Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10](F)[CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1.Cl>CS(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:26](=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[OH:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:9]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(=C(O)c1ccc(F)cc1)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
Potassium carbonate (3.3 g, 24 mmol) was added to a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (2.45 g, 11 mmol) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (2.7 g, 13 mmol) in DMSO (11 mL). The yellow solution turned purple and the reaction was stirred at r.t. After 8 h, the reaction was neutralized with 25 mL of 1 N HCl and extracted with EtOAc. The organic phase was washed with water (×3) and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography on a Biotage 40+M column (gradient elution 5% to 25% EtOAc/hexanes over 10 column volumes, fraction collection at λ=254 nm) to afford the title compound as a viscous amber oil, 4.8 g (105% yield, contains ˜10 weight % EtOAc by 1H NMR). 1H NMR (˜0.6:1 ratio of keto:enol tautomers, 500 MHz, CDCl3) δ ppm 13.47 (s, 1H) 7.94-8.05 (m, 2H) 7.86 (d, J=8.55 Hz, 1H) 7.62-7.72 (m, 1.2H) 7.51 (dd, J=8.55, 2.14 Hz, 1H) 7.29-7.35 (m, 2H) 7.15-7.21 (m, 1.2H) 7.12 (d, J=2.14 Hz, 1H) 6.94 (t, J=8.55 Hz, 2H) 6.35 (s, 0.6H) 4.20-4.34 (m, 2H) 4.04-4.11 (m, 1.2H) 1.23-1.27 (m, 2H) 1.18 (t, J=7.17 Hz, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18.5 μm 4.6×50 mm; 2 peaks elute with HPLC Rt=1.69 and 1.83 min (˜1:2 ratio), (ES−) m/z (M−) for both=408, 410 (1:1 ratio).
Reaction SMILES: [OH-:1].[Li+].[C:3]([O:7][C:8]([NH:10][C@H:11]([CH:32]1[CH2:36][C@@H:35]([CH3:37])[C:34](=[O:38])[O:33]1)[CH2:12][C@@H:13]([CH:29]([CH3:31])[CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>COCCOC.O>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:12][C@@H:13]([CH:29]([CH3:31])[CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)[C@@H:32]([OH:1])[CH2:36][C@@H:35]([CH3:37])[C:34]([OH:33])=[O:38])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: [OH-]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C2C[C@@H](C)C(=O)O2)C(C)C)ccc1OC
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
28.5 ml of 1N lithium hydroxide solution are added to 3.6 g of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one in 210 ml of 1,2-dimethoxyethane/water (2:1) at room temperature. The reaction mixture is stirred at room temperature for a further 1 hour and then concentrated by evaporation. Ice and 10% aqueous citric acid solution are added to the residue. Repeated extraction with chloroform yields the crude title compound: Rf (ethyl acetate/hexane=1:1)=0.05; HPLC Rt =16.41 minutes.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC>C1COCC1>[C:16]1([CH:14]([C:11]2[S:10][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:13][CH:12]=2)[OH:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cnc(C#Cc2ccccc2)s1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cnc(C#Cc2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-phenylethynyl-thiazole-5-carbaldehyde (Example 205, 197 mg, 0.924 mmol) in THF (5.0 mL) was cooled at 0° C. and treated with a 3.0 M solution of phenyl magnesium bromide in Ether (340 μL, 1.0 mmol). After stirring for about 30 minutes at 0° C., the reaction was quenched with saturated aqueous ammonium chloride (25 mL), diluted with EtOAc (25 mL), transferred to a 125-mL separatory funnel and extracted. The layers were separated and the aqueous layer was extracted again with EtOAc (25 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with 25% EtOAc in hexanes to afford the titled compound, pPhenyl-(2-phenylethynyl-thiazol-5-yl)-methanol (190 mg, 71%), as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:17])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 3 °C
Reaction time: 14 h

