Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>ClCCl>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc2oc(-c3ccccc3)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.5 %

Procedure:
To a solution of 2-phenylbenzo[d]oxazol-5-amine (100 mg, 0.48 mmol) in dichloromethane (2 mL) at room temperature was added pyridine (83 μL, 0.95 mmol) followed by propane-1-sulfonyl chloride (61 μL, 0.52 mmol). The resulting solution was then stirred at room temperature for 16 h. Dichloromethane was added and the organic layer was washed with saturated aqueous copper sulfate solution. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting insoluble solid was washed with saturated aqueous NaHCO3 to afford 37.2 mg (25%) of the title compound (LCMS RT=6.25 min, MH+ 317.0)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21]O)[CH:11]=3)=[CH:9][C:2]=12.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH3:47]>ClCCl>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][NH2:47])[CH:11]=3)=[CH:9][C:2]=12
Reactant: OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Reactant: N
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propan-1-ol [12 g, Example 2(a)] and carbon tetrabromide (19.1 g) in dichloromethane (300 mL) at ambient temperature was treated with a solution of triphenylphosphine (12.9 g) in dichloromethane (100 mL) over 5 minutes. After stirring at ambient temperature for 3 hour the reaction mixture was filtered and the solid was washed with sparing amounts of dichloromethane. The filtrate and washings were evaporated to yield a brown gum, which was mixed with liquid ammonia (ca 80 mL) in a sealed pressure vessel and allowed to stir at ambient temperature for 18 hours. The vessel was then cooled to −78° C. and then cautiously vented. The ammonia was allowed to evaporate and the residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane, methanol and concentrated ammonia (900:100:7, v/v/v) to give the title compound as a yellow solid (3 g), m.p. 170° C. 1H NMR [(CD3)2SO]: δ 8.28 (1H, d, J=2.7 Hz); 8.18 (1H, s); 8.10, 7.64 (each 1H, d, J=7.7 Hz); 8.09 (1H, d, J=2.7 Hz); 7.29, 7.23 (each 1H, td, J=7.1 and 1.0 Hz); 6.97 (1H, s); 4.32 (2H, t, J=7.0 Hz); 2.57 (2H, t, J=6.5 Hz); 1.89 (2H, quintet, J=6.4 Hz).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:13])[CH2:11][NH2:12].[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=O.[Na].C(=O)(O)[O-].[Na+]>CO.C(OCC)C.C(N(CC)CC)C>[ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:13])[CH2:11][NH:12][CH:16]1[CH2:15][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 37 %

Procedure:
Glycyl-L-proline methylester hydrochloride (16.0 g, 72.1 m mole) was dissolved in methanol (150 ml), and Indan-2-on (4.75 g, 36.0 m mole) and triethylamine (1.8 g, 18.0 m mole) were added thereto. Sodium syanoborohydride (2.27 g, 36.0 m mole) was gradually added thereto while cooling with ice and stirring. The mixture was stirred for 1 hour while cooling with ice and next for 5 hours at room temperature. A little insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. To the residue, water (100 ml) and ethyl ether (100 ml) were added, and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring to dissolve it. The ethyl ether layer was removed, and the remaining water layer was washed with ethyl ether (100 ml). The desired product was extracted from the water layer with chloroform (100 ml×3 times). The thus obtained chloroform as extracted was concentrated under reduced pressure until a tar-like residuse was obtained. To thus produced tar-like residue ethyl ether and 5% sodium bicarbonate (200 ml) were added and the mixture was stirred to dissolve the solid matter. The aqueous layer was removed and the ethyl ether layer was washed with an aqueous solution saturated with sodium chloride. To the ethyl ether layer water (150 ml) was added, and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring and ethyl ether was removed. The water layer was washed with ethyl ether (100 ml) and to the water layer chloroform (200 ml) was added. The solution was adjusted to pH 8.0 with sodium bicarbonate while stirring. The aqueous layer was removed, and chloroform layer was dried with anhydrous sodium sulfate, and the sodium sulfate was separated by filtration. Separately, anhydrous hydrogen chloride gas was brown into the chloroform, and thus obtained hydrogen chloride chloroform solution was added to the above mentioned chloroform layer. After checking to ascertain that the pH of the solution had been preserved, a distillation was carried out under reduced pressure, to yield N-(2-indanyl)glycyl-L-proline methylester hydrochloride (4.50 g, 13.3 m mole, yield: 37%).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.CN(C)[CH2:26][CH2:27]CN=C=NCC.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([O:15][CH2:26][CH3:27])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C

