Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]1CCC[CH2:10]1>>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:10]1=[O:9]
Reactant: Nc1ncccc1O
Reactant: C1CCOC1
Product: O=c1[nH]c2ncccc2o1

Procedure:
5.5 g (0.05 mol) of 2-amino-3-hydroxypyridine are introduced into a three-necked flask and the system is placed under argon. 100 ml of anhydrous tetrahydrofuran (THF) are added 12 15 g (0.075 mol) of 1,1-carbonyldiimidazole are then introduced. The mixture is heated to reflux for 5 hours (under argon) The THF is then evaporated off. The residue is taken up with dichloromethane. Washes of the organic phase are performed with NaOH solution (5%) (6 × 150 ml); the cyclized product passes into the aqueous phase and is precipitated at a pH in the region of 5 (by adding 2 N hydrochloric acid solution). The product is filtered off and stored in a desiccator.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1cccc(B(O)O)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cccc(C=O)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 obtained in Example 120-(1) and 3-formylphenylboronic acid were used and treated in a manner similar to Example 120-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 640 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) 3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene (100 mg) was dissolved in dichloromethane (2 ml), and added thereto was (diethylamino) sulfur trifluoride (0.30 ml). The mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate, and then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methyl benzene (82 mg). APCI-Mass m/Z 662 (M+NH4). (3) The above obtained 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienyl methyl)-4-methylbenzene was used and treated in a manner similar to Example 120-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 494 (M+NH4).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.O>CN(C=O)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH2:28])=[O:30])=[CH:13][CH:12]=1
Reactant: Nc1ccc(CCOCc2ccccc2-c2ccccc2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1ccc(CCOCc2ccccc2-c2ccccc2)cc1
Temperature: 50 °C
Yield: 48.1 %

Procedure:
To 100 mg (0.33 mmol) of the product of Example 27 step 1 in 15 mL of DMF was added 57 mg (0.50 mmol) of trimethylsilyl isocyanate the solution was heated to 50° C. for 1.5 hr. At the end of this time it was poured into 100 mL of water. The resulting precipitate was collected by filtration and taken up in hot ethyl acetate. The excess water was removed by decantation and the solution allow to cool. Hexane was introduced to cloudiness and the solution allow to cool further to yield 55 mg (48%) of product as a colorless solid, m.p. 143-144° C. NMR (400 MHz, DMSO) δ 8.42 (s, 1H); 7.34 (m, 10H); 7.10 (t, J=7.7 Hz, 1H); 6.73 (d, J=7.7 Hz, 1H); 5.77 (s, 2H); 4.30 (s, 2H); 3.53 (t, J=6.8 Hz, 2H); 2.72 (t, J=6.8 Hz, 2H). Anal. Calcd. for C21H21N O: C, 83.13; H, 6.98; N, 4.62 Found: C, 75.13; H, 6.41; N, 8.11. (+)FAB m/z 347 (M+H), 369 (M+Na).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[NH2:13][C:11]([C@@H:10]([NH:9][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH3:15])=[O:12]
Reactant: CC[C@H](N)C(N)=O
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCN[C@@H](CC)C(N)=O
Temperature: 80 °C

Procedure:
143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (S)-2-amino-butanamide hydrochloride ([alpha]D25 : +26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° C. and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>CCCCCC>[F:14][C:15]1[C:20]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Fc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a mixture of lithium diisopropylamide (1.5M in cyclohexane, 43 mL) and tetrahydrofuran (60 mL) cooled to -70° C. was added 2-fluoropyridine (6.0 mL) at such a rate that the temperature remained below -70° C. After 1.5 hours, tributyltin chloride (15 mL) was added, and the mixture was allowed to warm to room temperature. The mixture was diluted with hexane, washed with water, dried, filtered, and evaporated. Chromatography of the residue over silica gel (cyclohexane/ethyl acetate 98/2) gave 2-fluoro-3-tributylstannylpyridine (17 g).
Reaction SMILES: [C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Mg:11].[OH:12][CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16].[C:19]([O:28]CC[N+](C)(C)C)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22]>>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:19]([O-:28])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Mg+2:11].[OH:12][CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: [Mg]
Reactant: C[N+](C)(C)CCOC(=O)c1ccccc1O
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])c1ccccc1O
Product: [Mg+2]

