibromo-9-naphthalene-1-yl-carbazole was obtained.
Reaction SMILES: C[O-].[Na+].CO[C:6]([C:8]1([NH:16][C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]([CH3:28])=[CH:21][C:20]=2[CH3:29])[CH2:13][CH2:12][N:11]([O:14][CH3:15])[CH2:10][CH2:9]1)=[O:7]>CN(C)C=O>[CH:25]1([C:23]2[C:22]([CH3:28])=[CH:21][C:20]([CH3:29])=[C:19]([C:18]3[C:17](=[O:30])[NH:16][C:8]4([CH2:9][CH2:10][N:11]([O:14][CH3:15])[CH2:12][CH2:13]4)[C:6]=3[OH:7])[CH:24]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)C1(NC(=O)Cc2cc(C3CC3)c(C)cc2C)CCN(OC)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON1CCC2(CC1)NC(=O)C(c1cc(C3CC3)c(C)cc1C)=C2O
Temperature: 65 °C
Yield: 23.9 %

Procedure:
To 1.3 g of sodium methoxide in 10 ml of dimethylformamide is added a solution of 3.2 g of crude 4-[2-(5-cyclopropyl-2,4-dimethyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester in 10 ml of dimethylformamide and the reaction mixture is heated to 65° C. for 2 hours. The mixture is poured into ice water, extracted with dichloromethane, the combined organic phases dried with sodium sulfate, filtered and concentrated. The residue is subjected to column chromatography (dichloromethane/methanol 95:5) to yield 700 mg of 3-(5-cyclopropyl-2,4-dimethyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one as a wax.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:22][N:21]=4)[C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:34]=1)=O.CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[OH:2][CH2:3][C:5]1[C:6]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:22][N:21]=4)[CH:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:34]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)(C)O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)C1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of (R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (109 mg, 0.196 mmol) in DCM (4 mL) was added a solution of DIBAL-H in DCM (0.98 mL of a 1.0 M solution, 0.98 mmol) dropwise at −78° C. The reaction slowly warmed to −10° C. over approximately 1 h, at which point 1 mL of MeOH was added to quench the excess DIBAL-H. Sat. aq. Rochelle salt (potassium sodium tartrate (KNaC4H4O6)) solution (5 mL) and DCM (5 mL) were added and the mixture stirred vigorously for 15 min. The DCM layer was separated and the aqueous layer was extracted with DCM (2×5 mL). The DCM layers were combined, dried using Na2SO4 and evaporated to give the crude product. Purification using ISCO FCC eluting with 70% EtOAc in Hexanes gave 71 mg of 2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol as a racemic mixture (69%). LC-MS MS (ESI) m/z 528.25 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.72 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 6.01 (d, J=7.6 Hz, 1H), 5.27 (d, J=4.4 and 14.0 Hz, 1H), 5.00-4.86 (m, 2H), 4.26-4.08 (m, 2H), 3.74-3.67 (m, 1H), 3.15 (s, 3H), 3.15-3.10 (m, 1H), 2.47-2.40 (m, 1H), 1.96 (b, 1H), 1.59 (s, 6H), 1.23 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:30]=[CH:29][C:15]2[C:16]3[C:24]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:22]=[CH:21][C:17]=3[O:18][C:19](=[O:20])[C:14]=2[C:13]=1[Br:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].CCCCCCC.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:30]=[CH:29][C:15]2[C:16]3[C:24]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:22]=[CH:21][C:17]=3[O:18][CH:19]([OH:20])[C:14]=2[C:13]=1[Br:31])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc2c(c1Br)c(=O)oc1cccc(OC(F)F)c12)OCc1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=C(Nc1ccc2c(c1Br)C(O)Oc1cccc(OC(F)F)c1-2)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 27D (0.52 g, 1.08 mmol) in dichloromethane (100 mL) at −78° C. was treated with disobutylaluminum hydride in heptane (1.30 mL, 1.30 mmol), stirred for 30 minutes at −78° C., and treated with ethyl acetate (10 mL) and sodium potassium tartrate (50 mL) to provide two layers. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)Q1MS) m/z 490 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([OH:19])[CH:16]=[C:17]([OH:18])[C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)(=O)[CH3:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:23][N:22]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([OH:19])[CH:16]=[C:17]([OH:18])[C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCc1c(O)cc(O)cc1S2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1)CCc1c(O)cc(O)cc1S2
Temperature: 120 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
In ethanol, 180 mg of 8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol (63) was dissolved, and an aqueous solution of 49 mg of hydroxylamine hydrochloride and 100 mg of sodium acetate dissolved in 1 mL of water was added thereto. The mixed solution was stirred at 120° C. for 3 hours, concentrated under reduced pressure and then, extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and then, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1). Upon recrystallization from chloroform-hexane, 120 mg of skin-colored amorphous title compound was obtained (yield 63%).
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:20])[CH2:7][C:6]2[C:8]([CH3:19])=[C:9]([NH:16]C=O)[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]=2[O:4]1.Cl.C(=O)(O)[O-].[Na+]>CO.O.C(OCC)(=O)C>[I:1][CH2:2][C:3]1([CH3:20])[CH2:7][C:6]2[C:8]([CH3:19])=[C:9]([NH2:16])[C:10]([CH3:15])=[C:11]([CH:12]([CH3:13])[CH3:14])[C:5]=2[O:4]1
Reactant: Cc1c2c(c(C(C)C)c(C)c1NC=O)OC(C)(CI)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CI)O2
Yield: 84.2 %