Procedure:
0.47 cm3 of butyryl chloride is added to 750 mg of 6-chloro-1H-indazole-3-amine in 10 cm3 of pyridine, after the reaction medium has been cooled to about 3° C. The medium is then allowed to return to 19° C. over 14 hours. The reaction medium is evaporated to dryness under reduced pressure (2 kPa; 40° C.). The residue is taken up in 50 cm3 of ethyl acetate, 50 cm3 of tetrahydrofuran and 50 cm3 of distilled water. The organic phase is washed again with 50 cm3 of distilled water and with 50 cm3 of saturated aqueous sodium chloride solution, and then dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with cyclohexane/ethyl acetate (70/30 by volume) and collecting 25 cm3 fractions. The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.). After drying (90 Pa; 45° C.), 200 mg of N-(6-chloro-1H-indazol-3-yl)-butanamide are obtained in the form of a white solid melting at 230° C.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9].[OH:13][C:14]1[CH:22]=[CH:21][C:17]2[CH2:18][CH2:19][O:20][C:16]=2[CH:15]=1>>[CH3:12][C:4]([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:13][C:14]1[CH:22]=[CH:21][C:17]2[CH2:18][CH2:19][O:20][C:16]=2[CH:15]=1
Reactant: CC(=CCBr)CCC(C)=C(C)C
Reactant: Oc1ccc2c(c1)OCC2
Product: CC(=CCOc1ccc2c(c1)OCC2)CCC(C)=C(C)C

Procedure:
1-bromo-3,6,7-trimethyl-2,6-octadiene and 6-hydroxy-2,3-dihydrobenzofuran are reacted to form 6-[(3,6,7-trimethyl-2,6-octadienyl)-oxy]-2,3-dihydrobenzofuran of boiling point 124°-126° C./0.001 mmHg; nD20 = 1.5412;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:18]([C:20]1[CH:21]=[C:22]([CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]=1[O:30][CH2:31]OCCOC)[C:23]([O:25][CH3:26])=[O:24])=[O:19]>>[CH2:31]([O:30][C:29]1[C:28]([C:2]2[CH:3]=[C:4]([S:10](=[O:12])(=[O:11])[NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[CH:18]=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)NC(C)(C)C)cc1Br
Reactant: COCCOCOc1c(C=O)cc(C(=O)OC)cc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)c1cc(C=O)c(OCc2ccccc2)c(-c2cc(S(=O)(=O)NC(C)(C)C)ccc2OC)c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide and methyl 3-formyl-4-(2-methoxyethoxy-methoxy)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzoate, gave methyl 6-benzyloxy-5′-tert-butylsulfamoyl-5-formyl-2′-methoxy-biphenyl-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:16])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:16])[CH2:10][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Solvent: CC#N
Product: C[C@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Yield: 59.2 %

Procedure:
Heat a mixture of (R)-methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester (0.083 mol, 20 g) and morpholine (0.83 mol, 72.2 g) in acetonitrile (210 mL) to 65° C. for 16 h. Concentrate the reaction mixture, dilute the residue with water, extract with dichloromethane, combine organic layer and wash with water. Dry the organic layer over anhydrous sodium sulfate, filter and concentrate under vacuum to obtain the title compound (12 g, 62%) as yellow thick oil. 1H NMR (400 MHz, CDCl3) δ 1.13 (d, 3H), 1.43 (s, 9H), 2.21 (dd, 1H), 2.26-2.32 (m, 1H), 2.35-2.39 (m, 2H), 2.48-2.55 (m, 2H), 3.63-3.70 (m, 5H), 4.68 (br s, 1H, —NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][CH:28]=[C:29]4[C:32]([O:34]C)=[O:33])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][CH:28]=[C:29]4[C:32]([OH:34])=[O:33])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3cccc(C(=O)O)c3c2)cc1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
A solution of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.122 g, 0.22 mmol) in THF (2.2 mL) was placed in a microwave reaction tube. Methanol (1.1 mL) was added, followed by 1N sodium hydroxide (0.33 mL, 0.33 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.095 g, 77% as 0.4 tetrahydrofuran) 1H NMR (DMSO-d6): δ 13.3-13.1 (broad s, approximately 1H), 9.05 (s, 1H), 8.14-8.12 (m, 2H), 8.04 (d, J=9 Hz, 1H), 7.82-7.79 (m, 1H), 7.63-7.52 (m, 6H), 6.92 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.46 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). HRMS C30H23NO4Cl2 m/z 532.1082 (M+H)+Cal; 532.1074 (M+H)+Obs.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([NH2:12])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>N1C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([NH:12][C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: Nc1nc(-c2ccccc2)ns1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)ns2)cc1OC
Temperature: 25 °C
Reaction time: 46 h
Yield: 14.4 %

