Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[N:26]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:32][CH2:33][OH:34])[CH2:27][CH2:28]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[CH:12][CH:13]=1
Reactant: COc1cc(-c2c(-c3ccc(F)cc3)nc3ccc(Cl)nn23)ccn1
Reactant: OCCN1CCNCC1
Solvent: CCCCCO
Product: COc1cc(-c2c(-c3ccc(F)cc3)nc3ccc(N4CCN(CCO)CC4)nn23)ccn1
Temperature: 135 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
A mixture of 0.25 g (0.70 mmol) of 6-chloro-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo-[1,2-b]pyridazine and 0.37 g (2.8 mmol) of 2-(piperazin-1-yl)ethanol in 6 mL of pentanol is stirred at 135° C. for 18 hours. The solvent is then evaporated off under reduced pressure and the oily residue is chromatographed on a column of silica gel, eluting with a stepwise gradient of methanol and aqueous ammonia in dichloromethane (0/0/100 to 2/1/98). 0.136 g of product is isolated after trituration in diisopropyl ether, filtering off and drying under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>CC(C)=O.O.CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:18])[NH:19][S:26]([CH3:25])(=[O:28])=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 2 h

Procedure:
To 10 mmol of (S)-N2-(benzyloxycarbonyl)-arginine suspended in a mixture of acetone/water 80/20 there is added, at 0° C., a sufficient amount of 4N sodium hydroxide solution to bring the pH of the reaction mixture to between 11 and 11.5. After stirring for 2 hours, there is then added a solution of methanesulphonyl chloride in acetone and then, after stirring for a further 3 hours, the mixture is neutralised using 1N hydrochloric acid solution; the acetone is then evaporated off, and the residue obtained is extracted with ether and then washed, dried, filtered and evaporated. The pale yellow oil thereby obtained is purified by chromatography over silica (eluant: dichloromethane/methanol 7/3) to yield the expected product in the form of a whitish meringue.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][C:11]=2[N+:19]([O-:21])=[O:20])[C:7](=[O:22])[C:6]=1[CH2:23][Cl:24])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C(Cl)(=O)OCC.[CH2:37]([NH2:53])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>O.C(N(CC)CC)C>[C:1]([C:5]1[O:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:17])[NH:53][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:12][C:11]=2[N+:19]([O-:21])=[O:20])[C:7](=[O:22])[C:6]=1[CH2:23][Cl:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1on(-c2ccc(C(=O)O)cc2[N+](=O)[O-])c(=O)c1CCl
Reactant: CCCCCCCCCCCCCCCCN
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCCNC(=O)c1ccc(-n2oc(C(C)(C)C)c(CCl)c2=O)c([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 0.83 h

Procedure:
81.6 g of 5-t-butyl-4-chloromethyl-2-(4-carboxy-2-nitrophenyl)-4-isoxazolin-3-one and 480 ml of ethyl acetate were mixed with each other, then cooled to -15° C. To this suspension was dropwise added 32.6 ml of triethylamine. Then, 22.0 ml of ethyl chlorocarbonate was dropwise added thereto while keeping the temperature of the mixture at not higher than -10° C. After reacting under such conditions for 50 minutes, 49 g of hexadecylamine was added thereto. After reacting for 10 minutes at -10° C., the temperature of the reaction mixture was gradually raised to room temperature, and the mixture was left overnight. Then, 400 ml of water was added thereto, and the organic layer was separated and concentrated using an evaporator to dryness. The residue was crystallized from methanol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH:13][CH:14]([C:16]2[N:21]=[N:20][C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[N:18][CH:17]=2)[CH3:15])=O)=[CH:3]1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:15][C:14]1[N:13]=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[N:21]2[C:16]=1[CH:17]=[N:18][C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[N:20]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cn(C)c4ccccc34)nn2)cc1
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cn(C)c5ccccc45)n3n2)cc1
Yield: 54 %

