Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](OCC)=O)[CH:19]=[CH:20][CH:21]=1.C(O)C.[H-].[Na+]>O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][C:23]1[NH:14][C:12](=[O:13])[C:3]2[CH:4]=[N:5][N:6]([CH:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[C:2]=2[N:1]=1
Reactant: NC(=O)c1cnn(C2CCCC2)c1N
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1cnn2C1CCCC1

Procedure:
Under argon, 180 mg (0.91 mmol) of 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxamide and 575 mg (2.72 mmol; 3 equiv.) of ethyl (3-chlorophenyl)acetate are introduced into 3.5 ml of absolute ethanol. At 0° C., 127 mg of sodium hydride (60% dispersion in mineral oil; 3.18 mmol; 3.5 equiv.) are slowly added in a countercurrent of argon. The resulting mixture is slowly warmed and stirred under reflux for 18 h. The mixture is worked up by adding 50 ml of water and extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].O.C(=O)([O-])[O-].[K+:38].[K+]>CO>[K+:38].[C:20]([N:7]1[C@@H:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:5]([C:3]([O-:4])=[O:2])[O:9][CH:8]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2O[C@@H](C(=O)[O-])[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c(OC)c1
Reaction time: 1 h

Procedure:
A 100 mg (0.23 mM) quantity (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (Preparation No. 6, 5Ba) is stirred at room temperature under nitrogen in 3 mL MeOH. Added 0.1 mL water and 43 mg (0.31 mM) potassium carbonate. After 1 hour, TLC shows no starting material left. Store in freezer overnight. The next morning the solvent is evaporated to give (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid potassium salt (6Ba). The residue is partitioned between methylene chloride and water containing 0.9 mL 1N HCl. The layers are separated and the aqueous layer reextracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated. This leaves (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (7Ba) as a white solid.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH2:34]F)[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:25]2>O1CCCC1.ClCCl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH3:34])[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[N:25]2
Reactant: O=C(NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1)c1ccccc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(CNCC(F)(F)F)c(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
Lithium triethylborohydride (1.13 mL, 1.13 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C27) (60 mg, 0.11 mmol) in tetrahydrofuran (4 mL). The reaction mixture was allowed to stir at room temperature for 16 hours and then partitioned between ethyl acetate (25 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted further with ethyl acetate (3×25 mL). The combined organics were then washed sequentially with water (100 mL) and with brine (100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a white solid. The organic crude was re-dissolved in dichloromethane (20 mL) and the resulting solution was washed with 1 N sodium hydroxide (3×25 mL), water (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the product as an orange solid (60 mg), which was taken directly to the following step. LCMS m/z 514 [M+H+].
Reaction SMILES: [Cl:1][C:2]1(F)[C:5]([F:7])([F:6])[C:4]([F:9])([F:8])[C:3]1(F)Cl.FC1(F)C(F)=C(F)C1(F)F>>[F:6][C:5]1([F:7])[C:2]([Cl:1])=[CH:3][C:4]1([F:9])[F:8]
Reactant: FC1(F)C(F)(F)C(F)(Cl)C1(F)Cl
Agent: FC1=C(F)C(F)(F)C1(F)F
Product: FC1(F)C=C(Cl)C1(F)F

Procedure:
The conversion of 1,2-dichlorohexafluorocyclobutane was 30%, the selectivity of the targeted hexafluorocyclobutene was 96% and a 3.5% selectivity of tetrafluoro-1-chlorocyclobutene was formed as the by-product. The selectivity and the conversion were calculated by multiplying the correction coefficient, which was independently determined by the gas chromatography peak areas. The same procedure was used for the following operations.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH:44][C:45]3[S:49][N:48]=[CH:47][N:46]=3)(=[O:43])=[O:42])=[CH:37][C:36]=2[C:50]#[N:51])=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:16]=2)[CH:14]=1.C(Cl)Cl>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH:44][C:45]3[S:49][N:48]=[CH:47][N:46]=3)(=[O:42])=[O:43])=[CH:37][C:36]=2[C:50]#[N:51])=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:16]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3Oc3ccc(S(=O)(=O)Nc4ncns4)cc3C#N)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(Cl)cc1-c1ccnc(N2CCNCC2)n1
Reaction time: 1 h
Yield: 42.1 %

