Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([F:27])[CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)(=O)=O>CN(C)C=O>[F:27][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=3)[CH2:23][CH2:22]2)=[C:18]2[C:13]=1[N:12]=[C:11]([CH3:10])[CH:20]=[CH:19]2
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCNCC3)ccc(F)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)ccc(F)c2n1
Temperature: 100 °C
Yield: 46 %

Procedure:
N,N-Diisopropylethylamine (0.25 mL; 3 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)-8-fluoro quinoline (0.170 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.17 g; 1 eq) in dimethylformamide (4.0 mL). The reaction mixture was heated to 100° C. for 10 hours. The dark solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with a gradient from dichloromethane to dichloromethane-methanol (98:2) affording the title compound in 46% yield (0.126 g).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:20])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CC1
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC2CC2)C1(C)C

Procedure:
The product from Example 173 and cyclopropylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.30-0.42 (m, 2H), 0.47 (s, 3H), 0.56-0.60 (m, 2H), 0.90 (7.3 Hz, 3H), 1.17 (s, 3H), 1.18 (s, 3H), 1.23-1.44 (m, 3H), 1.56 (s, 9H), 1.56-1.67 (m, 3H), 1.95-2.07 (m, 1H), 2.56-2.67 (m, 4H), 2.71-2.82 (m, 1H), 7.63 (d, J=4.0 Hz, 1H), 8.50 (s, 1H). (ESI+) m/z 434 (M+H)+. Anal. calcd. for C24H39N3O2S: C, 66.47; H, 9.06; N, 9.69. Found: C, 65.95; H, 9.13; N, 9.44.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=2)[O:10][CH:9]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:16]2[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=2[OH:10])=[N:22][NH:23][CH:9]=1
Reactant: NN
Reactant: O=c1c(-c2ccccc2Br)coc2cc(O)c(Cl)cc12
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2Br)cc1Cl
Yield: 70 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(2-Bromo-phenyl)-6-chloro-7-hydroxychromen-4-one (0.4 g, 1.1 mmol), hydrazine hydrate (10 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-[4-(2-Bromo-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol as a white solid (0.28 g, 70%); Rf 0.6 ethyl acetate/hexane (80/20).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)=[O:7]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 3-bromobenzoic acid (500 mg, 2.49 mmol), 3-(trifluoromethyl)aniline (0.31 ml, 2.49 mmol) and DIEA (2.06 ml, 12.45 mmol) in DMF (6 ml) was treated with HATU (1.04 g, 2.74 mmol) and the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with sat'd NaCl(aq.), dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc) gave a yellow oil which solidified on standing (622 mg, 73%).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][C:16]1[O:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:21]([C:19]2[N:20]=[C:16]([CH3:15])[O:17][C:18]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:22])[CH:9]=[N:8]1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C)o1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: Cc1nc(C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c(-c2ccccc2C)o1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 2-methyl-5-o-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=403.22.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:13][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)Nc1ccccc1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and aniline as starting materials to give the aimed compound.
Reaction SMILES: [N:1]([C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)=[N:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=O.[NH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23].[Cl-].[Na+]>CO>[N:2]([C:3]([CH3:8])([CH3:9])[C:4]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])=[O:6])=[N:1][C:10]([CH3:16])([CH3:15])[C:11]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])=[O:13]
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Reactant: NCCNCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(N=NC(C)(C)C(=O)NCCNCCO)C(=O)NCCNCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a constantly stirred mixture comprising 23.0 g of V-601, 22.9 g of 2-(2-aminoethylamino)ethanol and 5 ml of methanol, 4.7 g of 28% CH3 ONa was added dropwise. The reaction was carried out with stirring at room temperature for 8 hours. After standing overnight, the reaction mixture was mixed with 50 ml of saturated sodium chloride solution, and extracted with 100 ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and solvent was distilled off, and there was obtained 29.8 g (yield 80%) of 2,2'-azobis[N-(2-hydroxyethylamino)ethyl-2-methylpropionamide] of yellow viscous liquid.
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].O=S(=O)=O.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=2)[N:12]=1>S(=O)(=O)(O)O.CC(C)=O>[OH:21][C:14]1[C:13]2[N:12]=[C:11]([CH3:10])[CH:20]=[CH:19][C:18]=2[C:17]([S:2]([OH:5])(=[O:3])=[O:1])=[CH:16][CH:15]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CC(C)=O
Product: Cc1ccc2c(S(=O)(=O)O)ccc(O)c2n1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Oleum (18-24% SO3, 20 ml) was added to a solution of 2-methyl-quinolin-8-ol (10 g, 62.8 mmol) in concentrated sulfuric acid (40 ml). After warming to 65° C. for 2 hours, the reaction mixture was poured onto 200 g of crushed ice. The suspension was diluted with acetone (60 ml) and stirred for 10 minutes, whereupon solids were filtered off. After washing with acetone (3×60 ml) and drying under high vacuum, the title compound (14.13 g, 94%) was obtained as a slightly yellowish solid. 1H NMR (400 MHz, d6-DMSO): δ=9.60 (d, J=8.3 Hz, 1H), 8.02-7.94 (m, 2H), 7.29 (d, J=7.7 Hz, 1H), 2.94 (s, 3H). MS (ES+): 240.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1COCC1>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:18](=[O:19])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1ccccc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)c1ccccc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 33.9 %

