Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:35][C:36]1[S:37][C:38]2[C:43]([N:44]=1)=[CH:42][CH:41]=[C:40]([O:45][C:46]1[C:47]([Cl:67])=[CH:48][C:49]([F:66])=[C:50]([NH:52][C:53](=[O:65])[C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([C:63]#[N:64])([CH3:62])[CH3:61])[CH:55]=3)[CH:51]=1)[N:39]=2>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:67][C:47]1[C:46]([O:45][C:40]2[N:39]=[C:38]3[S:37][C:36]([NH:35][C:8](=[O:10])/[CH:7]=[CH:6]/[C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[N:44][C:43]3=[CH:42][CH:41]=2)=[CH:51][C:50]([NH:52][C:53](=[O:65])[C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([C:63]#[N:64])([CH3:62])[CH3:61])[CH:55]=2)=[C:49]([F:66])[CH:48]=1
Reactant: O=C(O)/C=C/c1ccco1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)/C=C/c5ccco5)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a solution of (2E)-3-furan-2-ylprop-2-enoic acid (24 mg, 0.173 mmol) in pyridine (1.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (65.7 mg, 0.173 mmol), and the mixture was stirred at room temperature for 10 min. N-{5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (80 mg, 0.166 mmol) produced in Example C52(v) was added to the obtained solution, and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (37.2 mg, 87%) as a colorless powder.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].[CH3:18][CH:19]([CH3:36])[CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH:30]2[O:33][CH:31]2[CH3:32])=[CH:27][CH:26]=1>>[OH:33][CH:31]([CH2:30][O:29][C:28]1[CH:34]=[CH:35][C:25]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH:19]([CH3:36])[CH3:18])=[CH:26][CH:27]=1)[CH2:32][NH:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: NCCNC(=O)N1CCOCC1
Reactant: CC(C)COCCOc1ccc(OC2OC2C)cc1
Agent: O=S(=O)([O-])[O-]
Product: CC(C)COCCOc1ccc(OCC(O)CNCCNC(=O)N2CCOCC2)cc1

Procedure:
N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)-4-morpholinecarboxamide was prepared in accordance with example 4 using 10.1 g of the neutral sulphate of N-2-aminoethyl-4-morpholinecarboxamide and 9.3 g of 3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy-1,2-epoxypropane as starting materials. Yield 3.9 g. Melting point 95°-96° C. (base). The structure was determined using NMR-analysis.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]3[CH:44]=[CH:43][NH:42][C:39]3=[N:40][CH:41]=2)O1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:8]1[C:6]2[N:7]=[C:2]([C:36]3[CH:37]=[C:38]4[CH:44]=[CH:43][NH:42][C:39]4=[N:40][CH:41]=3)[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[S:10][C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(-c2ccccc2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12
Temperature: 150 °C

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine from Example 12 (0.2 g, 0.5 mmol), phenylboronic acid (60 mg, 0.5 mmol), and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 25 μmol) in 1 M aqueous Na2CO3 (1 mL) and acetonitrile (1 mL) were heated to 100° C. in a sealed microwave reactor for 10 min. Upon completion, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (180 mg 0.75 mmol) and bis(triphenylphosphine)palladium(II) dichloride (13 mg, 20 μmol) were added and the mixture was heated to 150° C. in a sealed microwave reactor for 20 min. The mixture was extracted with EtOAc and CH2Cl2. The combined organics were concentrated to yield 420 after reverse phase HPLC purification (57 mg). MS (Q1) 428 (M)+
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[O:18][C:19]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:20]=4[C:21]=3[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[CH:8]=1)C.[OH-].[K+]>C1COCC1.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:19]2[O:18][C:17]([C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])[CH:16]=[CH:15]4)=[C:21]([C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:20]=2[CH:28]=1
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccc(Cl)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)O)ccc3c2)oc2ccc(Cl)cc12
Yield: 90 %