Procedure:
3-Cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 43.6 mg, 0.154 mmol), tert-butyl 4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate (Preparation 873, 50.0 mg, 0.128 mmol) and potassium carbonate (53 mg, 0.38 mmol) in dimethyl sulfoxide (1 mL, 10 mmol) was stirred at 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude intermediate, tert-butyl 4-[4-(5-chloro-2-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate, as a yellow solid. Trifluoroacetic acid (300 uL, 4 mmol) was added to a solution of tert-butyl 4-[4-(5-chloro-2-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate (83 mg, 0.154 mmol) in methylene chloride (2.9 mL, 46 mmol). After 1 hour, the reaction mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the product as a white solid (trifluoroacetic acid salt, 36 mg, 51%).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14](C#N)=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2].[CH:27]([N-:29]C=O)=[O:28].[Na+].O>CC(N(C)C)=O>[C:25]([C:13]1[C:14]([NH:29][CH:27]=[O:28])=[N:15][C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)[N:12]=1)#[N:26]
Reactant: O=C[N-]C=O
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)n1nc(-c2nc(C#N)c(NC=O)nc2-c2ccccc2)ccc1=O
Temperature: 102.5 °C
Yield: 8.3 %

Procedure:
A suspension of 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (343 mg) and sodium diformylamide (190 mg) in DMA (1 ml) was heated at 100-105° C. for an hour. After addition of water, the reaction mixture was extracted with CHCl3, dried over MgSO4, concentrated under reduced pressure and subjected to column chromatography on silica gel. With elution of a mixture of n-hexane and EtOAc (50:50 v/v) was obtained [3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2-pyrazinyl]formamide as a solid (30 mg) and with elution of a mixture of n-hexane and EtOAc (30:70 v/v) was obtained [3-cyano-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinyl]-formamide as a solid (22 mg).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:6]=[C:7]([C:20]2[CH:25]=[C:24]([S:26](=[O:33])(=[O:32])[NH:27]C(C)(C)C)[CH:23]=[CH:22][C:21]=2[O:34]C)[C:8]([O:13]COCCOC)=[C:9]([CH:11]=O)[CH:10]=1.Cl.[NH2:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[NH2:48])[C:42]([NH2:44])=[NH:43].C1(=O)C=CC(=O)C=C1.Cl.N1C=CC=CC=1>CO>[C:42]([C:41]1[CH:45]=[CH:46][C:47]2[NH:48][C:11]([C:9]3[CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:36])[CH:6]=[C:7]([C:20]4[CH:25]=[C:24]([S:26](=[O:32])(=[O:33])[NH2:27])[CH:23]=[CH:22][C:21]=4[OH:34])[C:8]=3[OH:13])=[N:38][C:39]=2[CH:40]=1)(=[NH:43])[NH2:44]
Reactant: COCCOCOc1c(C=O)cc(CC(=O)OC)cc1-c1cc(S(=O)(=O)NC(C)(C)C)ccc1OC
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Solvent: c1ccncc1
Product: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Temperature: 180 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Methyl[5′-tert-butylsulfamoyl-5-formyl-2′-methoxy-6-(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (0.496 g, 1.1 mmol), prepared as in Reference 8, was dissolved in methanol (20 mL) and the solution was charged with 3,4-diaminobenzamidine-HCl (1.25 mmol, 0.23 g) and 1,4-benzoquinone (1.25 mmol, 0.135 g). The mixture was refluxed for 2 hours and then concentrated by evaporation. This residue was taken up in trifluoroacetic acid (10 mL) and the mixture was stirred for 1 hour. Evaporation and further pumping down yielded a purple amorphous residue. Pyridine hydrochloride (5.0 g) was added and the reaction mixture was heated at 180° C. for 30 minutes. The mixture was cooled and a resulting solid was dissolved in 20 mL of preparative hplc sample solvent (20% acetonitrile/20 mmol HCl). The product was purified by preparative hplc (C-18, 2,2,25 acetonitrile). The fractions containing the pure product were collected and lyophilized to give [5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetic acid (0.31 g, 59%). LCMS: Calcd 481.49; Obsd (MH+)=482.0, (MH−)=480.2. NMR (DMSO-d6) d 3.621 (s, 2H), 7.07 (d, J=8 Hz, 1H), 7.15 (br s, 2H), 7.27 (d, J=2 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.65 (m, 2H), 7.73 (d of d, J=2, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.08 (d, J=2 Hz, 1H), 8.17 (s, 1H), 9.10, 9.39 (2s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]([CH2:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28])=[O:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[CH2:25][C:23]([O:22][CH3:21])=[O:24])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: COC(=O)Cc1ccccc1N
Product: COC(=O)Cc1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 69.9 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5 H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and o-methoxycarbonylmethylaniline (180 mg, 1 mmol) to give 340 mg of the title compound (70%): mp 206°~207° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 9.51 (s, 1H), 7.36 (bd, 1H, J=8.6 Hz), 7.26~7.29 (m, 3H), 7.16~7.19 (m, 2H), 5.16~5.25 (m, 1H), 3.70 (s, 2H), 3.59 (s, 3H), 3.07 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.60 (d, 2H, J=7.6 Hz), 2.11 (dm, 1H, J=13.5 Hz), 1.80~1.96 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1ccc(C=CC(=O)O)cc1OCCOC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCOc1ccc(CCC(=O)O)cc1OCCOC
Yield: 74.5 %

