Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[C:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20]O>[Ni]>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=1)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]2
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C(=O)[O-])c2[nH]1
Reactant: CO
Agent: [Ni]
Product: COC(=O)c1cc(N)cc2cc(C(C)(C)C)[nH]c12
Yield: 68 %

Procedure:
A solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.0 g, 7.2 mmol) and Raney Nickel (200 mg) in CH3OH (50 mL) was stirred for 5 h at the room temperature under H2 atmosphere. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate (1.2 g, 68%) 1H NMR (CDCl3, 400 MHz) δ 9.34 (brs, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.10 (s, 1H), 6.12 (d, J=1.6 Hz, 1H), 3.88 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].CC#N.[Br:19][CH:20](Br)[CH3:21]>CCOCC>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=Cc1cccc(OCCBr)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-hydroxybenzaldehyde (5.17 g, 42.33 mmol), K2CO3 (58.5 g) and CH3CN (100 ml) was stirred at room temperature for 15 minutes, then dibromoethane (18.3 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes, then at reflux for 3-4 hours. Additional dibromoethane was added and then the reaction mixture was refluxed overnight. The reaction mixture was cooled, filtered, and the filtrate was stripped to afford an oil. The oil was dissolved in ether (300 ml), washed with 5N NaOH (2×75 ml) and the ether layer was dried over MgSO4 and stripped. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 5.23 g of 3-(2-bromoethoxy)benzaldehyde.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCOCCBr
Reactant: C1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOCCN1CCCCCC1
Yield: 65 %

Procedure:
[2-(2-methoxyethoxy)ethyl]azepane was obtained using procedure 1a, from azepane (10.3 g, 0.103 mol) in methanol (50 cm3), 1-bromo-2-(2-methoxy-ethoxy)ethane (10.0 g, 0.103 mol) and potassium carbonate (16.0 g). After distillation in vacuo (66-68° C., 1.0 mmHg), [2-(2-methoxyethoxy)ethyl]azepane was obtained as a colourless liquid in ca. 65% yield. δH (500.13 MHz, CDCl3) 3.59 (6H, m), 3.38 (3H, s), 2.73 (2H, t), 2.68 (4H, m), 1.59 (8H, br m). ESI-MS: m/z=202 [M+H]+ (100). Calcd. for C11H23NO2: 202.1807; found: 202.1802.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[C:10]3[CH2:12][CH2:13][CH2:14][C:9]3=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=O)=[CH:18][CH:17]=3)[CH:7]=2)=[CH:2]1.[NH3:28]>CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[C:10]3[CH2:12][CH2:13][CH2:14][C:9]3=[C:8]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH2:28])=[O:25])=[CH:20][CH:21]=3)[CH:7]=2)=[CH:2]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ccsc3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3ccsc3)nc3c2CCC3)cc1
Yield: 50 %

Procedure:
Following general procedure C, ethyl 2-(4-((2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.065 g, 0.17 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL), followed by formation of the hydrochloride salt to afford the title compound (0.033 g, 50%) as a light yellow solid. MW=385.91. 1H NMR (DMSO-d6, 500 MHz) δ 13.84 (s, 1H), 9.69 (s, 1H), 8.35-8.31 (m, 1H), 7.81-7.76 (m, 1H), 7.59-7.56 (m, 1H), 7.51 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.05 (s, 1H), 6.92 (s, 1H), 3.43 (s, 2H), 3.15 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.23 (quin, J=7.5 Hz, 2H); APCI MS m/z 350 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12]C)=[CH:5][C:4]=1[CH3:14].B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[CH:5][C:6]([OH:12])=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])c(O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A solution of 1,4-dimethoxy-2-methyl-5-nitrobenzene (6.0 g) in methylene chloride (30 mL) was cooled to −20° C., and a solution of boron trichloride (1.0 M in CH2Cl2) (30 mL) was added dropwise at −20° C. thereto. Then the reaction mixture was allowed to warm to room temperature and stirred for 16 h. To the reaction solution was then added saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography over silica gel using hexane/ethyl acetate (9:1) to give the title compound (4.25 g).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:26]4[CH2:27][C:28]5[S:29][CH:30]=[CH:31][C:32]=5[C:25]=4[N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>C(Cl)Cl>[Br:8][C:30]1[S:29][C:28]2[CH2:27][C:26]3[C:22]([C:19]4[CH:20]=[CH:21][C:16]([N:13]5[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]5)=[CH:17][CH:18]=4)=[N:23][N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:25]=3[C:32]=2[CH:31]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)CC1
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(Br)cc3-4)cc2)CC1
Reaction time: 2 h
Yield: 84 %