Procedure:
Following the procedure described in Step 4 of Example 6, [6-(5-chloro-3-pentanoyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.26 g, 0. mmol) was hydrolyzed with potassium hydroxide (0.300 g, 5.36 mmol) in THF (20 mL) and water (10 mL). Crystallization from ethyl acetate afforded the title compound as an off-white solid (0.22 g), mp 158-160° C. Mass spectrum (−APCl, [M−H]−) m/z 435, 437. 1HNMR (400 MHz, DMSO-d6): δ13.14 (br s, 1H), 8.37 (d, 1H, J=1.2 Hz), 8.03-8.01 (m, 2 H), 7.97 (d, 1H, J=8.5 Hz), 7.81 (dd, 1H, J=8.3, 1.7 Hz), 7.77 (d, 1H, J=8.8 Hz), 7.48 (dd, 1H, J=8.8, 2.2 Hz), 7.40 (d, 1H, J=2.7 Hz), 7.32 (dd, 1H, J=9.0, 2.5 Hz), 4.85 (s, 2H), 2.69 (t, 2H, J=7.3 Hz), 1.55-1.48 (m, 2H), 1.13-1.05 (m, 2H), and 0.69 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C25H21ClO5.0.4H2O: Calculated: C, 67.61; H, 4.95; N, 0.00. Found: C, 67.51; H, 4.66; N, 0.05.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([NH:16][N:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][C:10]=2[Cl:25])[C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([O:35][CH3:36])[CH2:31][N:32]=[C:33]=[O:34]>C(#N)C.C1CCN2C(=NCCC2)CC1>[CH:18](=[N:17][N:16]([C:12]1[CH:11]=[C:10]([Cl:25])[C:9]([CH:6]([C:7]#[N:8])[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]([Cl:15])[CH:13]=1)[C:33]([NH:32][CH2:31][CH:30]([O:35][CH3:36])[O:29][CH3:28])=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(CN=C=O)OC
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(NN=Cc2ccccc2)cc1Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1)OC
Reaction time: 1 h
Yield: 87.8 %

Procedure:
In 20 ml of acetonitrile was suspended 3.2 g of benzaldehyde 4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl hydrazone. To the suspension were added 1.5 g of 2,2-dimethoxyethyl isocyanate and 20 mg of DBU. The reaction was allowed to proceed for one hour at room temperature, then the resulting crystalline precipitate was collected by filtration, which was washed with hexane, followed by drying to afford 3.7 g of the titled compound as colorless crystals, m.p. 190-191° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH2:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][N:22]=[C:23]=[O:24].O>O1CCCC1>[CH3:21][NH:22][C:23]([NH:13][CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[CH2:4][CH2:5]1)=[O:24]
Reactant: NC1CCC(=O)c2ccccc21
Reactant: CN=C=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)NC1CCC(=O)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a stirred mixture of 10 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine hydrochloride in 200 ml of dry tetrahydrofuran (THF) under a nitrogen atmosphere, 76 ml of triethylamine is added dropwise. The mixture is stirred for an additional 5 minutes, and 3 ml of methylisocyanate is added dropwise. The reaction mixture is stirred for 1 hour at room temperature and the solid collected. The filter cake is washed with THF and then with 3 × 50 ml of water. The THF filtrate is concentrated in vacuo to afford some product. The water-insoluble solid is air dried to afford 8.8 g of the title compound melting point 219°-221° C. Recrystallization from about 150 ml of methanol yeilds 7.4 g of the above product, melting point 220°-223° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25]>O1CCCC1.O>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1cc(C=O)oc1C
Reactant: Cc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(O)c2cc(C)c(C)o2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2-Bromo-6-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6 M hexane solution (5.6 ml) of n-butyllithium was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature while stirring. Water was added to the reaction solution to stop the reaction, and the solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give (4,5-dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanol (1.4 g, yield 74%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[C@@H:3]([CH3:6])[O:4][CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>ClC(Cl)C.O>[C:13]([O:12][C:10](=[O:11])[NH:1][C@H:2]([CH2:7][OH:8])[C@H:3]([O:4][CH3:5])[CH3:6])([CH3:15])([CH3:14])[CH3:16]
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CC(Cl)Cl
Solvent: O
Product: CO[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.02 h
Yield: 103.6 %

Procedure:
To a cold solution (−15° C.) of BocThr(Me)OH (5.14 g, 22 mmol) in dichloroethane (22 mL) were successively added N-methyl morpholine (2.44 mL, 22 mmol) and isobutyl chloroformate (2.99 mL, 22 mmol). After one min, the precipitate was filtered and washed with dichloroethane (5×4 mL). The filtrate and washings were combined in a large three neck flask in an ice-salt bath. A solution of NaBH4 (1.26 g, 33 mmol) in H2O (11 mL) was added at once, proceeding a strong evolution of gas, followed by H2O (500 mL). The mixture was then extracted with EtOAc (5×150 mL). The combined EtOAc was dried (Na2SO4) and concentrated to give the titled compound (5 g). MS (MH+ 220).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:22])(=O)=O>[OH-].[K+]>[CH3:22][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(Oc2ccccc2Cl)ccc1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(Oc2ccccc2Cl)cc1C=O
Temperature: 25 °C
Yield: 72.8 %