Procedure:
3-Phenyl-1,2,4-thiadiazol-5-amine (326 mg, 1.84 mmol) was dissolved in dry pyridine (10 mL). Then 3,4-dimethoxybenzenesulfonyl chloride (529 mg, 2.23 mmol) was added. The solution was stirred at room temperature under Argon. After 46 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between EtOAc and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. After drying over Na2SO4, the solvent was removed in vacuo to give a solid (100 mg) which was crystallized from EtOAc. Yield was 29.3 mg; mp 170-171° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([Cl:24])=[CH:17][N:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[Cl:24][C:18]1[CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:15]([O:3][C:4]2([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]2)=[N:16][CH:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: CC(C)(C)OC(=O)C1(O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(Oc2ncc(Cl)cc2[N+](=O)[O-])CC1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Under ice cooling, to a toluene suspension (60 ml) of 63% sodium hydride (2.81 g) was added dropwise a toluene solution (30 ml) of tert-butyl 1-hydroxycyclopropanecarboxylate (11.65 g) over 15 minutes, followed by stirring as it stood for 30 minutes, and further at room temperature for 2 hours. After cooling again using an ice bath, a toluene solution (30 ml) of 2,5-dichloro-3-nitropyridine (7.13 g) was added, and the temperature was brought back to room temperature, followed by stirring for 3 hours. After a 10% aqueous citric acid solution was added, the separated organic layer was washed with saturated sodium chloride solution, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 1-[(5-chloro-3-nitropyridin-2-yl)oxy]cyclopropanecarboxylate (9.61 g).
Reaction SMILES: [CH3:1][C:2]([N:6]1[Si:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][Si:7]1([CH3:14])[CH3:13])([CH3:5])[C:3]#[CH:4].[CH2:15]([Li])CCC.CI>O1CCCC1>[CH3:5][C:2]([N:6]1[Si:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][Si:10]1([CH3:11])[CH3:12])([CH3:1])[C:3]#[C:4][CH3:15]
Reactant: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: -5 °C

Procedure:
The product from Step 1 (13.0 g) in dry tetrahydrofuran (140 ml) was cooled to −70° C. under an atmosphere of nitrogen with stirring and a solution of n-butyl lithium (23.1 ml of 2.5M solution in hexanes) was added at −65 to −70° C. during 5 minutes. The mixture was allowed to warm to −5° C. and methyl iodide (3.93 ml) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to 10° C. when an exothermic reaction occurred. The mixture was maintained at 20° C. by cooling for 2 hours then evaporated under reduced pressure to a small volume. The residue was dissolved in hexane, filtered to remove the insoluble material and evaporated under reduced pressure to give 1-(1,1-dimethyl-2-butynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane as a yellow oil, 13.0 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH2:10].I.CS[C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1.C(O)C.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH:10][C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1
Reactant: NCCOc1ccccn1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: c1ccc(OCCNC2=Nc3cccc4cccc2c34)nc1

Procedure:
A mixture consisting of 3.0 grams of 2-(2-pyridinyloxy) ethylamine, 6.5 grams of 2-methylthiobenz(cd)indole hydriodide, and 150 ml of ethanol was stirred and heated under reflux, utilizing the conditions of Example 16. The crude free base (weight, 7.1 grams) was dissolved in 20 ml of acetone and added to a stirred boiling solution of 5.5 grams of fumaric acid in 1200 ml of acetone. After cooling the precipitate of the title compound was collected, washed with acetone, and dried; yield, 7.6 grams; mp 184° C.-185° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[I:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[CH3:20]>CC(C)=O>[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[I:12])[CH2:6][CH2:7][C:8]2=[O:11])[CH3:20]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1CCc2cc(I)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cc2c(cc1I)CCC2=O

