Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O>CO>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH3:2])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Product: COC(=O)c1[nH]c2ccc(C)cc2c1Sc1ccc(Cl)cc1
Yield: 90 %

Procedure:
Following the method used to prepare 24a, the use of 1b (0.51 g, 1.60 mmol) and oxalyl chloride (0.32 mL, 3.65 mmol) followed by allowing the intermediate acid chloride to react with MeOH (5 mL) provided 0.95 g (90%) of product 7 as a white solid, mp 230-233° C. 1H NMR (300 MHz, DMSO-d6) δ 2.34 (s, 3H), 3.84 (s, 3H), 7.05 (d, J=8 Hz, 2H), 7.16-7.20 (m, 1H), 7.25-7.28 (m, 3H), 7.45 (d, J=8 Hz, 1H), 12.41 (s, 1H). LC-MS (CI): m/z 332.1 [(M+H)+ C17H14ClNO2S requires 331.04]. Purity (100%). Calcd for C17H14ClNO2S.0.2H2O: C, 60.87; H, 4.33; N, 4.18; S, 9.56; Cl, 10.57. Found: C, 60.89; H, 4.08; N, 4.14; S, 9.81; Cl, 10.77.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[CH3:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>CO>[CH3:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Reactant: COC(=O)C(C)(C)CN
Solvent: CO
Product: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Temperature: 150 °C
Yield: 81.3 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (50 mg, 0.13 mmol) and 3-amino-2,2-dimethyl-propionic acid methyl ester (52 mg, 0.40 mmol) in MeOH (2 mL) was heated at 150° C. in a microwave reactor for 3 h. The solvent was evaporated, and the residue was purified by column chromatography (0-40% EtOAc/hexanes+2% AcOH) to give 46 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ ppm=14.0 (s, 1H), 8.20-8.35 (m, 2H), 7.87 (d, 1H, J=1.2 Hz), 6.40-6.70 (m, 6H), 3.79 (s, 3H), 3.61 (d, 2H, J=7.0 Hz), 1.30 (s, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=O.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:2]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NCC(F)(F)F
Yield: 32 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (38 mg, 32%) which was obtained as a white solid. MS: m/e=443.0 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:15]1[O:17][CH2:16]1
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(F)c1OCC1CO1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 12.62 g of 2,4-difluoro-6-nitrophenol, 36 ml of epichlorohydrin, 3.3 g of sodium hydroxide, 15 ml of water and 320 ml of ethanol was stirred at 80° C. for 24 hours. After cooling the reaction solution to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated to dryness under a reduced pressure. The resulting residue was dissolved in an ether-hexane (1:2) mixed solvent, washed with water and saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The residue was applied to a silica gel column chromatography and developed with an ethyl acetate-hexane (1:9) mixed solvent, and then the fractions containing the compound of interest were concentrated to obtain 11.28 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:20])[CH3:21])[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) was dissolved in 10 mL DMF and stirred for 10 min at 0° C. Sodium hydride (300 mg, 7.5 mmol) was added portionwise at RT and stirred for 10 min. 4-(2-Methyl-oxiranyl)-pyridine (472 mg, 3.5 mmol) was added dropwise at the same temperature and stirred for 4 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (2×60 mL). The combined organic layer was washed with water (5×75 mL), dried over anhydrous sodium sulfate and concentrated and the residue was crystallized in EtOH and hexane to obtain 175 mg of 1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-4-yl-propan-2-ol. 1H NMR (CDCl3, Free base) δ (ppm): 8.58 (d, 2H), 7.40 (d, 2H), 7.25 (s, 1H), 7.16 (d, 1H), 6.92 (d, 1H), 4.18-4.0 (dd, 2H), 3.50-3.38 (dd, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.44 (s, 3H), 2.42 (s, 3H), 1.58 (s, 3H). Separation by chiral HPLC provided enantiomers 19a and 19b. Optical rotations: Compound 19a, (+)22.35 (c 0.58, Chloroform, 98.36% HPLC purity); Compound 19b, (−)22.43 (c 0.55, Chloroform, 99.09% HPLC purity).
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C@H:8]1[O:13][C@H:12]([CH2:14]I)[CH2:11][C@H:9]1[OH:10])([CH3:4])[CH3:3].[N-:28]=[N+:29]=[N-:30].[Li+]>CN(C)C=O.O>[N:28]([CH2:14][C@H:12]1[O:13][C@H:8]([CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:9]([OH:10])[CH2:11]1)=[N+:29]=[N-:30]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CI)C[C@H]1O)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution, under argon, of 5.0 g of product from Example 275 in 10 ml of dry N,N-dimethylformamide is treated with 0.986 g of lithium azide. The minute is stirred at 80° C. for 1 hour followed by room temperature for 18 hours. The reaction is diluted with water, extracted with diethyl ether, concentrated in vacuo, purified by chromatography (silica gel: 5-50% ethyl acetate/hexane) to give 4.0 g of the desired product.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:10]([C:13]1[CH:14]=[C:15]([C:19](=[S:21])[NH2:20])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>C(O)C>[N+:10]([C:13]1[CH:14]=[C:15]([C:19]2[S:21][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:20]=2)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cccc([N+](=O)[O-])c2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A solution of ethyl bromopyruvate (2.14 g) in ethanol (5 ml) was added to a suspension of 3-nitrobenzenecarbothioamide (2.00 g) in ethanol (15 ml) at room temperature. The reaction mixture was stirred at 50° C. for 2 hours and ten minutes. The solvent was removed by evaporation under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate (50 ml) and ethyl acetate (100 ml). The precipitates were collected by filtration and recrystallized from a mixture of chloroform and n-hexane to give ethyl 2-(3-nitrophenyl)-4-thiazolecarboxylate (1.59 g).
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[NH2:20][OH:21].Cl.[OH-].[Na+]>CCO.O>[OH:21][N:20]=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=NO)C(C3)C2
Temperature: 80 °C
Yield: 90 %