Procedure:
5 g of Boc-Phe(4-NO2)—OH, 3.09 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 5 ml of ethanol and 2 g of dimethylaminopyridine were stirred in dichloromethane for 3 days. The obtained substance was washed with 1N hydrochloric acid, an aqueous solution of saturated sodium hydrogen carbonate and saturated NaCl solution, and dried with magnesium sulfate. The solvent was removed to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:17][NH2:18]>C1COCC1.CN(C=O)C.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:18][CH3:17])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1ccnc(Cl)c1
Temperature: 0 °C

Procedure:
2-Chloro-isonicotinic acid (12-1, 5.15 g, 32.7 mmol) was stirred in 65 mL anhydrous THF under N2. The reaction (not homogeneous) was cooled to 0° C. and oxalyl chloride (2.85 mL, 32.7 mmol) was added, followed by addition of 1 drop anh DMF. Slight bubbling occurs. The reaction was allowed to warm to RT. After 4 h reaction is homogeneous and after a total of 5 h the reaction was quickly added by pipet to a solution of methylamine (7.11 g, 228 mmol) in EtOH (20 mL). The resulting solution was concentrated in vacuo and diluted with sat NaHCO3 (aq). The solution was extracted 3× with EtOAc and the organic extracts were dried over Na2SO4, filtered ands concentrated to provide the titled compound. 1H NMR (CDCl3) δ 8.50 (d, 1H, J=5.1 Hz), 7.66 (s, 1H), 7.53 (d, 1H, J=5.1 Hz), 6.36 (bs, 1H), 3.04 (d, 2H, J=5.0 Hz).
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH:3]12[O:24][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (10.0 g, 49.2 mmol) in dichloromethane (197 mL) at 0° C. was added m-CPBA (16.98 g, 98 mmol) in several portions and the resulting mixture was allowed to warm to rt and stir overnight. The resulting white heterogeneous mixture obtained was diluted with dichloromethane (150 mL) and aq. sat. sodium bicarbonate (150 mL). The mixture was stirred and the resulting layers were separated and the organic portion was washed successively with aq. sat. sodium bicarbonate (150 mL), water, brine, before drying over anhyd. sodium sulfate, filtering and concentrating in vacuo to a colorless oil (˜14 g). This crude material was subjected to purification by preparative chromatography using Hex/EtOAc mixtures as the eluant and an 80 g silica gel cartridge. Fractions containing the major product were combined and concentrated to afford the title compound (9.60 g, 43.8 mmol, 89%) as a colorless oil. LCMS: 220.2 (M+H)+; 1H NMR (400 MHz, METHANOL-d4): δ 7.41-7.31 (m, 4H), 5.14 (d, J=1.1 Hz, 2H), 3.84-3.74 (m, 4H), 3.42 (t, J=13.8 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(COc2ccc(CC3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
4-{4-[4-(Trifluoromethyl)benzyloxy]benzyl}piperidine-1-carboxylic acid tert-butyl ester (2.64 g, 5.9 mmol), dichloromethane (5 ml) and trifluoroacetic acid (5 ml) were mixed and stirred at room temperature for 2 hours. After concentrating the reaction mixture, dichloromethane was added to the residue, and 5 N sodium hydroxide was further added, followed by vigorous stirring. The organic layer was separated, washed with water, dried over sodium sulfate, and then concentrated to afford the title compound as a colorless powder (2.06 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([F:27])[CH:17]=2)[CH:15]=1)[CH2:5][CH:6]([CH2:8][CH3:9])[CH3:7].[Li+].[OH-]>CO.O>[F:27][C:18]1[CH:17]=[C:16]([C:14]2[CH:15]=[C:10]([CH:4]([CH2:5][CH:6]([CH2:8][CH3:9])[CH3:7])[C:3]([OH:38])=[O:2])[CH:11]=[C:12]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)[CH:13]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]([F:25])([F:24])[F:26]
Reactant: CCC(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(OC(F)(F)F)c(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(OC(F)(F)F)c(F)c2)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 564.6 %

Procedure:
A mixture of 2-(3-fluoro-4-trifluoromethoxy-4″-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-yl)-4-ethyl-pentanoic acid methyl ester (2 mg) THF (1 mL), 10% LiOH in MeOH (0.3 mL) and H2O (0.3 mL) was stirred at 30° C. for 3 h. The solution was concentrated in vacuo and the residue was diluted with H2O and then acidified with concentrated HCl. The aqueous solution was extracted with DCM and filtered through polytetrafluoroethylene filter. The solution was concentrated in vacuo to give a solid residue. The solid was purified using reverse phase preparative HPLC (MeCN, H2O) to give the title product (11 mg, 44%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[CH:8][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:16][N:14]([CH:13]=[C:7]([C:6](=[O:10])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH3:15]
Reactant: c1csc(-c2ccno2)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)c1cccs1