Procedure:
NBS (0.18 g, 1.0 mmol) was added to a solution of 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.23 g, 0.5 mmol) in CH2Cl2 (5.0 mL). After 2 hr, the solution was evaporated and washed with EtOAc, filtered, and concentrated to give the corresponding 2-Bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.23 g, 0.42 mmol) as brown solid in 85% yield.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([N:12]1[C:13]2[C:18](=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)=[O:33]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)n1cc(C2=CCN3CCCC3C2)c2cnccc21
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a THF (1 mL) solution of 3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-5-azaindole (10 mg, 0.0418 mmol) at RT, 1M NaN(TMS)2 (100 μl, 0.1 mmol) was added and the mixture stirred for 10 mins. 2-chlorobenzoyl chloride (13 μL, 0.103 mmol) was added and the reaction mixture stirred overnight. After dilution with dichloromethane, purification by column chromatography with 2% methanol (2M/NH3) in dichloromethane gave 1-(2-chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole (8.9 mg, 56.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10][C:9]2=O)=[CH:4][CH:3]=1.[CH2:18]([C:25]1[CH:29]=[CH:28][NH:27][C:26]=1CO)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:12]([CH:13]([CH3:15])[CH3:14])[C:11]([O:10][CH2:9][C:26]2[NH:27][CH:28]=[CH:29][C:25]=2[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(Nc1ccc(Cl)cc1)C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (336 mg, 1.32 mmol) and 4-dimethylaminopyridine in 5 ml of dry tetrahydrofuran is added a solution of 3-benzylpyrrolylmethyl alcohol (1.26 mmol) in 3 ml of dry tetrahydrofuran. The reaction mixture is stirred for about 20 hours, under dry air, and then diluted with ether followed by washing with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. After drying over calcium sulfate, solvent is evaporated. The crude product is chromatographed on a rotary chromatograph eluting with 15% ether/hexane to give 3-benzylpyrrolylmethyl 2-(4-chlorophenylamino)-3-methylbutanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.Cl[CH2:19][C:20](=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:19][C:20](=[O:22])[CH3:21])[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: CC(=O)CCl
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CC(C)=O)CC3
Yield: 55 %

Procedure:
Prepared by the method described for Example 26 from 1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.46 g, 0.015 moles) and 1-chloro-2-propanone (2.0 g, 0.022 moles). Recrystallization from methanol gave the product (2.37 g), mp 123°-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1C=CN=C1.[N+:19]([CH:22]=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][S:24]1)([O-:21])=[O:20]>C(COC)OC.C(Cl)Cl>[N+:19]([C:22](=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][S:24]1)[C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:9])([O-:21])=[O:20]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(C(=C1NCCCS1)[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution/suspension of 20.4 g of p-nitrobenzoyl chloride in 25 ml of monoglyme was added dropwise at 5°-10° to a solution of 9.09 g of N-methylimidazole in 75 ml of monoglyme and the mixture was stirred for an additional 30 minutes at 5°-10°, after which was added dropwise (same temperature) a solution/suspension of 16.0 g of tetrahydro-2-(nitromethylene)-2H-1,3-thiazine in 25 ml of monoglyme, after which the stirred mixture was allowed to warm to room temperature and stirred for 96 hours. The mixture then was taken up in methylene chloride, washed with water and saturated sodium chloride solution, dried (Na2SO4) and the solvent evaporated under reduced pressure to give an oil which was chromatographed on florosil using methylene chloride as eluent to give a gum, which was washed with ether to give 17, as a yellow solid, m.p.: 158°-160.5°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C.Cl>[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH2:11])=[CH:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCOc1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of 4-hydroxybenzenesulfonamide (1.211 g, 7.0 mmol) and tert-butyl(4-bromobutyl)carbamate (1.26 g, 5.0 mmol) in acetonitrile (50 mL) was added anhydrous K2CO3 (1.38 g, 10 mmol). The reaction mixtures were stirred at 75° C. for overnight. Solvent was evaporated under reduced pressure to give a residue. The residue was diluted with 1 N HCl (20 mL), extracted with DCM, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with DCM to 10% MeOH in DCM to afford tert-butyl(4-(4-sulfamoylphenoxy)butyl)carbamate as a white solid (0.720 g, 42%). 1H NMR (400 MHz, DMSO) 7.70 (d, J=8.8 Hz, 2H), 7.16 (s, 2H), 7.04 (d, J=8.8 Hz, 2H), 6.82 (brs, 1H), 4.01 (t, J=6.6 Hz, 2H), 2.94 (q, J=6.4 Hz, 2 II), 1.69-1.64 (m, 2H), 1.52-1.46 (m, 2H), 1.35 (s, 9H); MS (ESI), 367.1 (M+Na)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)[NH:39][C:40]4[N:44](C5C=NN(CCOS(C)(=O)=O)C=5)[N:43]=[C:42]([CH:57](C)C)[CH:41]=4)CC3)C=CC2=NN=1>>[NH2:39][C:40]1[N:44]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[N:43]=[C:42]([CH3:57])[CH:41]=1
Reactant: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Reactant: Oc1cccc(I)c1
Product: Cc1cc(N)n(-c2cccc(O)c2)n1