Procedure:
An aqueous solution (30 ml) of potassium hydroxide (8.2 g) was added portionwise to a mixture of 2-hydroxy-5-(2-chlorophenoxy)benzaldehyde (10.4 g) and dimethyl sulfate (10.5 g) with stirring at room temperature, and the mixture was stirred at 70° C. for an hour. After cooling, the reaction mixture was extracted with diethyl ether, and the extract was washed with water, dried and evaporated. The residue was crystallized from methanol to give 2-methoxy-5-(2-chlorophenoxy)benzaldehyde (8 g). mp 65°-66° C.
Reaction SMILES: [CH3:1][O:2][S:3]([O:6]C)(=[O:5])=[O:4].[CH3:8][N:9]([CH2:11][C:12]1[C:20]2[C:15](=[CH:16][N:17]=[C:18]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:10]>C1COCC1>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[N:21]1([C:18]2[CH:19]=[C:20]3[C:12]([CH2:11][N+:9]([CH3:1])([CH3:8])[CH3:10])=[CH:13][NH:14][C:15]3=[CH:16][N:17]=2)[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: CN(C)Cc1c[nH]c2cnc(-n3cncn3)cc12
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COS(=O)(=O)[O-]
Product: C[N+](C)(C)Cc1c[nH]c2cnc(-n3cncn3)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
A mixture of dimethylsulphate (0.13ml, 1.4 mmol) and dry THF (5ml) was cooled to 0° C. under nitrogen and N,N-dimethyl-[5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]methylamine (0.15 g, 0.62 mmol) was added portionwise over a period of 5 min. The mixture was stirred at 0° C. for 90 min. The resulting precipitate was collected by filtration and washed with THF to afford the title compound (0.23 g, 100%) as a colourless solid; mp 182°-185° C. 1H NMR (250 MHz, d6 -DMSO) δ 3.06 (9H, s), 3.38 (3H, s), 4.77 (2H, s), 8.08 (1H, s), 8.30 (1H, s), 8.38 (1H, s), 8.78 (1H, s), 9.31 (1H, s), 12.40 (1H, br s).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1>C(O)(=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[C:9]([O:15][CH3:16])[CH:10]=1)[C:6]([OH:7])=[N:2][C:1]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1)=[CH:3]2
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(CC#N)c(C(=O)O)c(OC)c1
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(O)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 255.5 %

Procedure:
A mixture of 2-Cyanomethyl-4,6-dimethoxy-benzoic acid (1.75 g×3), 3-amino-5-methylpyrazole (1.5 g×3) in acetic acid (10 ml×3) were sealed in microwave process vial (20 ml×3). The mixture was heated at 140° C. for 30 minutes under microwave irradiation. The mixture was evaporated to oil, and the oil was dissolved in 1.5 ml MeOH. This solution was added dropwise to 50 ml water. After stirred for 1 hour, solid was collected and was purified by flash column chromatography to give product (6.07 g, 85%). LC-MS: m/e 301 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH3:16])=[N:13]2)=[CH:8][CH:7]=1.[Se](=O)=[O:18]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH:16]=[O:18])=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=[Se]=O
Reactant: COCCOc1ccc2ccc(C)nc2c1
Solvent: O
Solvent: C1COCCO1
Product: COCCOc1ccc2ccc(C=O)nc2c1
Yield: 68.3 %

Procedure:
To a solution of 7-(2-methoxyethoxy)-2-methylquinoline (0.16 g, 0.76 mmol) in dioxane (15 mL) and water (0.15 mL) was added selenium dioxide (0.10 g, 0.91 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.12 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>CCO.[Pt]=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)cc(Cl)c1O
Agent: O=[Pt]
Solvent: CCO
Product: Cl
Product: Nc1cc(F)cc(Cl)c1O
Yield: 141.6 %

Procedure:
A mixture of compound 711 (23.4 g, 0.122 mol) and platinum oxide (2.3 g) in absolute EtOH (120 mL) was placed under 1 atm of hydrogen and stirred until complete reduction had occurred. The hydrogen was replaced with nitrogen and the reaction was filtered through Celite. The filtrate was diluted with Et2O (300 mL) and gaseous hydrochloric acid was bubbled through the solution to provide a white precipitate. The solid was collected and dried under vacuum to provide 17.1 g of compound 712 as a white solid. ##STR91##
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9]([F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:15][OH:16]>CCO>[NH2:13][C:12](=[N:15][OH:16])[C:10]1[C:9]([F:14])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1
Reactant: NO
Reactant: COC(=O)c1cc(F)c(C#N)cc1Cl
Solvent: CCO
Product: COC(=O)c1cc(F)c(C(N)=NO)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl 2-chloro-4-cyano-5-fluorobenzoate (1.65 g; 7.72 mmol; 1 eq.) was suspended in EtOH (33 mL). Hydroxylamine (1.14 mL; 38.62 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 6 hours. The obtained suspension was filtered affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.98 (br s, 1H), 7.74-7.67 (m, 2H), 6 (hr s, 2H), 3.87 (s, 3H). LC/MS (Method B): 247.0 (M+H)+; 245.1 (M−H)−. HPLC (Method A) Rt 1.80 min (Purity: 90.4%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][C:33](Cl)=[O:34]>C([O-])(O)=O.[Na+].C1COCC1>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([C:3]2[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][C:17]=2[O:18][CH3:19])/[C:6](=[O:11])[NH:7]3)=[CH:25][CH:24]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc(O)cc3)c21
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccc(O)cc3)c21
Yield: 42.4 %

