Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20])(C(C)(C)C)(C)C.O.C(O)(=O)C.O1CCCC1>[Cl-].[Na+]>[CH:29]1([CH:9]([OH:8])/[CH:10]=[CH:11]/[CH:12]2[CH2:19][CH2:18][CH:17]3[CH:13]2[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]3=[O:20])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)CCC/C=C1\CC2C(/C=C/C(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CCC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(O)C3CCCCC3)CCC2C1=O
Yield: 138.1 %

Procedure:
6-[(E)-3-tert-Butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octane-2-one (12 mg), prepared as described in Reference Example 15 and in the form of (±)-6β-[(E)-3β-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl(5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoate, and a solution of water, glacial acetic acid and tetrahydrofuran (0.5 ml; 35:65:10 by volume) were stirred together at 40° C. for 4 hours. After cooling, the mixture was diluted with saturated aqueous sodium chloride solution and extracted with diethyl ether. The ethereal extracts were washed with aqueous sodium bicarbonate solution (1M) and then with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulphate. Concentration under reduced pressure gave 6-[(E)-3-cyclohexyl-3-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (12.7 mg), in the form of (35)-6β-[(E)-3-cyclohexyl-3β-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl(5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoate.
Reaction SMILES: [Si](O[C@:9]([C@@H:21]([CH:23]([O:25][Si](C(C)(C)C)(C)C)O)[OH:22])([OH:20])[C:10]([F:19])([F:18])[C:11]([O:13]S(C)(=O)=O)=O)(C(C)(C)C)(C)C.[F:33][C:34]1[C:35]([O:45][Si](C)(C)C)=[N:36][C:37]([O:40][Si](C)(C)C)=[N:38][CH:39]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(Cl)Cl>CO>[F:33][C:34]1[C:35](=[O:45])[NH:36][C:37](=[O:40])[N:38]([C:11]([C:10]([F:18])([F:19])[C@@H:9]([C@@H:21]([CH2:23][OH:25])[OH:22])[OH:20])=[O:13])[CH:39]=1
Reactant: C[Si](C)(C)Oc1ncc(F)c(O[Si](C)(C)C)n1
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)OS(C)(=O)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(n1cc(F)c(=O)[nH]c1=O)C(F)(F)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.1 g. of 3,5-bis(t-butyldimethylsilyloxy)-1-methanesulfonyloxy-2-desoxy-2,2difluororibose, 0.83 g. of 5-fluoro-2,4-bis(trimethylsilyloxy)pyrimidine, and 0.655 g. of trifluoromethanesulfonyloxytrimethylsilane in 20 ml. of methylene chloride was refluxed for approximately 17 hours under nitrogen. The reaction mixture was cooled to room temperature and 3 ml. of methanol was added thereto. The resulting solution was stirred for approximately 30 minutes at room temperature and the precipitated solid was collected by filtration. The filtrate was evaporated to dryness under vacuum at 50° and the residue was dissolved in 15 ml. of methylene chloride saturated with anhydrous hydrogen bromide. The resulting suspension was stirred for approximately 30 minutes and the volatiles were removed in vacuo at 45° . The residue was dissolved in 15 ml. of water and the aqueous solution was extracted one time with 10 ml. of ethyl acetate. The aqueous layer was neutralized with sodium carbonate to a pH of approximately 7 and the solution was evaporated to dryness in vacuo at 50°. The residue was dissolved in about 6 ml. of water and the resulting solution was chromatographed in 2 ml. portions on a Whatman ODS-3 50 cm reverse-phase column using water as the eluent to provide 30 mg. of 1-(5-fluoro-2,4-dioxo-1H,3H-pyrimidin-1-yl)-2-desoxy-2,2-difluorori (CD3OD, 90 MHz) δ 3.63-4.6 (m, 4H), 4.79 (s, 3H), 6.04 (t, J=7 Hz, 1H), 8.07 (d, J=6 Hz, 1H); mass spec. m/e=282 =p.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([N:17]=C(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:13][C:12]=3[CH3:31])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F-].[K+]>O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[CH3:31])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(N=C(c2ccccc2)c2ccccc2)cnc1C1CCC2(CC1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N)cnc1C1CCC2(CC1)OCCO2
Yield: 74.1 %