Procedure:
This example illustrates the preparation of a non-stable, solid choline magnesium salicylate composition by a granulation technique employing liquid choline salicylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Cl)cc2)cc1
Yield: 68.2 %

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Example 1 (6.2 g, 15.4 mmol) and p-toluenesulfonic acid monohydrate (0.9 g, 4.7 mmol) in toluene (300 mL) was heated to reflux for 84 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentrating in vacuo, the crude mixture was purified by chromatography on silica gel using hexane/ethyl acetate (1/1) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (4.21 g, 71%) as a white solid: mp (DSC) 183° C. Anal. Calc'd. for C17H12N2SO2F3Cl: C, 50.94; H, 3.02; N, 6.99. Found: C, 50.64; H, 3.03; N, 6.85.
Reaction SMILES: [CH2:1]=O.[C:3]([CH2:5][C:6](O)=O)#[N:4].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[N:9]1([CH2:1][C:5](=[CH2:6])[C:3]#[N:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: C=O
Reactant: N#CCC(=O)O
Solvent: O
Product: C=C(C#N)CN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Formaldehyde (75 ml of 40% solution) was added to a stirred solution of cyanacetic acid (43g) and piperidine (85g) in water at 15° C. The solution was stirred for 1 hour at room temperature and then boiled under reflux for 2 hours. On cooling the reaction mixture separated into two layers, the top layer was separated and distilled to give a colourless oil, boiling point 117°-118° C 0.5mm.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([NH:18]N)[C:12]=1[CH3:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)CO.O.[O:27]1[CH:31]=[CH:30][CH2:29][CH2:28]1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C:11]1[C:12]([CH3:20])=[C:13]2[C:14]([C:30]([CH2:29][CH2:28][OH:27])=[CH:31][NH:18]2)=[C:15]([Br:17])[CH:16]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1=COCC1
Reactant: Cc1c(NN)cc(Br)cc1C(=O)OCc1ccccc1
Agent: Cl
Solvent: OCCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)OCc2ccccc2)cc(Br)c2c(CCO)c[nH]c12
Temperature: 40 °C
Reaction time: 2.25 h
Yield: 26.9 %

Procedure:
A 1000 mL RBF was charged with 5-bromo-3-hydrazino-2-methyl benzoic acid benzyl ester hydrochloride (30.0 g, 0.081 mol), ethylene glycol (350 mL), and water (60 mL). This mixture was heated to 40° C., and dihydrofuran (7.63 mL, 0.101 mol) was added. The reaction mixture was next heated to 100–105° C. with stirring for 2.25 hours. The reaction was then cooled to ambient temperature, diluted with EtOAc, washed with saturated NaCl (2×), dried (MgSO4), and concentrated. The resulting oil was chromatographed on SiO2, eluting with a 10% EtOAc/DCM to 50% EtOAc/DCM gradient. Isolation of the product as an impure solid, followed by trituration with DCM and hexanes, afforded 8.45 g (27.0%) of a pale yellow solid. 1H NMR (CDCl3) δ 8.28 (br s, 1 H), 7.94 (s, 1H), 7.40 (m, 6H), 5.36 (s, 2H), 3.96 (q, J=6.4 Hz, 2H), 3.28 (t, J=6.4 Hz, 2H), 2.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:19][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:13]=3[C:12]=2[C:20]([NH2:22])=[O:21])=[CH:4][CH:3]=1.[CH:24]1[CH:25]=[CH:26][C:27]2[N:32](O)[N:31]=[N:30][C:28]=2[CH:29]=1.CCN=C=NCCCN(C)C.Cl.CN([CH:49]=[O:50])C>>[NH:30]1[C:28]2[CH:29]=[CH:24][C:25]([C:49]([N:16]3[CH2:17][CH2:18][C:13]4[C:12]([C:20]([NH2:22])=[O:21])=[C:11]([NH:10][C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[O:23])[S:19][C:14]=4[CH2:15]3)=[O:50])=[CH:26][C:27]=2[N:32]=[N:31]1
Reactant: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 28 %