Procedure:
Applying the Cyclization Procedure 2, using 1-methyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-1H-indole-3-carboxamide (Intermediate 54) (107 mg, 0.26 mmol), pyridine (2.65 mL), 1,2,4 triazole (55 mg, 0.80 mmol) and phosphorus oxychloride (0.037+0.010 mL, 0.50 mmol), to afford 5-methyl-7-(1-methyl-1H-indol-3-yl)-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (54 mg) as a yellow solid. MS m/z 385 (M+1).
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.[Na].Cl[CH2:17][C:18]1[O:22][N:21](C2CCC=CO2)[C:20](=[O:29])[CH:19]=1.Cl>C(O)C.CC(C)=O>[CH2:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:17][C:18]2[O:22][N:21]=[C:20]([OH:29])[CH:19]=2)=[CH:10][CH:11]=1)[C:4]([CH3:13])=[O:14]
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Reactant: O=c1cc(CCl)on1C1CCC=CO1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(=O)Cc1ccc(OCc2cc(O)no2)cc1
Reaction time: 4 h

Procedure:
A solution of (4-hydroxyphenyl)propan-2-one ethylene ketal (1.4 g) in ethanol, was treated with a solution of sodium (0.16 g) in ethanol (25 ml) and heated under reflux for 10 minutes. A solution of 5-chloromethyl-2-(1,2,3,4-tetrahydropyran-2-yl)isoxazol-3-(2H)one (1.5 g) in ethanol was added dropwise, and the reaction was heated for 18 hr. The cooled solution was evaporated in vacuo, the residue partitioned between ethylacetate and water, the organic layer separated, dried (magnesium sulphate), and the solvent removed in vacuo to give an oil which was chromatographed on silica. Elution with ether: 60:80 petrol (1:1) gave an oil which was dissolved in acetone and treated with 2M hydrochloric acid solution (5 ml) and allowed to stand at room temperature for 4 hr. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with 1.2M sodium bicarbonate solution (1×50 ml), dried (magnesium sulphate , filtered and evaporated to give 5-(4-acetonylphenoxymethyl)3-hydroxyisoxazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:22]1[CH:21]=[C:20]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:11][CH3:12])[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Clc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(F)ccc1-c1ccnc(Cl)c1
Yield: 73.4 %

Procedure:
To a solution of 4-fluoro-2-methoxyphenylboronic acid (440 mg, 2.58 mmol) in 8 ml of 1,4-dioxane was added 2.5 ml of saturated aqueous sodium carbonate solution. Argon gas was purged for 30 min at room temperature. 4-Bromo-2-chloropyridine (500 mg, 2.58 mmol) and tetrakis(triphenylphosphine)palladium (0) (150 mg, 0.129 mmol) were added to reaction mixture simultaneously and argon gas was bubbled for another 40 min. The reaction mixture was heated to reflux for 16 h, TLC confirms completion of reaction and the mixture was concentrated under reduced pressure. The residue was partitioned between DCM and water. The organic layer was separated, washed with brine, water, dried (Na2SO4) and concentrated. The obtained crude residue was purified through silica gel column chromatography eluting with 15% ethyl acetate in DCM to provide 2-chloro-4-(4-fluoro-2-methoxyphenyl)pyridine (450 mg, 73.3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2C(C#N)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[O:10][CH2:11][C:2]=12.Cl.[C:19]([OH:22])(=[O:21])[CH3:20].[OH-].[Na+]>ClCCl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH:20]([C:19]([OH:22])=[O:21])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:8][C:9]=3[O:10][CH2:11][C:2]=12
Reactant: CC(=O)O
Reactant: N#CC1c2ccccc2OCc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C1c2ccccc2OCc2ncccc21