Procedure:
The title compound was prepared starting from 5-methyl-2H-amino pyrazol (500 mg, 5.1 mmol) and 3-iodo-phenol (1.25 g, 5.7 mmol) by using an analogous procedure to that described for Intermediate A step b. LCMS (Method 3): Rt 0.99 min, m/z=190 [MH+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C=O.[NH2:12][C:13](N)=O>>[NH2:12][CH2:13][CH2:2][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: NC(N)=O
Reactant: CC(=O)c1ccccc1
Agent: C=O
Product: NCCC(O)c1ccccc1

Procedure:
The compounds of formula (I) may be prepared by condensing an acetophenone of general formula (II): ##STR3## (in which R1 and R2 are as defined above) in a Mannich reaction with formaldehyde and a primary or secondary amine, reducing the amino-ketone thus formed to a 3-amino-1-phenyl-propan-1-ol, and subsequently dehydrating this 3-amino-1-phenyl-propan-1-ol. The compound so produced is of general formula (I) in which A is CH=CH; subsequently, if desired, this compound may be hydrogenated to produce a compound of formula (I) in which A is CH2CH2.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.0 g (98.3 mmol) of 9-phenylanthracene was put into a 1-L three-neck flask, and 300 mL of carbon tetrachloride was added thereto. A solution in which 15.6 g (98.3 mmol) of bromine was dissolved in 40 mL of carbon tetrachloride was dropped in the reaction solution at the room temperature. After the dropping, the reaction solution was stirred at the room temperature for 1 hour. Thereafter, the reaction is completed by adding a sodium thiosulfate aqueous solution, and the solution was further stirred for 1 hour. An organic layer of the reaction mixture was washed with aqueous sodium hydroxide (2.0 mol/L) and saturated saline and dried with magnesium sulfate. This mixture was filtrated naturally, and the filtrate was condensed to obtain a solid. The solid was dissolved in toluene, and the solution was subjected to suction filtration through Florisil, celite, and then alumina. The filtrate was concentrated to obtain a solid, and the solid was recrystallized with a mixture solution of dichloromethane and hexane, whereby 27.8 g of a light yellow powdery solid that was a target matter was obtained with the yield of 85%.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[C:18]([C:21]1[C:29](=[O:30])[N:28]2[C:24]([S:25][C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=32)=[N:23][CH:22]=1)([OH:20])=O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[NH:37]1[C:36]([NH:35][C:18]([C:21]2[C:29](=[O:30])[N:28]3[C:24]([S:25][C:26]4[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=43)=[N:23][CH:22]=2)=[O:20])=[N:40][N:39]=[N:38]1
Reactant: O=C(O)c1cnc2sc3ccccc3n2c1=O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cnc2sc3ccccc3n2c1=O