Procedure:
To a solution of 6-(1,4-dioxaspiro[4.5]decan-8-yl)-N-(diphenylmethylene)-5-methylpyridin-3-amine (2.87 g), palladium acetate (314 mg) and potassium fluoride (1.63 g) in tetrahydrofuran (35 ml) and water (16 ml) was slowly added dropwise polymethylhydrosiloxane (PMHS) (1.67 ml) at room temperature with stirring, and then stirred at room temperature for 5 hours. During that time, polymethylhydrosiloxane (PMHS) (1.67 ml) was added twice. After completion of the reaction, water was added thereto, the mixture was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (1.28 g) as a gray solid. MS (ESI) m/z: 249 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2nccc3ccccc23)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Cl)c(NC(=O)c2nccc3ccccc23)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.3 %

Procedure:
Ethyl (5-chloro-2-fluoro-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate (690 mg, 1.78 mmol) was dissolved in THF (18 ml). To the resulting solution was added 0.25N NaOH (10.7 ml, 2.68 mmol), and the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into 1N HCl (3.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (5-chloro-2-fluoro-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetic acid (583 mg, 91%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1)=O.Cl.[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][NH2:25])[CH:20]=[CH:19][C:18]=12.N1C=CC=CC=1>C(O)C>[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][N:25]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=3)[CH3:1])[CH:20]=[CH:19][C:18]=12
Reactant: NOCc1ccc2nonc2c1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(C)=NOCc2ccc3nonc3c2)cc1O
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 3-hydroxy-4-methoxyacetophenone (0.070 g, 0.421 mmol), (benzo[c][1,2,5]oxadiazol-5-yl)methoxyamine hydrochloride (0.126 g, 0.625 mmol) and pyridine (0.16 ml, 1.98 mmol) in ethanol (6 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a yellow oil which was diluted with water. The resultant suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water, dried over magnesium sulphate, filtered and concentrated to a yellow oil. The crude product was purified by column chromatography (SiO2), eluting with 8:2 petrol/ethyl acetate, to give a slightly sticky solid which was further triturated with petroleum spirit (40-60°), to give 1-(3-hydroxy-4-methoxyphenyl)ethanone-O -[(benzo[c][1,2,5]oxadiazol-5-yl)methyl]oxime (CP9-33) as a light yellow solid (0.119 g, 90%).
Reaction SMILES: I[C:2]1[C:3](=[O:21])[NH:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Zn].C(O)(=O)C>[O:8]([C:7]1[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:4][C:3](=[O:21])[CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc(Oc2ccccc2)c1I
Agent: [Zn]
Solvent: CC(=O)O
Product: O=c1cc(Oc2ccccc2)nc(-c2ccccc2)[nH]1
Yield: 125.6 %

Procedure:
A mixture of 7.07 g (18.1 mmol) of crude 5-iodo-6-phenoxy-2-phenyl-4(3H)-pyrimidinone, 2.02 g (31.1 mmol) of zinc dust and 25 mL of glacial acetic acid was heated to reflux. After 15 min an additional 2.06 g (31.7 mmol) of zinc dust was added, followed 15 min later by a further 2.04 g (31.4 mmol) of zinc dust. The mixture was maintained at reflux for 2 h, cooled and filtered to remove unreacted zinc. The filtrate was rotovaped to leave a semi-solid which was triturated with 75 mL of boiling water to afford 6.01 g (57% from 4,6-dihydroxy-2-phenylpyrimidine) of 6-phenoxy-2-phenyl-4(3H)-pyrimidinone as a yellow solid. 1H-NMR (d6-DMSO) δ 5.5(1H,s), 7.1-7.5(8H), 8.1(2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[S:15][C@H:14]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:11].C1(OC)C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]([OH:24])=[O:23])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[S:15][C@H:14]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Sc2ccccc21
Agent: Br
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 25 °C
Yield: 78.3 %

Procedure:
While a mixture of 5 g of tert-butyl trans-3-(2-indolecarboxamido)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 15 ml of acetic acid and 2 ml of anisole is stirred at room temperature, 21 ml of a 30% solution of hydrobromic acid-acetic acid is added to the mixture dropwise. After the mixture is stirred at room temperature for 9 hours, the resulting crystals are collected by filtration and washed with ethyl acetate to give 3.5 g of trans-3-(2-indolecarboxamido)- 4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, m.p. 260°-270° C. (decomposition).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[C:17]([NH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:32]=[CH:31]2)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:17]([O:19][CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[O:18])[CH:29]=4)[CH:34]=3)(=[O:40])=[O:39])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Reactant: O=C(Nc1ccc2cc(S(=O)(=O)Cl)ccc2c1)OCc1ccccc1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4cc(NC(=O)OCc5ccccc5)ccc4c3)C2=O)cs1

