Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]2[S:3]1>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
Zinc powder (0.9 g) was added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (0.69 g), mp 120° to 130° C., in a mixture of dimethylformamide (5 ml) and acetic acid (1 ml), and the mixture was stirred for 1.5 hours, followed by filtration of the reaction mixture, after which the filtered zinc was washed with a small amount of dimethylformamide. The filtrate and the washings were combined and the combined solution was poured into a mixture of ethyl acetate (30 ml), water (30 ml) and 10% hydrochloric acid (2 ml), after which the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate (10 ml). The ethyl acetate layer was combined, and the combined solution was in turn washed with water, a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was distilled off. The residue was crystallized by adding a small quantity of acetonitrile, and the precipitated crystals were collected by filtration and dried to give 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid (0.34 g), mp 121° C., which is an isomer at 2 position of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid, mp 109° C. (dec.), which was obtained in Example 19.
Reaction SMILES: [CH2:1]([C:7]1[C:8](CO)=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([CH2:13]O)[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:33])=O.[CH2:35]([Cl:37])Cl>>[CH2:1]([C:7]1[C:8]([CH2:35][Cl:37])=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([CH2:13][Cl:33])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: ClCCl
Reactant: CCCCCCc1cc(CO)c(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1CO
Reactant: O=S(Cl)Cl
Product: CCCCCCc1cc(CCl)c(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A 250 mL 3 neck round-bottom flask equipped with a condenser was flushed with nitrogen and then loaded with 5-hexyl-1,4-bis(hydroxymethyl)-2,3-di(4-fluorophenyl)-benzene (1.35 g, 3.3 mmol), thionyl chloride (7 g, 58.8 mmol) and methylene chloride (10 mL) was stirred at room temperature for 1 hour, and then refluxed for an additional 2 hour, and finally stirred at room temperature overnight. The solvent was then removed by rotary evaporation to give a pale yellow oil (1.1 g, 74.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[OH:24])=[CH:4][CH:3]=1.I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[O:24][CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-ol (I-(4A-7)b; 50 mg, 0.14 mmol), 2-iodopropane (26 mg, 0.15 mmol), and cesium carbonate (50 mg, 0.15 mmol) were combined in dimethylformamide (0.7 ml) and stirred overnight. Additional 2-iodopropane (13 mg, 0.76 mmol), and cesium carbonate (25 mg, 0.76 mmol) were added and stirred an addional day. The reaction mixture was diluted with ethyl ether and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), evaporated to dryness, and then purified on a Biotage™ Flash 12S column using 0–70% ethyl acetate in hexanes as eluant to afford title compound 31A-1 (34 mg, 56%); 1H NMR: +ESI MS (M+1) 399.4; (400 MHz, CD2Cl2) δ 8.51 (s, 1H), 7.56 (dd, J=7.5, 1.7 Hz, 1H), 7.47–7.34 (m, 5H), 7.23 (d, J=9.1 Hz, 2H), 5.71 (septuplet, J=6.2 Hz, 1H), 1.50 (d, J=6.2 Hz, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Br[C:12]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([CH2:21][C:13]2[CH:12]=[CH:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=2)[CH:3]=1)=[O:7])[CH3:10]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cnn(Cc2ccc(C(=O)O)cc2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl pyrazole-4-carboxylate (500 mg, 3.57 mmol) and bromo-para-toluic acid (767 mg, 3.57 mmol) in acetone (10 ml) was added potassium carbonate (2.465 g, 17.84 mmol). The suspension was stirred at 50° C. overnight. Water was added to the reaction, and the aqueous phase was washed with ethyl acetate. The pH of the aqueous phase was acidified with 1M hydrochloric acid, and the product was extracted with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (method G) Rt=1.642 min; UPLC (method F) Rt=0.69 min, [M+H]+275.3 [M−H]− 273.3.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:10](=[O:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([CH:14]([CH3:16])[CH3:15])[O:5][C:4]=2[CH:3]=1.O.[OH-].[Na+].Cl>C(OC)(C)(C)C>[OH:5][C:4]1[CH:3]=[C:2]([CH3:1])[O:11][C:10](=[O:12])[C:9]=1[C:8](=[O:13])[CH:7]=[CH:6][CH:14]([CH3:15])[CH3:16]
Reactant: Cc1cc2c(c(=O)o1)C(=O)CC(C(C)C)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Reaction time: 4 h
Yield: 43.4 %

Procedure:
To a mixture of 189 mg of 2,3-dihydro-7-methyl-2-(1-methylethyl)- 4H, 5H-pyrano[4,3-b]pyran-4,5-dione, 4mloftoluene and 4 ml of water, 0.20 g of sodium hydroxide was added and stirred. After 4 hours, methyl t-butyl ether and 3% hydrochloric acid were added to the reaction mixture. The separated organic layer was washed with saturated brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 82 mg of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:23]([C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)(=[O:25])=[O:24]
Reactant: COc1ccccc1N
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1NS(=O)(=O)c1cccnc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
o-Anisidine (377 mg, 3.0 mmol) was dissolved in toluene (10 ml) to which were subsequently added pyridine (0.48 ml, 6.0 mmol) and 3-pyridinesulfonylchloride hydrochloride (642 mg, 3.0 mmol) at room temperature. After 1.5 hours of stirring at 100° C., the resulting reaction solution was mixed with water (20 ml), adjusted to pH 7 to 8 with anhydrous sodium carbonate, extracted with ethyl acetate and then washed with water and saturated brine. After drying on anhydrous sodium carbonate and removing the solvent by evaporation, the resulting orange solid was purified by a silica gel column chromatography (ether:hexane=3:1) to obtain a light orange solid which was subsequently washed with an ether-hexane (1:3) mixture solution to obtain 662 mg (83.5%) of the title compound in the form of colorless prism crystals.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([CH2:19][CH2:20][CH2:21][C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:23]=3)=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:33]N1C(=O)CCC1=O>C1COCC1>[Br:33][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([CH2:19][CH2:20][CH2:21][C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=4)=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCc3nc(-c4ccccc4)no3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCCc3nc(-c4ccccc4)no3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
To the solution of 9-pentyl-3-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.50 g, 1.16 mmole) in THF (125 ml) at room temperature was added N-bromosuccinimide (0.309 g, 1.73 mmole). The mixture was stirred at 70° C. for 1 h. The mixture was concentrated and purified by preparative LCMS to yield the desired product (122 mg, 21% yield). LCMS calculated for C22H24BrN8O2 (M+H): 511.1. found: 511.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[C:11]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CCCCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCCCC#Cc1ccc(CNCCc2cccc(Cl)c2)cc1
Product: Cl
Yield: 50 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using [2-(3-chlorophenyl)ethyl]amine and 4-dodec-1-ynylbenzaldehyde gave the title compound as a white powder (50%). 1H NMR (DMSO-dr, 300 MHz) δ 9.27 (br s, 1H), 7.51-7.24 (m, 8H), 4.15 (br s, 2H), 3.14 (br s, 2H), 2.98 (m, 2H), 1.99 (m, 2H), 1.55-1.40 (m, 16H), 0.85 (t, 3H, J=6.6 Hz). M−(LC/MS(ESI)): 411. HPLC (Condition A), Rt: 5.30 min (HPLC purity: 99.9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH:17][CH2:18][CH3:19])=[N:7][C:6]=1[CH3:20])[CH3:2].[N:22]([O-])=O.[Na+]>>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]2[N:16]=[N:22][N:17]([CH2:18][CH3:19])[C:8]2=[N:7][C:6]=1[CH3:20])=[O:21])[CH3:2]
Reactant: O=N[O-]
Reactant: CCCCNc1c(N)c(NCC)nc(C)c1C(=O)OCC
Agent: [Na+]
Product: CCCCNc1c(C(=O)OCC)c(C)nc2c1nnn2CC
Yield: 73 %

Procedure:
5-Amino-4-butylamino-6-ethylamino-2-methylnicotinic acid ethyl ester is treated with sodium nitrite following the procedure of Example 3c. 7-Butylamino-3-ethyl-5-methyl-3H-[1,2,3]-triazolo[4,5-b]pyridine-6-carboxylic acid ethyl ester is obtained, yield 73%, m.p. 42°-43°. Treatment with 2N hydrochloric acid in ethanol yields the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1([CH3:50])[O:47][C@@H:46]([CH2:48]O)[CH2:45][O:44]1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C(OCC)(=O)C.C1COCC1>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([O:21][CH2:48][C@H:46]5[CH2:45][O:44][C:43]([CH3:50])([CH3:42])[O:47]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Reactant: CC1(C)OC[C@H](CO)O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
Under nitrogen atmosphere, 3-bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ2, 356 mg, 1.00 mmol) and triphenylphosphine (317 mg, 1.2 eq.) were added with THF (3 ml), followed by dropwise addition of ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (148 μl, 1.2 eq.) and diisopropyl azodicarboxylic acid (252 μl, 1.3 eq.). The mixture was then stirred at 50° C. for 2 hr. After cooling, the reaction solution was added with ethyl acetate, washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to yield the solid, which was then washed with dichloromethane to obtain the title compound (white powder, 241.6 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13].[CH2:16](I)[CH3:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][N:10]=[C:9]1[S:15][CH2:16][CH3:17]