Procedure:
A mixture of Compound 4 (13.0 g, 86 mmol) and dimethylformamide dimethyl acetal (22.4 g, 188 mmol) was refluxed under nitrogen for 3 hrs. Solid precipitated from the reaction mixture. The reaction mixture was cooled, diluted with dichloromethane and ether (1:10, 200 mL). The solid was collected by filtration, triturated with a solution of dichloromethane and ether (1:20, 100 mL). Compound 5 was obtained as an orange solid (13.5 g, 65.4 mmol, 76%). GC/MS, m/z=206 at tR=13.39 min (100%). LC/MS, [M+H]′=207.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.P1(O)(OC2C=CC3C(C=2C2C4C(C=CC=2O1)=CC=CC=4)=CC=CC=3)=O>[F:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: Fc1c(Br)cccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: O=P1(O)Oc2ccc3ccccc3c2-c2c(ccc3ccccc23)O1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Fc1c(N2CCNCC2)cccc1C(F)(F)F
Temperature: 80 °C
Yield: 54.5 %

Procedure:
To a solution of 3-bromo-2-fluorobenzotrifluoride (1.72 g, 7.1 mmol) in toluene (50 ml) under nitrogen, was added piperazine (0.89 g, 10.6 mmol), potassium tert-butoxide (0.95 g, 9.9 mmol), b is (dibenzylideneacetone)palladium(0) (0.19 g, 0.21 mmol) and (+/−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (0.13 g, 0.21 mmol). The resulting mixture was heated at 80° C. for 20 h. Filtration through a pad of celite and evaporation of the filtrate gave 2.1 g of crude product. The residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.96 g). MS m/z (rel. intensity, 70 eV) 248 (M+, 23), 207 (10), 206 (bp), 190 (17), 163 (8).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:14]([S:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([S:18][C:19](=[O:24])[CH:20]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[C:21](=[O:23])[CH3:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(CBr)cc1
Product: CCS(=O)(=O)c1ccc(CC(C(C)=O)C(=O)SC(C)(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-ethanesulfonylbenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH:6]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:9])[C:5]([CH3:17])([CH3:16])[CH2:4][O:3]1.[CH:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([OH:26])[CH:20]=1>>[OH:26][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:8]([CH:6]2[C:5]([CH3:17])([CH3:16])[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[O:7]2)=[O:9])=[CH:19][CH:20]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)Nc2ccc(O)cc2)O1
Yield: 97.5 %

Procedure:
3-[N-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid (1.04 g) and 0.665 g of p-aminophenol were reacted in the same manner as in Reference Example 15 to obtain 1.37 g of the objective compound (yield: 98%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[NH:9][CH:8]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.CCOC(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:5][CH2:4][OH:3])=[CH:8][NH:9]2
Reactant: CCOC(=O)C(=O)c1c[nH]c2cccc(Cl)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCc1c[nH]c2cccc(Cl)c12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chloro-3-(1H)-indoleglyoxylic acid ethyl ester (7.04 g, 30.0 mmol) in dry THF (0.4 L), at 0° C. under argon was added portionwise LiAlH4 (5.4 g, 135.2 mmol). The suspension was stirred at 0° C. for 20 min and at reflux for 3.5 h, cooled to 0° C., and water (17.6 mL) was added. It was stirred for 10 min, and then diluted with EtOAc. The reaction mixture was filtered. The solid was washed with EtOAc. The combined EtOAc portions were washed with water and brine, dried, filtered, and concentrated to give the title compound: TLC Rf=0.38 (9:1 CH2Cl2/Me2CO); MS (ESI−) m/z 194.0; 13C NMR (75 MHz, CDCl3) δ 138.02, 126.42, 124.21, 124.12, 122.70, 120.61, 112.63, 110.06, 63.59, 29.78.
Reaction SMILES: [H-].[Na+].O=[C:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:13])[CH3:12])[CH2:6][CH2:5]1.C1C[O:17][CH2:16][CH2:15]1>>[OH:17][CH2:16][CH:15]=[C:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:13])[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(=O)NC1CCC(=O)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)NC1CCC(=CCO)CC1

Procedure:
To a stirred suspension of sodium hydride (1.2 mmol) in THF was added triethyl phosphonoacetate (1.2 mmol) drop wise. The mixture was allowed to stir until it became colorless and a solution of N-(4-oxocyclohexyl)acetamide (1.0 mmol) in THF (1 mL) was added. The solution was allowed to stir at rt until the reaction was complete (by TLC). The solvent was removed under reduced pressure and the crude residue was filtered through a small plug of silica gel to afford the desired product, which was used directly in the next synthetic step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][N:14]([CH3:24])[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>Cl>[CH3:24][N:14]([CH3:13])[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][C:20]2([NH:1][C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=3[S:9](=[O:11])(=[O:10])[NH:12]2)[CH2:19][CH2:18]1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Reactant: CN(C)CCC1CCC(=O)CC1
Agent: Cl
Product: CN(C)CCC1CCC2(CC1)Nc1ccc(Cl)cc1S(=O)(=O)N2