Procedure:
The title compound is prepared from 4-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)thiophene-2-carbonitrile hydrochloride as described in EXAMPLE 125, Part C using N-Cbz-6-aminonaphthalene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:8]1[CH:9]=[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])[C:3]([C:4]#[N:5])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1ccc(F)cc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-4-fluorobenzonitrile was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 51 to give 5,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.25-7.33 (2H, m), 7.40-7.44 (1H, m), 7.86 (1H, dd, J 9 and 6), 8.35-8.42 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[C:10]=2[N:11]=1.[Cl:24][C:25]1[C:30]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])(=[O:34])=[O:33])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:24][C:25]1[C:30]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])(=[O:34])=[O:33])=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=4)[C:10]=3[N:11]=2)=[CH:27][N:26]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: FC(F)(F)Oc1ccc(Nc2ncnc3ccc(Cl)nc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(Nc4ccc(OC(F)(F)F)cc4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A mixture of 6-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (Intermediate 23) (0.050 g, 0.147 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.070 g, 0.161 mmol), PdCl2(dppf)-CH2Cl2Adduct (5.99 mg, 7.34 μmol) and 1 N aq. sodium bicarbonate (0.294 ml, 0.294 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(4-(trifluoromethoxy)phenylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.049 g, 55%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 6.88-7.05 (2H, m), 7.34 (2H, d, J=8.8 Hz), 7.85-7.95 (1H, m), 8.05-8.10 (2H, m), 8.19 (1H, d, J=8.8 Hz), 8.34 (1H, d, J=8.4 Hz), 8.84 (1H, s), 8.85-8.90 (2H, m), 9.26 (1H, br s). 1NH was not detected. m/z=609.1 [M+1]+.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[N:15][CH:16]=2)[CH:2]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[C:17]([C:13]1[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]3[C:10](=[N:1][CH:2]=2)[N:9]([C:20]([NH2:28])=[O:27])[CH2:8][CH2:7][CH2:6]3)[CH:16]=[N:15][CH:14]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 50 °C
Yield: 50.6 %

Procedure:
1-[5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-ethanone (50 mg, 0.20 mmol) and benzoyl isocyanate (48 mg, 0.30 mmol) are dissolved in 2.0 mL of DCM. The mixture is heated at 50° C. for 16 hrs. Then the solvent is removed in vacuum and the residue is dissolved in 2.0 mL of EtOH. K2CO3 (46 mg, 0.34 mmol) is added and the mixture is heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (75 mL). The aqueous layer is separated and extracted with DCM (2×30 mL). The organic layers are combined and concentrated to give the crude product. EtOAc (2 mL) is added to the crude and the white solid formed is filtered, rinsed with more EtOAc (2×3 mL) and dried to give 30 mg of the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[F:24][S:25]([C:28]1[CH:40]=[CH:39][C:31]([C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])=[CH:30][CH:29]=1)(=[O:27])=[O:26].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[O:17]=[C:11]1[NH:12][C:13]2[C:9](/[C:10]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:36](=[O:37])[CH2:35][NH:34][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([S:25]([F:24])(=[O:27])=[O:26])=[CH:40][CH:39]=3)[CH:7]=[CH:6][CH:5]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)F)cc1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1ccc(S(=O)(=O)F)cc1)Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.100 mmol) (from Example 4 supra), crude (4-fluorosulfonyl-benzoylamino)-acetic acid (28 mg, 0.107 mmol) (from step B above), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 45 mg, 0.119 mmol) (Advance ChemTech), 1-hydroxybenzotriazole hydrate (HOBT, 16 mg, 0.118 mmol) (Aldrich), and N,N-diisopropylethylamine (52 μL, 0.300 mmol) (Aldrich) in 3 mL of dry N,N-dimethylformamide (Fisher Scientific) was stirred at 50° C. under a nitrogen atmosphere for 7 h then stirred at room temperature under a nitrogen atmosphere for 12 h. The reaction mixture was diluted with 40 mL ethyl acetate and washed with distilled water. The organic phase was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 40% acetone-hexanes then 70% acetone-hexanes elution) provided pure (Z)-N-[2-[[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]phenyl]amino]-2-oxoethyl]-4-(fluorosulfonyl)benzamide (yield: 13 mg, 24%) as a yellow solid (mp 248-250° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.C(=O)([O-])O.[Na+]>ClCCl>[C:16]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: COc1cc2c(cc1C(C)=O)CCC(=O)C2(C)C
Reaction time: 3 h