Reactant: NC(=O)CNC(=S)Nc1ccccc1Cl
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccccc1Cl
Yield: 65.9 %

Procedure:
A mixture of 2-[3-(2-chlorophenyl)-thioureido]-acetamide (12.2 g), ethyl iodide (15.6 g), and ethanol (200 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with water (2×300 mL). The organic phase was then extracted with 2N HCl (2×500 mL). The acid extract was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous MgSO4 then evaporated to dryness. The residue was dissolved in ethanol and the solution was saturated with hydrogen chloride. The solvent was evaporated and the residue was crystallized from ethyl acetate to give the hydrochloride salt of the title compound (8.4 g) as an off-white solid, m.p. 149°-150° C. (dec.). Anal. Calcd. for. C11H11Cl N2O S. HCl: C, 45.37; H, 4.15; N, 9.62. Found: C, 44.97; H, 4.06; N, 9.51. Mass spectrum (EI, M.+) m/z 254/256. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.69 (m, 1H), 7.50-7.58 (m, 3H), 4.45 (q, 2H), 3.11-3.17 (m, 2H), and 1.27 ppm (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: O=C(O)Cc1ccccc1Nc1cccc([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-nitroaniline to yield 2-[(3-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.ClCCl.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>O>[CH3:19][S:20]([O:7][CH2:6][CH:4]1[CH2:5][C:2]([F:8])([F:1])[CH2:3]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(F)(F)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
1.35 g (11.06 mmol) of (3,3-difluorocyclobutyl)methanol were initially charged in 41.8 ml of abs. dichloromethane, 3.08 ml (22.11 mmol) of triethylamine and 1.03 ml (13.27 mmol) of methanesulphonyl chloride were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the filtrate was concentrated. This gave 2.37 g (quantitative yield) of the target compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][C:13]([NH:17][CH2:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)([CH3:21])[CH3:20])=[CH:14][C:15]=2[CH3:16])=[CH:6][C:3]=1[C:4]#[N:5].OO.C([O-])([O-])=[O:32].[K+].[K+]>CS(C)=O.CCOC(C)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:20])([CH3:21])[CH2:18][NH:17][C:13]2[N:12]=[N:11][C:10]([C:7]3[CH:6]=[C:3]([CH:2]=[CH:9][CH:8]=3)[C:4]([NH2:5])=[O:32])=[C:15]([CH3:16])[CH:14]=2)=[CH:23][CH:24]=1
Reactant: Cc1cc(NCC(C)(C)c2ccc(F)cc2)nnc1-c1ccc(F)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(NCC(C)(C)c2ccc(F)cc2)nnc1-c1cccc(C(N)=O)c1
Yield: 50.4 %

Procedure:
A 0° C. solution of 2-fluoro-5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-4-methylpyridazin-3-yl)benzonitrile (0.80 g, 2.2 mmol, 1.0 equiv), 30% hydrogen peroxide (0.45 mL, 4.4 mmol, 2.0 equiv), and K2CO3 (600 mg, 4.4 mmol, 2.0 equiv) in DMSO (9.0 mL) was stirred for 1 hour. The mixture was diluted with EtOAc, washed with saturated NaCl, water and saturated NaCl again, and then dried over Na2SO4. Purification by reverse phase HPLC using a gradient of 20-70% CH3CN/water gave the desired product (420 mg, 51%) as a yellow solid. m/z=379.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][NH:49][CH2:50][C:51]1[CH:64]=[CH:63][C:54]([CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)=[CH:53][CH:52]=1>C(Cl)Cl>[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][C:54]2[CH:63]=[CH:64][C:51]([CH2:50][N:49]([CH3:48])[C:21]([C:19]3[N:20]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:17][CH:18]=3)=[O:23])=[CH:52][CH:53]=2)[CH2:57][CH2:58]1
Reactant: CNCc1ccc(CN2CCC(O)CC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(O)CC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (35 mg, 0.12 mmol), EDCI (26 mg, 0.14 mmol), HOBt (20 mg, 0.15 mmol) DIPEA (0.035 mL, 0.2 mmol), 1-{4-[(methylamino)methyl]benzyl}piperidin-4-ol dihydrochloride (32 mg, 0.14 mmol) and DCM (10 mL).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:28].[CH3:40][NH2:41]>>[F:37][C:36]([F:39])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:41][CH3:40])[CH2:7][CH2:8]2)=[CH:31][CH:32]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: CN
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNCCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-trifluoromethyl-phenyl chloroformate were reacted, followed by treatment with methylamine to give trans-Methyl-[4-(5-methylamino-pentyl)-cyclohexyl]-carbamic acid 4-trifluoromethyl-phenyl ester, MS: 401 (MH+).