Procedure:
Starting material 5 (847 mg, 2.4 mmol) was suspended in DMF (8 ml) and 1H-1,2,3-benzothiazole-5-carboxylic acid (473 mg, 2.9 mmol), dry HOBt (427 mg, 2.9 mmol) and EDCl (606 mg, 2.9 mmol) were added. The brown suspension was stirred at ambient temperature over the weekend. As the reaction was not complete yet, the reaction was further stirred at 80° for 4 h. Thereby a brown solution was formed. The solvent was evaporated in vacuo and the crude product was further purified by prep. HPLC (Method 1). The product fractions were merged, the solvent was evaporated and the product lyophilized. Thereby 310 mg of the desired product 6 (0.635 mmol, 28%) were isolated as a light brown solid and additional 58 mg of the same product with 76% content which could have been purified further.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:31].[NH2:32][N:33](C)[C:34](=O)OC(C)(C)C>>[ClH:31].[ClH:31].[CH3:34][N:33]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:32]1
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: Cl
Product: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (72 g, 160 mmol) was added hydrochloric acid (610 mL of 4.0 M, 2.5 mol). The reaction mixture was allowed to stir at 25° C. for 2 hours. Solvent was removed under vacuum, and the obtained solid was azeotroped with EtOH (3×700 mL). The resulting beige-white solid was dissolved in EtOH (685 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-methyl-carbamate (29 mL, 200 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid (200 mL of 4.0 M, 800 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick white slurry developed. The slurry was allowed to slowly cool to 25° C., and solids were collected by vacuum filtration. The filter cake was rinsed with a 10% solution of EtOH in hexane (2×500 mL). The solid was placed in a vacuum oven overnight (20 mm Hg/45° C.). 1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride (42 g, 78%) was obtained as an off-white solid. ESI-MS m/z calc. 255.3, found 256.3 (M+1)+; Retention time: 1.30 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 7.82-7.76 (m, 1H), 7.61 (s, 1H), 7.40-7.34 (s, 1H), 7.22-7.14 (m, 2H), 4.19 (s, 3H), 3.52-3.42 (m, 2H), 3.41-3.33 (m, 2H), 2.39-2.07 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[C:19]3[CH3:23])[C:5]2[C:6](=[O:10])[NH:7][N:8]=[CH:9][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]1[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].O>CN1C(=O)CCC1>[C:43]([O:42][C:41](=[O:47])[NH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@H:34]1[NH:33][C:2]1[N:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[C:19]3[CH3:23])[C:5]2[C:6](=[O:10])[NH:7][N:8]=[CH:9][C:4]=2[CH:3]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1c[nH]c2c(Nc3nc(Cl)cc4cn[nH]c(=O)c34)cccc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1c[nH]c2c(Nc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)cc4cn[nH]c(=O)c34)cccc12
Temperature: 120 °C

Procedure:
To 7-chloro-5-(3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one (177 mg, 0.543 mmol) in NMP (1 ml) in a sealable glass vial, was added DIPEA (0.190 ml, 1.087 mmol) and tert-butyl(1S,2R)-2-aminocyclohexylcarbamate (233 mg, 1.087 mmol). The vial was capped to close and the reaction mixture was heated on a sandbath at 120° C. for 3 days. The resulting mixture was poured into water (20 ml), and extracted with EtOAc (20 ml). The organic phase was washed with water and brine, dried over Na2SO4, then concentrated under vacuum. The residue was triterated with DCM, then collected by filtration and dried to give a gummy solid.
Reaction SMILES: [C-]#N.[K+].C(CCC1C=C2C(=CC=1)N[C:12](=[O:17])C2)#N.Cl[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.CS(C)=[O:33]>>[C:12]([CH2:19][CH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2)([OH:17])=[O:33]
Reactant: CS(C)=O
Reactant: N#CCCc1ccc2c(c1)CC(=O)N2
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Agent: [C-]#N
Agent: [K+]
Product: O=C(O)CCc1ccc2c(c1)CC(=O)N2
Temperature: 90 °C
Yield: 42 %