Procedure:
The mixture of ketone 1C (3 0 mmol), NH2OH—HCl (5 mmol), and NaOH (5 mmol) was diluted with EtOH (5 mL) and H2O (1 mL) and the reaction mixture was heated at 80° C. for 16 h. Upon cooling, the reaction mixture was extracted with DCM (10 mL×3) and the combined organic layers were dried (Na2SO4) and concentrated to provide oxime 14A in 90% yield as a solid. The material was used in the next step without further purification. Data: LC/MS (ESR) m/z 281 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[Cl:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH:3]=2)[CH:22]=1
Reactant: Nc1cc(Nc2cc(Cl)ncn2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Nc2cc(Cl)ncn2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3′-amino-4′benzyloxyphenyl)amino-6-chloro-pyrimidine (630 mg) in dry dichloromethane was added pyridine (8 ml) followed by methane sulfonyl chloride (0.3 ml). The mixture was stirred at room temperature overnight then evaporated under reduced pressure. The residue was dissolved in water and dichloromethane and the organic phase separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was then subjected to column chromatography (SiO2;ethyl acetate:petroleum ether (40/60) 1:1) to afford N-{5-[6-chloropyrimidin-4-ylamino]-2-benzyloxy-phenyl}-methanesulfonamide (200 mg). δH (d6 DMSO): 3.14 (3H, s, SO2Me), 5.40 (2H, s, CH2Ph), 6.94 (1H, s, HetH), 7.30-7.40 (1H, m, ArH), 7.50-7.85 (7H, m, ArH), 8.70 (1H, s, HetH), 9.30 (1H, s, NH), 10.00 (1H, s, NH)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[N:8]=3)[CH2:14][CH2:13]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)n1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 1-[6-(trifluoromethyl)pyridin-2-yl]piperazine (249 mg, 1.08 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (300 mg, 1.10 mmol), triethylamine (0.45 mL, 3.2 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (524 mg, 1.18 mmol). After being stirred overnight, the reaction was quenched with saturated sodium NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. Purification by column chromatography on silica gel (20% EA/hex to 40% EA/hexanes) provided 310 mg of the desired product. MS calculated for C24H36F3N4O3: (M+H) 485.3; found 485.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:17][CH2:18][CH3:19])[CH2:10][N:11]([CH:15]=O)[NH:12][CH:13]=O.C([NH2:22])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:17][CH2:18][CH3:19])[CH2:10][N:11]1[CH:15]=[N:22][CH:13]=[N:12]1
Reactant: NC=O
Reactant: CCCC(CN(C=O)NC=O)c1ccc(Cl)cc1Cl
Product: CCCC(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
6.2 g of the 1-[2-(2,4-dichlorophenyl)-pentyl-1,2-diformylhydrazine obtained according to Example 14 are heated, without purification, in 50 ml of formamide at 170° C. for 6 hours. Chromatography of the product obtained yields 1-[2-(2,4-dichlorophenyl)-pentyl]-1H-1,2,4-triazole, the 1H-NMR spectrum of which agrees with the 1H-NMR spectrum of the same compound described in Example 12.
Reaction SMILES: C(OC([N:8]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)[C@@:10]2([C@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][C@H:11]2[C:24]([Br:26])=[CH2:25])[C:9]1=[O:34])=O)(C)(C)C>FC(F)(F)C(O)=O>[Br:26][C:24]([C@H:11]1[C@:10]2([C:27]3[C:32](=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[NH:8][C:9]2=[O:34])[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:14][C:13](=[O:23])[NH:12]1)=[CH2:25]
Reactant: C=C(Br)[C@@H]1NC(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Product: C=C(Br)[C@@H]1NC(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 76.4 %

Procedure:
A solution of chiral (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (9 mg, 0.016 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature for 10 min, then concentrated in vacuo. The residue was purified by Prep-HPLC to give title compound (5.7 mg, 76%). m/z (M+H)+: 465
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:12][CH:13]([F:22])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([F:12])[F:22])=[CH:21][CH:20]=2)=[O:8])[CH:10]=1
Reactant: FC(F)COc1ccccc1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(OCC(F)F)cc1)c1cc(Br)ccc1Cl
Temperature: 0 °C
Yield: 100.3 %