Procedure:
To a stirred solution of 2-isopropylaniline (200 mg, 1.5 mmol) in THF (9 mL) was added pyridine (0.24 mL, 3.0 mmol), then phenyl chloroformate (0.28 mL, 2.2 mmol) at rt. Some solid precipitated out. The mixture was stirred at rt for 4.5 h. Water was added to the reaction and it was extracted with EtOAc. The organic solution was washed with water (5 mL) and dried over MgSO4 and then filtered. The filtrate was concentrated in vacuo and crystallized from EtOAc-hexanes (1:9 v/v) to afford the title compound (130 mg, 34%). 1H-NMR (DMSO-d6) δ 9.45 (s, 1H), 7.44 to 7.36 (m, 2H), 7.35 to 7.28 (m, 2H), 7.25 to 7.14 (m, 5H), 3.27 (m, 1H), 1.17 (d, J=6.9 Hz, 2H); TLC Rf=0.33 (9:1 v/v hexanes-EtOAc).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])[CH2:34][CH2:33]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Product: Cc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 84 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](N2C=CN=C2)=[O:40])=[CH:34][C:33]=1[CH3:46]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:40])=[CH:34][C:33]=1[CH3:46]
Reactant: COC(=O)c1ccc(NC(=O)n2ccnc2)cc1C
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (49.5 mg, 0.117 mmol) and 4-[(Imidazole-1-carbonyl)-amino]-2-methyl-benzoic acid methyl ester (342.4 mg, 1.32 mmol) in CH2Cl2 (8 mL) was stirred rt for 16 hrs. The reaction mixture was then purified by flash column to give 4-{[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-2-methyl-benzoic acid methyl ester (63.2 mg, 88%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].Br[CH2:19][C:20]#[CH:21].C1COCC1>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:15]([CH2:21][C:20]#[CH:19])(=[O:17])=[O:16])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2cc(S(=O)O)ccc2c1
Reactant: C#CCBr
Solvent: O
Solvent: C1CCOC1
Product: C#CCS(=O)(=O)c1ccc2cc(NC(C)=O)ccc2c1
Yield: 90.5 %