Procedure:
Synthesis of 5-Cyanoethyl-2-indolinone Potassium cyanide (2.02 g) was added to 15 mL of dimethylsulfoxide and heated to 90° C. 5-Chloroethyl-2-indolinone (3.0 g) dissolved in 5 mL of dimethyl sulfoxide was added slowly with stirring, and the reaction heated to 150° C. for 2 hours. The mixture was cooled, poured into ice water and the precipitate collected by vacuum filtration, washed with water, and dried to give crude product. The crude material was chromatographed on silica gel in 5% methanol in chloroform to give 1.2 g (42% yield) of the title compound.
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].[CH2:13]([SH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[C:1](=[O:12])([S:20][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCCCS
Product: CCCCCCC/C=C/C(=O)SCCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-heptanethiol as starting materials to give the aimed compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:19]=1.N1C2C=CC=C(S(Cl)(=O)=O)C=2N=CC=1>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:22](=[O:23])[C:21]1[CH:25]=[C:26]([Cl:27])[C:18]([Cl:17])=[CH:19][C:20]=1[NH:28][S:29]([C:32]1[C:33]2[N:34]=[CH:35][CH:36]=[N:37][C:38]=2[CH:39]=[CH:40][CH:41]=1)(=[O:31])=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Agent: O=S(=O)(Cl)c1cccc2nccnc12
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (prepared from quinoxaline-5-sulfonyl chloride as in EXAMPLE 14, Part A) as in Example 1, Part C. HPLC: RT=10.50 min. MS (ESI−): mass calcd. for C25H18BrCl2FN4O5S, 656.31; m/z found, 653/655/657 [M−H]−. 1H NMR (400 MHz, CDCl3): 10.99 (s, 1H), 8.96 (d, J=1.7, 1H), 8.93 (d, J=1.7, 1H), 8.55 (dd, J=7.3, 1.1, 1H), 8.33 (dd, J=8.5, 1.1, 1H), 7.91-7.85 (m, 2H), 7.31-7.22 (m, 2H), 7.07-6.94 (m, 2H), 6.52 (d, J=7.3, 1H), 4.89 (q, J=5.8, 1H), 3.81 (s, 3H), 3.21-3.08 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@:27]([OH:42])([C@H:34]([S:36][CH:37]([CH2:40]O)[CH2:38][OH:39])[CH3:35])[CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[O:39][CH2:38][C@H:37]([S:36][C@H:34]([CH3:35])[C@:27]([C:21]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=4[F:19])([OH:42])[CH2:28][N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)[CH2:40][O:15]3)=[CH:10][CH:9]=2)=[CH:17][CH:18]=1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(Cl)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(3) a reaction was carried out using 4′-chloro-4-formylbenzanilide (300 mg, 1.2 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (359 mg, 1.0 mmol) and p-toluenesulfonic acid monohydrate (342 mg, 1.8 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (290 mg, yield 48%) as a colorless solid and the cis isomer (82 mg, yield 14%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15](O)[C:14]3[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:22])=O>>[C:1]1([C:7]2[CH:16]=[C:15]([Cl:22])[C:14]3[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
2-phenyl-4-hydroxy-7-methoxy-quinoline (2.73 g, 10.9 mmol., 1 eq) was suspended in neat phosphorus oxychloride (30 mL). The reaction mixture was heated under reflux. After 2 h, LCMS analysis showed full consumption of the starting material. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was partitioned between ethyl acetate (100 mL) and 2M aqueous sodium hydroxide solution (80 mL). The mixture was stirred at ambient temperature for a further 10 min, and then the two layers were separated. The organic phase was washed with water (2×50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The obtained beige solid was further dried under high vacuum for 2 hours to give 2.66 g (91%) of the title compound. 1H NMR (250 MHz, DMSO-d6) δ ppm 8.25-8.35 (m, 2H), 8.21 (s, 1 H), 8.09 (d, J=9.14 Hz, 1 H), 7.47-7.61 (m, 4H), 7.38 (dd, J=2.55, 9.18 Hz, 1 H), 3.97 (s, 3 H). LC-MS: purity 100% (UV), tR 2.58 min, m/z [M+1]+ 270.00.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C>[CH2:16]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)[CH3:17]
Reactant: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(C)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 3-methyl-5-nitro-1H-indazole (1.50 g, 8.44 mmol, commercially available) in dry DMF (30 mL) under Argon was added NaH (0.43 g, 17.79 mmol) portionwise at 0° C. After 30 min, ethyl iodide (1.98 g, 1.03 mL, 12.7 mmol) was added and the mixture stirred at ambient temperature for 1 h then quenched by the addition of H2O (2 mL), concentrated and redissolved in EtOAc (30 mL) then washed with H2O (3×15 mL). The combined aqueous layers were extracted with EtOAc (3×15 mL) and the combined organic layers dried over Na2SO4, filtered and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 50:50) afforded the title compound (1.17 g, 67%) as a yellow solid. MS m/e: 206.0 [M+H]−.