Procedure:
Under Ar protection, 5-bromo-2-chloro-benzoyl chloride 12n (37.7 g, 148.6 mmol) was dissolved in 350 mL dichloromethane and 2,2-difluoroethoxybenzene 12c (25 g, 158.6 mmol) was added and stirred until dissolved, and cooled to 0° C., followed by addition of AlCl3 (19.1 g, 142.4 mmol) in batch. The reaction mixture was stirred for 2 hours at 0° C., then poured into 300 mL ice water and stirred for 30 minutes and partitioned. The aqueous layer was extracted with dichloromethane (100 mL). The organic layer was combined and partitioned after methanol (50 mL), dichloromethane (100 mL) and water (200 mL) were added. The organic layer was washed with saturated NaCl solution (200 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-[4-(2,2-difluoroethoxy)phenyl]methanone 12o (56 g, yellow grease), yield: 99.0%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)C(=O)c1nc(C(N)=O)n[nH]1

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 3.4 g. of pivaloyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 24 hours. The off-white solid is collected by filtration and washed thoroughly with diethyl ether and then cold water. The ether-cold water filtrate deposits another solid almost immediately. This solid is collected by filtration and dried in vacuo for 3.5 hours, yielding 0.22 g. This 0.22 g. is extracted with hot, dry acetonitrile. Concentration of the acetonitrile filtrate to a very small volume gives a colorless, crystalline solid which is collected, washed with a small amount of acetonitrile and dried in vacuo for 2 hours, yielding 50 mg., m.p. 132°-140° C. (dec.).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][CH:13]3[C:18]([C:9]=2[CH:8]=1)=[N:17][N:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:15](=[O:26])[CH2:14]3.[H-].[Na+].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]Cl>O>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][O:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][CH:13]3[C:18]([C:9]=2[CH:8]=1)=[N:17][N:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:15](=[O:26])[CH2:14]3
Reactant: CN(C)CCCCl
Reactant: Cc1ccc(N2N=C3c4cc(O)ccc4CCC3CC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2N=C3c4cc(OCCCN(C)C)ccc4CCC3CC2=O)cc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To 60 ml of dry dimethylformamide is added 6.1 g of 9-hydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, and 0.96 g of 60% sodium hydride is added thereto while stirring at room temperature. After stirring at room temperature for 1 hour, 2.8 g of 3-dimethylaminopropyl chloride is added to the mixture. After the mixture is stirred over water bath under heating at 40°-50° C. for 5 hours, the reaction mixture is poured into a large amount of water, followed by extraction with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off. The residue is subjected to column chromatography and the eluate is converted into its maleate, which is recrystallized from a mixed solvent of methanol and isopropyl ether to give 7.2 g of 9-(3-dimethylaminopropoxy)-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.maleate, m.p. 159°-162° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][NH:10][CH3:11]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:10]([CH3:11])[CH3:9])(=[O:7])=[O:6]
Reactant: CNC
Reactant: O=S(=O)(Cl)CCCCl
Product: CN(C)S(=O)(=O)CCCCl

Procedure:
The procedure used for the preparation of Intermediate D was used to prepare the title compound from 3-chloropropanesulfonyl chloride and dimethylamine. High vacuum drying gave the title compound (2.1 g, 100%): 1H NMR (DMSO-d6) δ: 2.06-2.11 (2H, m), 2.75 (6H, s), 3.10-3.15 (2H, m), 3.72 (2H, t).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.[CH2:22]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[F:37])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:22]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:32][C:31]=1[F:37])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(OCc2ccccc2)c(F)c1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.59 g of pyrazine-2-carboxylic acid and 4.73 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a pyridine (60 ml) solution of 4.13 g of 4-benzyloxy-3-fluoroaniline, and the reaction liquid was stirred overnight at room temperature. Pyridine was evaporated away under reduced pressure, and then water was added to it. The resulting deposit was taken out through filtration to obtain the entitled compound as a brown solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([NH:26][NH2:27])=[O:25].C(N(CC)CC)C>O1CCCC1>[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]1[O:25][C:1](=[O:2])[NH:27][N:26]=1
Reactant: Cc1cccc(Nc2ccccc2C(=O)NN)c1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(Nc2ccccc2-c2n[nH]c(=O)o2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1,1'-Carbonyldiimidazole (912.3 mg, 5.63 mmoles) is added to a 0° C. solution of 2-[(2,3-dimethylphenyl)amino]benzoic acid hydrazide (1.041 g, 4.08 mmoles) and triethylamine (608 μl, 4.36 mmoles) in 20 ml of tetrahydrofuran. The reaction is stirred at room temperature for one hour. The volatiles are removed in vacuo, and the residue is dissolved in 1:1 ethyl acetate/ether. The organic solution is washed consecutively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant white solid is purified by flash chromatography with 1:1 hexane/ethyl acetate as eluant to give 968.8 mg (85%) of 5-[2-[(2,3-dimethylphenyl)amino]phenyl]-1,3,4-oxadiazol-2(3H)-one, mp 239°-241° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][O:22][N:23]=[C:24]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCC(=NOCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(3-pyridyl)butyrate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(3-pyridyl)butyric acid (378 mg, yield 77%) as colorless crystals. m.p. 158-159° C.