Procedure:
To a solution of 3-[3,4-Bis-(2-methoxy-ethoxy)-phenyl]-acrylic acid (20 g, 67.5 mmol) in EtOAc (100 ml) and MeOH (100 ml) was added carefully 10% Pd/C (1.5 g), then the mixture was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen. The solution was passed through a celite pad, and the filtrate was concentrated to give product (15 g, 78.5%). LC-MS: m/e 297 (M−1)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13].CN(C)C=O>O>[F:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[C:5]=1[OH:9])[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: Oc1c(F)cc(Br)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 4-bromo-2,6-difluorophenol (4.00 g, 19.0 mmol), copper (I) cyanide (1.72 g, 19.0 mmol), and dimethylformamide (40 mL) was refluxed for 6 hours, cooled to room temperature, diluted with water (150 mL), and filtered. The tan solids obtained were washed with water and retained. The combined filtrates were acidified (1N HCl) and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (Silica Gel 60, 20% ethyl acetate in hexanes) to give 1.03 g of pure title compound as an off-white solid, mp 195°-197° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:20])[N:11]([CH2:18][OH:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[P:21](Cl)(=[O:38])([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[P:21]([O:19][CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:20])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(COP(=O)(OCc3ccccc3)OCc3ccccc3)c3ccccc32)[nH]1