Procedure:
To the dichloromethane (70 ml) solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 3 g, 14.7 mmol), acetic anhydride (1.7 ml, 1.2 eq.) and aluminum chloride-nitrobenzene solution (1 M, 44 ml, 3 eq.) was added at 0° C., and stirred for 3 hr. Thereafter, the reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate and extracted twice with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound as a crude product.
Reaction SMILES: C(O)(=O)C.CO.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[N:16]1[C:20](=[O:21])[CH2:19][C:18]([NH:22][C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=3)[C:26]([Cl:39])=[CH:25][C:24]=2[Cl:40])=[N:17]1>[Fe].O>[Cl:15][C:10]1[CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]([Cl:7])[C:9]=1[N:16]1[C:20](=[O:21])[CH2:19][C:18]([NH:22][C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:31]=[CH:32][C:33]([NH2:36])=[CH:34][CH:35]=3)[C:26]([Cl:39])=[CH:25][C:24]=2[Cl:40])=[N:17]1
Reactant: O=C1CC(Nc2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2Cl)=NN1c1c(Cl)cc(Cl)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2cc(NC3=NN(c4c(Cl)cc(Cl)cc4Cl)C(=O)C3)c(Cl)cc2Cl)cc1
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
In a solvent mixture of 100 ml of glacial acetic acid, 10 ml of methanol and 10 ml of water was dispersed 10 g of 1-(2,4,6-trichlorophenyl)-3-[2,4-dichloro-5-(4-nitrophenoxy)anilino]-2-pyrazolin-5-one prepared as described in Step (1) above. To the dispersion was added 10 g of iron powder with heating under stirring over a 10 minute period. The reaction mixture was poured into 1 l of water and the precipitate crystallized out was recovered by filtration to obtain 8 g of the desired compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH2:20][OH:21].CCN(CC)CC>C(Cl)Cl.O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH:20]=[O:21]
Reactant: OCC#Cc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=CC#Cc1ccccc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
To a solution of oxalyl chloride (102 mL, 1.18 mol, 1.2 equiv) in CH2Cl2 (3L) at −78° C. was slowly added DMSO (167 mL, 2.35 mol, 2.4 equiv) while keeping the reaction temperature below −59° C. The mixture was stirred for 10 min and treated with a solution of 3-(2-fluorophenyl)prop-2-yn-1-ol (147 g, 0.98 mol) in CH2Cl2 (100 mL), keeping the reaction temperature below −65° C. The resulting thick white slurry was stirred for 15 min, then treated with Et3N (682 mL, 4.90 mol, 5 equiv). After 10 min the reaction mixture was allowed to warm to 0° C. and treated with water (2 L). The organic layer was washed with water (3×1L), dried (Na2SO4) and concentrated under reduced pressure to afford 3-(2-fluorophenyl)prop-2-ynal (148 g, 100%) as a brown oil which was stored suspended in frozen benzene (0.5 L): 1H NMR (CDCl3) δ 7.03-7.14 (m, 2H), 7.37-7.52 (m, 2H), 9.36 (s, 1H); 13C NMR (CDCl3) δ 88.1, 92.4 (d, JC−F=2.4 Hz, 1C), 108.2 (d, JC−F=14.5 Hz, 1C), 115.9 (d, JC−F=19.6 Hz, 1C), 124.4 (d, JC−F=3.6 Hz, 1C), 133.3 (d, JC−F=8.5 Hz, 1C), 134.8 162.6 (d, JC−F=246.3 Hz, 1C), 176.4; GCMS m/z (rel abundance) 149 (MH+, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=S(=O)(N[C@@H]1CCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A suspension of 4-chloro-N-(trans-2-hydroxymethylcyclopentyl)benzenesulfonamide (290 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and α-bromo-p-tolunitrile (253 mg, 1.2 mmol) in 2 mL dimethylformamide was stirred for 2 h. The reaction was diluted into 50 mL ethyl acetate and extracted with brine. The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 20 to 70% ethyl acetate in hexane over 25 min. to give 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (327 mg, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (2H, d, J=8.56 Hz), 7.57-7.63 (2H, m), 7.49 (3H, dd, J=10.83, 8.31 Hz), 4.64 (1H, d, J=16.62 Hz), 4.16 (1H, d, J=16.62 Hz), 3.99-4.12 (1H, m), 3.37-3.62 (2H, m), 1.99 (1H, t, J=6.17 Hz), 1.32-1.71 (7H, m). LC/MS R.T.=2.77 min; [M+H]+=404.12. HRMS [M+H]+ calc'd 405.1040, found 405.1054.