Procedure:
Using Method M above, (Z)-5-amino-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (28 mg, 0.08 mmol) (from Example 41 supra) was acylated with 2-thiopheneacetyl chloride (25.7 mg, 0.16 mmol) (Aldrich) in saturated aqueous NaHCO3 (0.16 mL) and THF (2 mL) at room temperature for 3 h to give (Z)-N-[2,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-5-yl]-2-thiopheneacetamide (yield: 16 mg, 42%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29].C(=O)([O-])[O-]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:21])=[O:22])[CH2:18][CH2:19]2)[CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C
Yield: 68.9 %

Procedure:
To a solution of 5-bromo-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (420 mg, 0.9 mmol) in dioxane (6.0 mL) and water (2.0 ml), (3-formylphenyl)boronic acid (750.0 mg, 5.0 mmol), Pd(PPh3)4 (100.0 mg, 10%) and cessium carbonate (800 mg, 1.8 mmol) were added. The reaction mixture was heated in a Smith synthesizer microwave at 160° C. for 20 min. All solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane, 1/1) to yield the desired product (300.0 mg, 70%).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[C:49]1([S:55](Cl)(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([S:55]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:57])=[O:56])[CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 7 (200 mg, 0.37 mmol) is dissolved in dry CH2Cl2 (4 mL) and the flask sealed under N2. DIEA (96 μL, 0.56 mmol) is added, followed by benzenesulfonyl chloride (46 μL, 0.36 mmol), then the mixture stirred at RT for 2 h. The reaction is subsequently diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 (50 mL), brine (50 mL) and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure to afford an oil which is purified by flash chromatography on silica gel (25% Et2O/CH2Cl2). The title compound is isolated as a colourless glass (216 mg, 86% yield): 1H NMR δ (CDCl3) 7.51-7.86 (m, 5H), 7.03-7.25 (m, 4H), 6.69 (v br s, 1H), 6.04 (br d, J=8.2 Hz, 1H), 5.16-5.25 (m, 1H), 4.29-4.75 (br m, 3H), 3.47-4.21 (br m, 3H), 2.69-2.88 (br m, 5H), 2.38-2.67 (m, 2H), 1.81-2.09 (m, 5H), 1.55 (s, 3H), 1.46 (s, 9H), 1.23-1.31 (br m, 2H), 0.84-0.92 (br m, 3H), 0.76 (d, J=6.7 Hz, 2H); LCMS (APCl+) 685.6 (MH+, 100%).
Reaction SMILES: CC1(C)CO[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[O:11][CH2:10]3)=[N:3]1.CN(C)C=O.C1(C)C=CC=CC=1>S(Cl)(Cl)=O>[C:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[O:11][CH2:10]2)#[N:3]
Reactant: CC1(C)COC(c2ccc3c(c2)COC3=O)=N1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(c1)COC2=O
Temperature: 25 °C

Procedure:
To a suspension of 4,4-dimethyl-2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline (23.1 g, 0.1 mol) in thionyl chloride (36 mL) is slowly added N,N-dimethylformamide (5 ml). The solution is heated at reflux for 1 hour and then allowed to cool to room temperature over 3 hours. Then toluene (150 mL) is added and the suspension is filtered and washed with toluene (2×50 mL). The wet crystals are taken into deionized water (150 mL) and the pH is adjusted to 8.0 with 25% aqueous ammonia. The solid is filtered and washed with deionized water (2×50 mL) and dried at 60° C. under reduced pressure. Yield: 11.9 g (75%) of an off-white product having a purity (HPLC, peak area)=92%. An analytical pure sample is obtained by crystallisation from acetic acid or toluene. 1H NMR (DMSO d-6, 500 MHz): 5.48 (2H, s), 8.04 (2H, s+s), 8.22 (1H, s).