Procedure:
160 g (0.64 mol) of 2-acetylaminonaphthalene-6-sulfinic acid were dissolved in 1000 ml of water at pH 6 and the solution was added dropwise to a solution of 84.1 g (0.7 mol) of 3-bromoprop-1-yne and 85 ml of THF. After the addition was complete, the reaction mixture was heated at from 40° to 60° C. until the reaction had ended (check by TLC). The precipitate formed was filtered off with suction at about 10° C., washed with water and dried, leaving 166.4 g of 2-acetylamino-6-(prop-1-yn-3-ylsulfonyl)naphthalene of the formula ##STR24## having a melting point of from 230° to 238° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[C:6]=2[CH:13]=1.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:14]([F:17])([F:15])[F:16])=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[C:6]=2[C:13]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)cc21
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 11.0g. (0.04 mole) of 6-chloro-1-ethyl-2-methyl-5-trifluoromethylbenzimidazole dissolved in 110 ml. of concentrated sulfuric acid was added 11 ml. of 90% fuming nitric acid while cooling with an ice bath. The addition required 3 hours and the resulting red-brown solution was stirred for 6 hours at 0°C. and then at room temperature for 2.5 days. After pouring onto ice, the product was precipitated by the addition of 350 ml. of concentrated ammonium hydroxide. The crude solid was isolated and dissolved in 300 ml. of chloroform. The chloroform solution was washed with water, dried over Na2SO4, filtered, and the filtrate evaporated. Crystallization of the residual solid from hexane --CCl4 (3:1) gave 9.0g. (70%) of reddish solid, m.p. 114°-116°C., whose nuclear magnetic resonance pattern confirmed it to be the desired product.
Reaction SMILES: [CH:1]1([C@H:4]([N:8]2[C:13](=[O:14])[C:12]([NH:15][C:16]3[C:17]([CH3:24])=[N:18][C:19]([OH:23])=[C:20]([CH3:22])[CH:21]=3)=[N:11][C:10]([C:25]#[N:26])=[CH:9]2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.[F-].[Cs+].[F:29][C:30]([F:42])(S(F)(=O)=O)C(O[Si](C)(C)C)=O>C(#N)C>[CH:1]1([C@H:4]([N:8]2[C:13](=[O:14])[C:12]([NH:15][C:16]3[C:17]([CH3:24])=[N:18][C:19]([O:23][CH:30]([F:42])[F:29])=[C:20]([CH3:22])[CH:21]=3)=[N:11][C:10]([C:25]#[N:26])=[CH:9]2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Reactant: COC[C@H](C1CC1)n1cc(C#N)nc(Nc2cc(C)c(O)nc2C)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COC[C@H](C1CC1)n1cc(C#N)nc(Nc2cc(C)c(OC(F)F)nc2C)c1=O
Reaction time: 1 h

Procedure:
A mixture of pure (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-hydroxy-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile (2.3 g, 6.5 mmol) and CsF (395 mg, 2.6 mmol) was added to acetonitrile (65 mL). To the resulting suspension, trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.82 mL, 19.4 mmol) was slowly added (use extreme caution! The reagent can cause dermatological damage and should always be handled in hood). LC-MS analysis after 1 h showed the reaction to be complete (89% conversion to required product), Volatiles were evaporated in vacuo and the residue was partitioned between EtOAc (3×120 mL) and H2O (˜100 mL). The organic layer was washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. The ethyl acetate was evaporated in vacuo and the residue was dissolved in DMF (10 mL). The solution was applied to C18 silica gel column (14 cm×5 cm) equilibrated with MeCN:H2O (1:2). The column was eluted with 33% MeCN/H2O (500 mL), 45% MeCN/H2O (500 mL), 60% MeCN/H2O (1000 mL), 70% MeCN/H2O (500 mL). Individual fractions were analyzed by LC-MS (product comes out in between 60%-70% MeCN/H2O). Fractions containing pure product were combined and concentrated in vacuo to give pure (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile (2.28 g, 87% yield) as pale yellow solid: 1H NMR (CDCl3) δ 8.43 (s, 1H); 8.01 (s, 1H); 7.56 (s, 1H); 7.49 (t, JH-F=73.8 Hz, 1H); 4.15-4.18 (m, 1H); 3.76 (dd, JAB=10.4, JAX=5.2 Hz, 1H); 3.68 (dd, JBA=10.4, JBX=3.1 Hz, 1H); 3.37 (s, 3H); 2.46 (s, 3H); 2.30 (s, 3H); 1.35-1.42 (m, 1H); 0.82-0.88 (m, 1H); 0.64-0.69 (m, 1H); 0.53-0.58 (m, 1H); 0.31-0.36 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 153.0, 151.5, 147.8, 143.8, 133.3, 129.4, 125.6, 119.1, 117.2, 114.8 (t, J=256.1 Hz, 1C), 107.6, 72.7, 62.6, 59.6, 20.0, 15.5, 11.4, 6.4, 4.2; 19F NMR (CDCl3) δ-88.73 (d); LRMS (ESI) m/e 406 [(M+H)+, calcd for C19H22N5O3F2 406]; tR=2.7 min (Solvent A: MeOH:H2O:TFA=10:90:0.1; Solvent B: MeOH:H2O:TFA=90:10:0.1; 40% B in A to 100% B in A linear gradient in a 3 min run with 1 min hold time at the end, λ=280 nm).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccc(Cl)cc2)c(-c2ccccc2)n1
Yield: 55.3 %