Procedure:
To a solution of 360 mg. of 1,1'-carbonyldiimidazole in 6 ml. of dry tetrahydrofuran at 140° C. is added dropwise 500 mg. of 3-carboxy-4-oxo-4H-pyrimido[2,1-b]benzothiazole in 6 ml. of dry dimethylformamide. After heating for 3 hrs., 186 mg. of 5-aminotetrazole is added, and the heating maintained for an additional 15 min. The reaction mixture is cooled and the precipitated product filtered. Recrystallization from dimethylformamide gives 200 mg. of the desired product, m.p. 330°-332° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]([C:14](=[O:21])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[Na+]>CO>[NH:16]1[C:17](=[O:20])[CH2:18][CH2:19][C@H:15]1[C:14]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][C:4]([OH:22])=[O:3])=[O:21]
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H]1CCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN(Cc1ccccc1)C(=O)[C@@H]1CCC(=O)N1
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
1.25 g N-(pyroglutamyl)-N-benzylglycine ethylester is dissolved in 5 ml methanol, treated with 3 ml 2N NaOH, and stirred for 5 min., after which the solution is concentrated to a small volume by removal of solvents. The residue is then dissolved in 10 ml H2O, acidified to pH2, extracted several times with ethyl acetate, and dried over anhydrous MgSO4. Following evaporation of solvent, the residue is chromatographed on silica gel (55 g) using chloroform/methanol/acetic acid (4:1:0.1). The first fractions give 0.36 g N-(pyroglutamyl)-N-benzylglycine as a white solid. TLC: (silica gel; CHCl3 /MeOH/HOAC=4:1:0.1) Rf =0.6, Mass: 276 (molecular ion).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:17]=1)([O-:7])=[O:6].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([N:13]1[C:12]2[CH:17]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCOc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 90 %

Procedure:
Under vigorous stifling at room temperature, acetyl chloride (1.02 g, 13 mmol) was added dropwise to a mixture of 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.8 g, 10 mmol) and NaHCO3 (7.14 g, 85 mmol) in CH2Cl2 (50 mL). After addition, the reaction was stirred for 1 h at this temperature. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with Et2O:hexane (1:2, 50 mL) under stifling for 30 min and then filtered to give 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a pale yellow solid (2 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)N=Cc2cccc(Cl)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=S1(=O)NCc2cccc(Cl)c21
Temperature: 0 °C
Yield: 97.4 %

Procedure:
A suspension of 17.9 g of 7-chloro-1,2-benziso-thiazole-1,1-dioxide in 180 ml of absolute ethanol was cooled to 0° C. and treated with 3.33 g of sodium borohydride at such a rate that the temperature remained below 5° C. The mixture was warmed to room temperature for 30 minutes, recooled to 0° C. and treated with glacial acetic acid to destroy excess hydride. The mixture was concentrated to dryness, the resulting solid suspended in water, filtered, washed with water and dried in vacuo at 50° C. for 16 hours to give 17.6 g of the title compound as a white powder, m.p. 159°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]OCF)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3F)[OH:27])[C:9]2=[O:36])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44]1[S:49](=[O:51])(=[O:50])[O:48]CC[CH2:45]1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:36])[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[CH:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:45][CH2:44][S:49]([OH:51])(=[O:50])=[O:48])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2F)C(c2ccc(OCCOCF)cc2)N1c1ccc(F)cc1F
Reactant: O=S1(=O)CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCS(=O)(=O)O)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute dimethylformamide. 337 mg of powdered potassium carbonate and 69 μl of 1,4,-butanesultone were added. The mixture was stirred at room temperature overnight. The reaction solution was filtered and concentrated under oil pump vacuum. The residue was chromatographed on a 10 g SiO2 cartridge (dichloromethane/methanol=5/1) and crystallized from diethyl ether. The product (131 mg) was obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[O:23][CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][NH:34][C:33]2=[O:42])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[C:33](=[O:42])[NH:34][CH:35]=2)=[O:40])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Reactant: O=C(O)c1c[nH]c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c[nH]c(=O)n(-c5ccc(F)cc5)c4=O)cc3OC)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenylamine (LCMS m/z=327 (M+1)) and 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. LCMS m/z=559 (M+1); 1H NMR (CDCl3) δ: 10.94 (s, 1H), 8.69 (s, 1H), 8.45 (d, 1H, J=6 Hz), 8.2 (d, 1H, J=5 Hz), 7.61 (s, 1H), 7.42 (s, 1H), 7.32-7.26 (m, 3H), 7.2 (s, 1H), 6.57 (d, 1H, J=7 Hz), 6.33 (d, 1H, J=7 Hz), 5.30 (s, 1H), 4.05 (s, 6H), 3.76 (s, 3H).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:13][CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: NCCC#Cc1cccc(CF)n1
Product: O=S(=O)(NCCC#Cc1cccc(CF)n1)c1ccccc1Cl
Yield: 18.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39 mg, 0.22 mmol, Example 189(D)) and 2-chlorobenzenesulfonyl chloride (60 mg, 0.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 14.4 mg (41 μmol, 19%) of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzenesulfonamide as an orange oil.