Procedure:
A mixture of 2.03 g of 5,11-dihydrobenzoxepino[3,4-b]pyridin-5-carbonitrile, 30 ml of hydrochloric acid and 30 ml of acetic acid was heated under reflux for 19 hours. The reaction mixture was allowed to stand at room temperature. Water and dichloromethane were added to the reaction mixture and the pH was adjusted to 3.4 with 10N sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 1.95 g of Compound U.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)C.[OH-].[Na+].[Na+].[Cl-]>ClCCl>[C:2]1([CH:1]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: CC=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: OC(c1ccccc1)C1CCNCC1
Temperature: 1 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
4-benzoyl-piperidine (7.35 g, 39.05 mmol) was added over a solution of 25 g of (−)-DIP-Cl (78.125 mmol) in dichloromethane (75 mL, dry) cooled down to 0-2° C. After reacting for 72 h, 5.2 mL of acetaldehyde (92.2 mmol) were added and stirred at room temperature for 3 h. 71 mL of an aqueous NaOH (6N) solution, dichloromethane and saturated aqueous NaCl solution were added. The phases were separated and the usual treatment of the organic phase provided (−)-α-phenyl-4-piperidinemethanol as a white solid with a m.p.=48-50° C. in a 85% yield (86% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl.C1(C)C=CC=CC=1>[N:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of solution of 4-isocyanato-pyridine (1.28 mL, 0.26 mmol) in toluene (from Example 58a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid pyridine-4-ylamide as a white solid. (Yield 23 mg, 21.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(Cl)cccc1Cl)n1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 72 h

Procedure:
2-(4-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (3.8 grams; 0.018 mole), toluene (50 ml) and triethylamine (2.8 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dichlorobenzoyl chloride (4.19 grams) dissolved in toluene (10 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 3 days. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate, is filtered and is stripped of solvent under reduced pressure. The residue is washed with a hexane-ether mixture to yield a brown solid. This solid is recrystallized from a benzene-hexane mixture to yield the desired product 2-(4-chlorophenyl)-4-(2,6-dichlorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione having a melting point of 112° to 116°C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.[Si](OCC)(OCC)(OCC)OCC.[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:28]=1[NH2:29])([CH3:26])[CH3:25].OS(O)(=O)=O>>[Br:10][C:6]1[CH:5]=[C:4]([C:2](=[N:29][C:28]2[C:30]([CH:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=[CH:33][C:27]=2[CH:24]([CH3:26])[CH3:25])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(=O)c1cccc(Br)c1
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: CC(=Nc1c(C(C)C)cccc1C(C)C)c1cccc(Br)c1
Temperature: 170 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
In 25 mL Claisens flask in an argon atmosphere, a mixture of 3.98 g (20.0 mmol) of 3-bromoacetophenone, 5.00 g (24.0 mmol) of Si(OEt)4, and 3.90 g (22.0 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.20 mL of 96% H2SO4 was added. This mixture was stirred at this temperature for 1 hr, and the formed ethanol was slowly distilled off. Later, 300 mL of cold water was added, and the product was extracted with 2×70 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 50:1, vol.). This procedure gave 6.30 g (88%) of 13.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23]OS(C)(=O)=O)[O:20][C:19]2=[O:29])=[CH:14][C:13]=1[F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.O>[N:37]([CH2:23][CH:21]1[O:20][C:19](=[O:29])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:10]3[CH:31]=[CH:32][C:33]([CH2:35][CH3:36])=[CH:34][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:13]([F:30])[CH:14]=2)[CH2:22]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ccc(Oc2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)c(OCc2ccccc2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Oc2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)c(OCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of methanesulfonic acid 3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester (120 mg, 0.23 mmol) in 2 ml of dry DMF under nitrogen was added sodium azide (57 mg, 0.88 mmol). The reaction mixture was stirred at 75° C. overnight. The reaction mixture was diluted with 15 ml water and extracted with ethyl acetate. The combined organic phase was washed with water, saturated brine solution, dried over anhydrous Na2SO4 and concentrated in vacuo to get 100 mg of the title compound which was used as such for the next step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:20]=1
Reactant: NC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Yield: 63.1 %