Procedure:
6-(4-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (125 mg, 56%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 4-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to the general procedure of Example 1.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[N:18]([CH:19]=2)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)=[CH:8][CH:7]=1.[N:24]([O-])=[O:25].[Na+]>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[N:24]=[O:25])[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To 700 ml of acetic acid was added 14 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole and after adding thereto 5 g of sodium nitrite with stirring at room temperature, the mixture was stirred for 3 hours. Thereafter, 500 ml of water was added to the mixture and the crystals thus formed were recovered by filtration and washed with water, then n-hexane, and further with 400 ml of chloroform to provide 10 g of 2-(p-chlorophenyl)-3-nitrosoimidazo[2,1-b]benzothiazole. The product was recrystallized from chloroform to provide crystals having a melting point of 203°-206° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:7]=2.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>ClCCl>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([OH:13])=[C:3]([NH:2][C:29](=[O:32])[CH2:30][CH3:31])[CH:4]=[N:5]2)=[CH:10][CH:9]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Yield: 96.5 %

Procedure:
To a stirred solution of 3-amino-7-benzyloxyquinolin-4-ol hydrochloride (40.4 g, 133.4 mmol), and triethylamine (2.5 eq., 33.8 g, 333.6 mmol) in dichloromethane (1000 mL) at room temperature, was slowly added propionyl chloride (1.1 eq., 13.6 g, 146.8 mmol). After 6 hours the reaction was quenched with water (250 ml). The reaction mixture was transferred to a separatory funnel and the layers were separated. The dichloromethane layer was concentrated to provide 41.5 g of N-(7-benzyloxy-4-hydroxyquinolin-3-yl)propionamide as a pale tan crystalline solid. MS (ACPI) m/z=323 (M+H)+. This material was carried on without further purification to the next step.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[NH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2>C(O)C.C(Cl)Cl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:7]
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: C=CC(=O)OCC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCNC1c2ccccc2-c2ccccc21
Reaction time: 36 h

Procedure:
1.0 ml of ethyl acrylate was added to a solution of 9-aminofluorene (1.24 g) in ethanol (20 ml). The resultant mixture was stirred at 80° C. for 5 hours and, then, at room temperature for 36 hours. The residue obtained by condensing the reaction mixture was dissolved in methylene chloride and, then, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: methylene chloride-ether) to give 1.25 g of N-(9-fluorenyl)-β-alanine ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
18 ml (0.117 mol) of ethyl piperidine-4-carboxylate and 32.4 ml (0.2325 mol) of triethylamine were dissolved in 580 ml of toluene and treated with 18 ml (0.155 mol) of benzoyl chloride. The mixture was stirred at room temperature for 2 hrs., filtered and the solvent was evaporated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:3→1:1) as the eluent. 28.3 g (92%) of ethyl 1-benzoyl-4-piperidine-carboxylate were obtained as white crystal; m.p. 75°-78°.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7](=O)[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)N)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.CC(O)=O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:31]2[C:28]3[C:27](=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:35][CH:36]=1
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 39 g methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate (Ketone 2) in a mixture of toluene (300 mL) and HOAc (150 mL) was added NaOAc (15 g) and 1-(4-methoxyphenyl)-1-(4-chlorobenzyl)-hydrazine hydrochloride (50 g). The reaction was stirred at r.t. for 3 days under argon in the dark. The mixture was poured onto H2O (1 L) and extracted with 3× EtOAc (500 mL). The EtOAc was washed with 3× H2O (500 mL) then once with NaHCO3 solution. The organic phase was dried (MgSO4), evaporated to dryness, and the residue crystallised from Et2O/hexane 2:1 to afford the title compound; m.p. 102°-103° C.