Procedure:
The title compound was prepared from (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (1) and dibenzyl phosphorochloridate (modification of procedure used to prepare {3(Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}methyl acetate (2)).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[F:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+]>C(O)(C)C>[C:21]1([NH:27][N:28]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[F:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2F)CC1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(Br)cc2F)CC1
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of 1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine (16.6 g, 0.051 mol), phenylhydrazine hydrochloride (16.6 g, 0.11 mol), sodium acetate, (22.2 g) and isopropanol (250 ml) was stirred and refluxed for 4 hours. The reaction stood at ambient temperature for 16 hours, and then was filtered. The filtercake was treated with water, and the insoluble hydrazone was collected and dried to yield 13.7 g. The isopropanol filtrate was concentrated in vacuo to a solid, which when triturated with ether yielded 6.1 g more of the hydrazone (total yield 19.8 g; 93%). The phenylhydrazone was a mixture of the two geometric isomers. A 3.5 g sample of the compound was recrystallized from isopropanol to yield 2.1 g of the phenylhydrazone; mp 174°-176° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][NH:4][S:5]([C:8]1[CH:19]=[C:12]2[C:13]([O:15]C(=O)[NH:17][C:11]2=[CH:10][CH:9]=1)=O)(=[O:7])=[O:6].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:13](=[O:15])[C:12]2[C:11](=[CH:10][CH:9]=[C:8]([S:5](=[O:6])(=[O:7])[NH:4][CH2:3][CH:2]([CH3:1])[CH3:20])[CH:19]=2)[NH2:17])[CH2:24][CH2:23]1
Reactant: CC(C)CNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CC(C)CNS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-[N-(2-methylpropyl)-sulfamoyl]-isatoic anhydride with 1-methylpiperazine yields 5-[N-(2-methylpropyl)-sulfamoyl]-anthranilic acid (4-methyl)-piperazide with a melting point of 162°-163° (from ethanol; melting point of the hydrochloride: 254°-255°).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:23])[CH2:22][CH2:21][CH2:20][CH:19]3[CH:15]2[CH2:16][CH2:17][NH:18]3)=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([OH:23])[CH2:22][CH2:21][CH2:20][CH:19]3[CH:15]2[CH2:16][CH2:17][N:18]3[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:12][CH:13]=1
Reactant: OC1(c2ccc(Cl)cc2)CCCC2NCCC21
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2C1CCCC2(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The starting material was produced as follows: 2.74 g of Cyclopropanecarboxylic acid chloride was added dropwise to a solution of 7.2 g of (3aRS, 4SR, 7aRS)-4-p-chlorophenylhexahydro-4-indolinol and 2.5 ml of pyridine in 30 ml of methylene chloride at 0° to 10°. The mixture was stirred at room temperature for 1 hour, and then was washed first with a 10% tartaric acid solution, then with a sodium bicarbonate solution, then with a saturated salt solution. The organic phase was dried over sodium sulphate and concentrated to afford (3aRS, 4SR, 7aRS)-4-p-chlorophenyl-1-cyclopropylcarbonylhexahydro-4-indolinol. (M.P. 167°-169°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[O-:11][C:12]#[N:13].[Na+].C(O)(C(F)(F)F)=O>C1C=CC=CC=1.[OH-].[Na+]>[C:12](=[O:11])([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[NH2:13]
Reactant: OCCc1ccccc1Br
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: NC(=O)OCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of commercially available 2-(2-bromophenyl)ethanol (1 eq.) in Benzene (0.85M) at room temperature was added sodium cyanate (2.1 eq) then TFA (2.2 eq) dropwise. The mixture was stirred at room temperature for 6 h, poured in aqueous NaOH (1N) and extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Recrystallization in Et2O afforded the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[N+:12]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][NH:21]2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[N:21]2[C:22]3[C:18](=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:23]=3)[CH2:19][CH2:20]2)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2c(c1)N(n1cnc3cnc(Cl)nc31)CC2
Reaction time: 72 h
Yield: 90.6 %

Procedure:
378 mg of 2,6-dichloropurine, 7 ml of butanol and 328 mg of 6-nitroindoline are mixed and brought to a temperature of 90° C. for approximately 3 days. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum at 50° C. are carried out, and 573 mg of expected product are obtained, in the form of beige crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26]C)=O)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:29]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24](=[O:26])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(C)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2c3cc(C)cc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 63 %

Procedure:
A solution of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole (0.92 g, 2.56 mM) in 38 ml THF and 154 mL concentrated aqueous ammonium hydroxide was sonicated for 6 h at 30-40° C. The precipitated solid was filtered, washed with water to afford 0.55 g (63%) of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (bs, 1H), 8.4 (bs, 1H), 7.75 (m, 1H), 7.4 (m, 2H), 7.15 (dd, J=8 and 8 Hz, 1H), 7.05 (m, 1H), 7.0 (s, 1H), 6.9 (s, 1H), 6.8 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 2.4 (s, 3H), 2.2 (s, 3H). MS (ES) m/e 328, 345.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[C:29]2[CH:30]=[CH:31][C:32]([OH:37])=[C:33]([CH2:34][CH2:35][CH3:36])[C:28]=2[O:27][N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:39][C:24]([F:23])([F:38])[C:25]1[C:29]2[CH:30]=[CH:31][C:32]([O:37][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:15]=[C:14]4[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]4)=[CH:8][CH:7]=3)=[C:33]([CH2:34][CH2:35][CH3:36])[C:28]=2[O:27][N:26]=1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: CCOC(=O)C1(CC)CCc2ccc(OCCCBr)cc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2)OC(CC)(C(=O)OCC)CC3)ccc2c(C(F)(F)F)noc12
Temperature: 70 °C
Yield: 85 %

Procedure:
To a 2 ml DMF solution of ethyl 7-(3-bromopropoxy)-2-ethylchromane-2-carboxylate (40 mg, 0.108 mmol) and 3-trifluoromethyl-7-propyl-6-hydroxybenzisoxazole (U.S. Pat. No. 6,090,836) (29 mg, 0.118 mmol) was added cesium carbonate (39 mg, 0.12 mmol). The resulting suspension was heated to 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and water. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 20% AcOEt/hexanes gave the title compound as a pale yellow oil 49 mg (85%).