Procedure:
A mixture of (E)-3-(4-trifluoromethylphenyl)-2-propenamide (17.9 g) and 1,3-dichloroacetone (14.8 g) in toluene (83 ml) was refluxed for 9 hours by use of Dean-Stark apparatus. After cooling, the reaction mixture was combined with water, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=6:1 to 5:1) to give the titled compound (15.1 g) as colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12OCCC[O:22]1)(=[O:11])=[O:10].[OH-].[CH2:28]([N+:35](C)(C)C)[C:29]1C=CC=C[CH:30]=1.O.C(Cl)Cl.CO>CCO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:30][CH2:29][CH2:28][N:35]=[C:16]3[C:15](=[O:22])[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCCCN12
Temperature: 59 °C
Yield: 290 %

Procedure:
A suspension of 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (6.8 g, 17.8 mmol) and benzyltrimethyl-ammonium hydroxide (40% by weight aqueous solution, 1.94 mL, 4.27 mmol, 0.25 eq) in absolute EtOH (80 mL) was heated to 59° C. and acryonitrile (2.93 mL, 44.5 mmol, 2.5 eq) was added drop-wise. After heating 5 hrs at 72° C. the reaction was cooled to room temperature, poured into H2O (160 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was flash chromatographed (Biotage KP silica gel, 99/1 then 98/2 CH2Cl2/CH3OH) to give the title compound as a white solid (4.5 g, 58% yield). Anal: Calc'd for C20H25N3O6S: C, 55.16; H, 5.79; N, 9.65; Found: C, 55.06, H, 5.94, N, 9.52; NMR (400 MHz, DMSO-d6): consistent. MS: (ES+) m/z 436[M+H] m.p.: 138-141° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[C:19]([OH:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+]([O-])([O-])=O.[Nd+3:33].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)C>[Nd:33].[O:1]([CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[C:19]([OH:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Nd+3]
Agent: O=C(O)c1cccc(CCOc2ccccc2)c1C(=O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: [Nd]
Temperature: 40 °C

Procedure:
The mono(2-phenoxyethyl)phthalic acid obtained in 6-1 was formed into a triethylamine salt in anhydrous ethanol, after which an ethanol solution of neodymium nitrate was added while stirring. That is, a reactor similar to the above was used to stir a solution obtained by adding 30 ml of an anhydrous ethanol to 88.6 g of the mono(2-phenoxyethyl)phthalic acid obtained in 6-1, while dripping 30.4 g of triethylamine while maintaining at 30° C. or less by cooling in an ice water bath. After dripping, the solution was heated for 30 minutes at 40° C. to prepare a synthesis solution of mono(2-phenoxyethyl)phthalic acid-triethylamine salts. Next, this synthesis solution was adjusted to 20° C., and a solution obtained by dissolving, 43.8 g of neodymium nitrate into 100 ml of ethanol was dripped in while stirring. After dripping, the solution was heated to 40° C. for 2 hours, to produce a synthesis solution of a neodymium salt of mono(2-phenoxyethyl)phthalic acid. Then, ethanol was distilled from this synthesis solution to concentrate, 300 ml of dichloromethane were added to the concentrate to form a solution, this solution was transferred to a 1 L separating funnel, shaken after pouring 400 ml of water into this separating funnel, and the resulting neodymium salts of mono(2-phenoxyethyl)phthalic acid were washed. After further washing this dichloromethane solution twice with 400 ml of water, the dichloromethane was distilled out. The solid obtained by distillation was crushed, then dried under reduced pressure at 50° C. to obtain 94.0 g of a neodymium salt of mono(2-phenoxyethyl)phthalic acid (yield 94%).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[C:28]1([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:9][CH2:8][CH2:7][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C1CCNC1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Yield: 42 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (60 mg, 0.13 mmol) and pyrrolidine (46.2 mg, 0.65 mmol) were allowed to react in the presence of K2CO3 (77 mg, 0.56 mmol) and NaI (Cat. 2.13 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (27 mg, 42%).