Procedure:
To a solution of N-[2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethylbenzofuran-5-yl]formamide (7.3 g) in methanol (40 mL) was added conc. hydrochloric acid (10 mL). The mixture was refluxed for 1.5 hours under nitrogen atmosphere, and poured into a suspension of sodium bicarbonate (20 g) in water and ethyl acetate The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, treated with activated carbon, filtrated and evaporated in vacuo. The residue was crystallized from hexane to afford 5.7 g of the title compound. Yield 84%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.[CH3:27][C:28]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][C:30]([CH3:37])([CH3:36])[CH2:29]2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[OH-].[Na+].Cl>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([N:33]2[CH2:34][C:28]3([CH3:27])[CH2:35][CH:32]2[CH2:31][C:30]([CH3:37])([CH3:36])[CH2:29]3)=[O:19])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCC(C(=O)N2CC3(C)CC2CC(C)(C)C3)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl) piperazin-1-yl]-2-phenylbutanoic acid (1.70 g, 5.0 mmole), 1,3,3-trimethyl-6-azabicyclo[3.2.1]-octane (0.77 g, 5.0 mmole), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 5.0 mmole) and triethylamine (0.55 g, 5.0 mmole) in methylene chloride (10 mL) was stirred at ambient temperature for 48 hr. The mixture was poured into 1N sodium hydroxide (75 mL) and extracted with ethyl acetate (3×75 mL). The combined ethyl acetate layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give crude product. This material was treated with 1.1 equivalent of 1N hydrogen chloride in ether (100 mL) to give 1.15 g of the title compound as the hydrochloride sequihydrate, m.p. 110°-145° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[Na+].[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.[OH-].[NH4+]>C(O)(=O)C>[N:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[N:10]/[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[CH:20][CH:19]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccncc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(N/N=C/c2ccncc2)c1