Reaction SMILES: [Na].[C:2]([S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)(=O)[CH3:3].[N+:13](CCOC(=O)C)([O-:15])=[O:14]>C(O)C>[N+:13]([CH2:3][CH2:2][S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)([O-:15])=[O:14]
Reactant: CC(=O)OCC[N+](=O)[O-]
Reactant: CC(=O)SC1C=CCCCC1
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])CCSC1C=CCCCC1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To 40 ml of absolute ethanol was added 1.38 g (0.060 gram atom) metallic sodium. When the reaction was completed, 10.2 g (0.060 mole) of 3-acetylmercaptocycloheptene in 20 ml of absolute ethanol was added and the reaction mixture was brought up to reflux for 15 minutes. The solution was then cooled to 0° and 7.98 g (0.060 mole) of 1-nitro-2-acetoxyethane in 20 ml absolute ethanol was added. The reaction was allowed to proceed for 3.0 hours at 0° and then was partitioned between 1 N HCl and methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic phases were pooled, dried over sodium sulfate, and evaporated to afford 12 g (99%) of pure 3-[2-nitroethylthio]cycloheptene as a colorless oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([C:18]2[C:19]3[CH:20]=[CH:21][C:22]([C:38]([O:40][CH3:41])=[O:39])=[CH:23][C:24]=3[N:25]3[CH2:31][C@H:30]([OH:32])[C@H:29](O)[C:28]4[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=4[C:26]=23)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:12]1([C:18]2[C:19]3[CH:20]=[CH:21][C:22]([C:38]([O:40][CH3:41])=[O:39])=[CH:23][C:24]=3[N:25]3[CH2:31][C:30](=[O:32])[CH2:29][C:28]4[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=4[C:26]=23)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Yield: 61.9 %

Procedure:
p-Toluenesulfonic acid (50 mg, 0.29 mmol) was added to methyl 13-cyclohexyl-6,7-dihydro-(5R,6S)-rel-5,6-dihydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (100 mg, 0.25 mmol) in 50 mL of dry toluene. The solution was heated under reflux for 18 hr with removal of water using a Dean-Stark trap. The solution was diluted with ethyl acetate and washed with brine (3×) and dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified utilizing a Biotage apparatus with a prepacked silica column and using gradients of hexanes:ethyl acetate of from (98:2) to (85:15) to afford the product as a light yellow solid (60 mg, 62%). ESI-MS m/z 388 (MH+); 1H NMR (500 MHz, CHLOROFORM-D) δ 1.22-1.68 (m, 4 H) 1.73-1.83 (m, 2 H) 1.91-1.99 (m, 1 H) 2.02-2.15 (m, 3 H) 2.95 (m, 1 H) 3.57 (d, J=14.04 Hz, 1 H) 3.84 (d, J=14.04 Hz, 1 H) 3.95 (s, 3 H) 4.44 (d, J=18.01 Hz, 1 H) 4.96 (d, J=18.01 Hz, 1 H) 7.35 (d, J=7.63 Hz, 1 H) 7.43 (m, 1 H) 7.48 (t, J=7.32 Hz, 1 H) 7.54 (m, 1 H) 7.81 (d, J=8.55 Hz, 1 H) 7.92 (d, J=8.55 Hz, 1 H) 8.09 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-])=O.[H][H]>[Ni].C(O)C>[F:20][C:19]([F:22])([F:21])[C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:1][C:4]=2[CH:18]=1
Reactant: [H][H]
Reactant: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1)N=Cc1ccccc1O2

Procedure:
A solution of 55 parts of the ether obtained in the preceding paragraph in 800 parts of ethanol is hydrogenated over Raney nickel catalyst at room temperature and atmospheric pressure. When hydrogen uptake ceases the catalyst is removed by filtration and the ethanol solvent is evaporated. The residue is then dissolved in 500 parts by volume of hexane, filtered, and then cooled. There is then obtained yellowish-white crystals which are separated by filtration to give 8-trifluoromethyl-dibenz[b,f][1,4]oxazepine melting at about 86°-88° C.