Procedure:
A mixture of 2-amino-5-chlorobenzenesulfonamide (8.0 g., 0.039 mole) and 4-(2-dimethylaminoethyl)cyclohexanone (13.5 g., 0.08 mole) in 0.6 N ethanolic HCl (110 ml.) is heated at reflux 18 hours. The solvent is evaporated at reduced pressure and the residue dissolved in water (100 ml.) and neutralized with sodium hydroxide to precipitate 4'-(2-dimethylaminoethyl)-7-chlorospiro-[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxide hemisemihydrate which melts at 234°-5° C. after recrystallization from n-propanol.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C@H:10]([NH:74]C(OCC1C=CC=CC=1)=O)[C:11]([NH:13][CH:14]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21]([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([S:34]([NH:37][C@@H:38]([CH2:42][NH:43][C:44]([C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[N:51]([CH2:55][CH2:56][CH2:57][NH:58][C:59]2[NH:60][CH:61]=[CH:62][N:63]=2)[N:50]=[CH:49]3)=[O:45])[C:39]([OH:41])=[O:40])(=[O:36])=[O:35])=[C:29]([CH3:64])[CH:28]=1)=[O:22])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CO.[Pd].O.C(#N)C>[NH2:74][C@@H:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:11]([NH:13][CH:14]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21]([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH3:64])[C:30]([S:34]([NH:37][C@@H:38]([CH2:42][NH:43][C:44]([C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[N:51]([CH2:55][CH2:56][CH2:57][NH:58][C:59]2[NH:60][CH:61]=[CH:62][N:63]=2)[N:50]=[CH:49]3)=[O:45])[C:39]([OH:41])=[O:40])(=[O:35])=[O:36])=[C:31]([CH3:33])[CH:32]=1)=[O:22])=[O:16])=[O:12]
Reactant: Cc1cc(OCCCC(=O)NCCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)N[C@@H](CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCCCC(=O)NCCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)cc(C)c1S(=O)(=O)N[C@@H](CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Reaction time: 3 h
Yield: 114.6 %

Procedure:
The product of step B (25 mg, 24 umol) in methanol (3 mL) was added to 10% palladium on carbon (14 mg) in methanol (3 mL) under nitrogen in a Parr bottle. It was hydrogenolyzed at 50 psi for 180 min, filtered through Celite, rinsed with methanol, and concentrated to afford a viscous oil. This was redissolved in 1:1 water/acetonitrile containing 0.1% TFA (nmL) and lyophilized (1:1 acetontrile/water/0.1% TFA) to afford the product as a white powder (29 mg, 100% yield) which analyzes for 2 equal peaks by HPLC (4.6×150 mm Zorbax C-18, 1 mL/min; Water/90% acetonitrile/0.1% trifluoroacetic acid, 2-100% B over 14 min) Rt=9.78 and 10.14 minutes. LRMS (ES): 1054.5 ([M+H]+, 10%) 527.8 ([M+2H]+2, 100%); identical for each peak. This was not further purified but taken into the next step as a mixture of two diastereomers.
Reaction SMILES: O[C:2]1[C:10]2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[N:7]=[CH:6][C:5]=2[O:4][C:3]=1C(OC)=O.Cl.C[Si](C=[N+]=[N-])(C)C.C(OCC)C>C(=O)([O-])O.[Na+]>[CH3:20][O:19][C:17](=[O:18])[CH2:16][CH2:15][C:8]1[N:7]=[CH:6][C:5]2[O:4][CH2:3][CH2:2][C:10]=2[C:9]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCc1ncc2oc(C(=O)OC)c(O)c2c1C(=O)OC
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Product: COC(=O)CCc1ncc2c(c1C(=O)OC)CCO2
Temperature: 150 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A mixture of dimethyl 3-hydroxy-5-(3-methoxy-3-oxopropyl)furo[2,3-c]pyridine-2,4-dicarboxylate (3.10 g, 9.19 mmol) and 12M hydrochloric acid (31 mL) was stirred at 150° C. for 1 hr and concentrated under reduced pressure. The residue was dissolved in methanol (60 mL), palladium-carbon powder (600 mg) was added, and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (60 mL) again, palladium-carbon powder (1.00 g) was added, and the mixture was stirred at 50° C. for 4 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (60 mL), 2M trimethylsilyldiazomethane/diethyl ether solution (9.2 mL, 18 mmol) was added under ice-cooling, and the mixture was stirred for 30 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.98 g, yield 81%).