Procedure:
3-(Trifluoromethyl)phenylhydrazine (176 mg, 1 mmol) in 5 ml of acetic acid were treated with sodium acetate (164 mg, 2 mmol) and pyridine-4-carbaldehyde (0.11 ml, 1 mmol) during 1 h at 50° C. The yellow solution was cooled and ammonium hydroxide 25% was added, the solid was collected, washed with water and recrystallized from EtOAc:n-heptane. The title compound was obtained as a yellow solid (195 mg, 74%). MS: 266.1 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][O:16][C:17](=[O:25])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1COCC1.[Cl:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]I>CCCCCCC.C(OCC)(=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][O:16][C:17](=[O:25])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][Cl:33])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(NCCOCCO)OCc1c2ccccc2cc2ccccc12
Reactant: ClCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(NCCOCCOCCCCCCCl)OCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A 100 ml round bottom flask was charged with [2-(2-Hydroxy-ethoxy)-ethyl]-carbamic acid anthracen-9-ylmethyl ester (1.12 g, 3 mmol) and fresh sodium hydride, 60% dispersion in mineral oil (360 mg, 9 mmol) under inert atmosphere. 20 ml anhydrous THF was added and the reaction allowed to stir for 30 minutes. The flask is then cooled to between −10 and −20° C. by means of an ice/NaCl bath. When the temperature is reached 1-chloro-6-Iodohexane (1 ml, 6 mmol) is added via syringe. The reaction is maintained at ice/NaCl temperature for 2 hours, then slowly allowed to warm to room temperature overnight. At this point silica gel 60 is co-absorbed onto the reaction mixture with loss of solvent under reduced pressure. Silica gel chromatography takes place initially with heptane as eluent, followed by 10%, 20%, and 25% ethyl acetate. A total of 0.57 g (41% yield) of product is isolated from appropriate fractions: 1H NMR (CDCl3) δ 8.48 (s, H-10), 8.38 (d, H-1, 8), 8.01 (d, H-4, 5), 7.52 (dt, H-2, 3, 6, 7), 6.13 (s, CH2-anth), 5.29 (bs, exchangeable, NH), 3.74 (m, 4H), 3.55-3.15 (m, 8H), 1.84 (m, 4H), 1.61 (m, 1H), 1.43 (m, 1H), 1.25 (m, 2H). Mass spectrum, m/e Calcd for C26H32ClNO4.H2O: 475.21 (100%), 476.22 (29.6%). Found: 475.21, 476.52.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH3:21].C=O>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:21]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Agent: C=O
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A mixture of methanol (275 ml.) and 2-chloroacetamido-5-chlorobenzophenone (154.2 g., 0.5 mol) was heated to reflux with a steady stream of ammonia bubbling in. At reflux 37% formaldehyde solution (237 ml) was fed in over ca. 40 minutes. The reaction mixture was then heated under reflux for 5 hours. The flow of ammonia was stopped and the slurry of crystals was cooled to room temperature, filtered, washed with methanol (2 × 125 ml), hot water (4 × 500 ml) and dried. There was obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (104.6 g., 77.3%), melting at 211.5° to 214.5° C.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:12]1[N:13]=[C:14]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:15]2[S:20][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25](S(C)(=O)=O)[CH2:24][CH2:23]3)=[CH:18][C:16]=2[N:17]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:4]1[N:5]([C:12]2[N:13]=[C:14]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:15]3[S:20][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][C:16]=3[N:17]=2)[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncc[nH]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1nccn1-c1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 2-isopropylimidazole (28 mg) in dry N,N-dimethylformamide (1 ml) was added sodium hydride (10 mg, 60% dispersion in mineral oil). After 30 minutes, 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was added and the reaction mixture was heated in the microwave for 45 minutes at 120° C. The reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo and the residue purified using flash chromatography to yield 176. NMR (400 MHz CDCl3): 1.19 (1H, s, CH), 1.30 (6H, d(J=6.84), 2.61-2.63 (4H, m, CH2), 2.74 (3H, s, CH3), 3.23-3.25 (4H, m, CH2), 3.79-3.82 (6H, m, CH2), 3.92-3.94 (4H, m, CH2), 6.92 (1H, s, ar), 7.18 (1H, s, ar), 7.66 (1H, d(J=1.49), ar). MH+ 506.30
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1C)([O-:3])=[O:2].[N+](C1C=CC(C)=CC=1)([O-])=O.Br.[N+](C1C=CC=CC=1[C:27]([OH:29])=[O:28])([O-])=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.[Ti].C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:27]([OH:29])=[O:28])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [Co+2]
Agent: [Mn+2]
Agent: [Ti]
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1

Procedure:
In a modified procedure of Example VI, ortho-nitrotoluene (35 g), para-nitrotoluene (7 g), acetic acid (300 g), cobalt (II) acetate (1 g), manganese (II) acetate (1 g), zirconium (IV) diacetate oxide (0.125 g), and 48% hydrobromic acid (1.4 g) were charged into a one liter titanium autoclave. The para-nitrotoluene and acetic acid were added in a semi-continuous procedure, with an initial charge of 7 g and 300 g, respectively. The oxidation was initiated by introducing air into the reactor at an initial temperature of 295° F. and an initial pressure of 250 psig. During the oxidation, a solution consisting of 28 g para-nitrotoluene, to give a 1:1 gram ratio and 1:1 mol ratio of o-nitrotoluene and para-nitrotoluene, and 120 g of acetic acid were added semi-continuously. LC analysis of the slurry indicated that ortho-nitrobenzoic acid was formed in 69.1 mol % yield, while p-nitrobenzoic acid was produced in 82.7 mol % yield. Ortho-nitrotoluene (24.1 mol %), para-nitrotoluene (8.1 mol %), para-nitrobenzaldehyde (1.8 mol %), and para-nitrobenzyl acetate (0.8 mol %) were also detected. Details are in Table V.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1cc(-c2ccccc2)cn1
Solvent: ClCCl
Product: Cn1cc(-c2ccc(S(=O)(=O)Cl)cc2)cn1
Reaction time: 1 h

Procedure:
0.5 g of 1-methyl-4-phenyl-1H-pyrazole (3.16 mmol) were dissolved in 20 ml of dichloromethane. At 0° C., 0.232 ml of chlorosulfonic acid were added and the reaction mixture was stirred for 1 h under ice cooling. Additional 0.7 ml of chlorosulfonic acid were added, the mixture was stirred at 0° C. for 30 minutes and then 90 minutes at 50° C. The two phases were separated and the lower layer put on ice, extracted twice with diethyl ether, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 0.496 g of the product.