Procedure:
A mixture of 6-hydroxy-5-iodoindan-1-one (6.36 g, 23.2 mmol), caesium carbonate (15.12 g, 46.4 mmol) and ethyl4-bromobutyrate (9.05 g, 46.4 mmol) in acetone (60 ml) is heated at reflux pendant 1 hour 15 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([OH:12])[CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:14][OH:15])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NO)c1ccc(Br)cc1O
Reaction time: 18 h
Yield: 89.6 %

Procedure:
A solution of methyl 4-bromo-2-hydroxybenzoate (Intermediate 22) (0.7 g) in dioxan (5 ml) was added dropwise to a solution of hydroxylamine hydrochloride (0.32 g) and sodium hydroxide (0.42 g) in water (10 ml) then stirred at room temp. for 18 h. The dioxan was removed under vacuum and the residue was stirred with 2N hydrochloric acid to give a precipitate which was collected by filtration, washed with water and dried to give the title compound as an off-white solid (0.63 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[N:11][C:10]([C:20]1[NH:24][C:23](=[O:25])[NH:22][N:21]=1)=[CH:9]2.CC1C=CC=C(C)N=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[C:34]([N:17]1[CH2:18][CH2:19][C@H:15]([NH:14][C:12]2[C:13]3[C:8](=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH3:2])[CH:9]=[C:10]([C:20]3[NH:24][C:23](=[O:25])[NH:22][N:21]=3)[N:11]=2)[CH2:16]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: COc1cccc2cc(-c3n[nH]c(=O)[nH]3)nc(N[C@H]3CCNC3)c12
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(OC)c23)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.1 %

Procedure:
To a mixture of (S)-3-(8-methoxy-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (120 mg, 0.33 mmol) in DCM (8 mL) was added 2,6-dimethylpyridine (106 mg, 0.99 mmol). The resulting mixture was cooled to −78° C. Acryloyl chloride (120 mg, 1.20 mmol, 10 mg/mL in dry DCM) was added dropwise and the reaction mixture was stirred at −78° C. for 1.5 hours. The reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (34 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 11.69 (s, 1H), 7.85 (dd, J=7.1, 14.5 Hz, 1H), 7.57-7.51 (m, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.72-6.54 (m, 1H), 6.16 (m, 1H), 5.73-5.61 (m, 1H), 5.21-5.03 (m, 1H), 4.16 (m, 1H), 4.04-3.89 (m, 3H), 3.79 (m, 1H), 3.71-3.61 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H), 2.42-2.21 (m, 1H), 2.09-1.90 (m, 1H); ESI-MS m/z [M+H]+ 381.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[CH3:33][N:34]([CH2:36][C:37](O)=[O:38])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:35])[CH2:36][C:37]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1)=[O:38]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNCC3)ccc21
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)CC1
Yield: 57.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide (52 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid piperidin-4-ylamide dihydrochloride (88 mg), dimethylamino-acetic acid (26 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 525.5. 1H NMR (DMSO-d6, 400 MHz): δ 8.40-8.38 (d, 1H), 8.11 (s, 1H), 7.96 (m, 1H), 7.80-7.78 (d, 1H), 7.55-7.50 (m, 2H), 7.43-7.40 (d, 1H), 4.43-4.25 (m, 2H), 4.09-4.08 (br. m, 1H), 3.68 (s, 3H), 3.67-3.65 (m, 1H), 3.57-3.50 (m, 1H), 3.22-3.17 (m, 1H), 2.93-2.82 (m, 6H), 1.96-1.89 (m, 2H), 1.59-1.46 (m, 2H), 1.30-1.25 (m, 1H) —NH proton signal was not observed.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])[O:6][CH:7]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[C:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])[O:6][CH:7]=1)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C[Si](C)(C)c1cc(CO)co1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)OCc1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-hydroxymethyl-2-trimethylsilylfuran (0.288 g., 1.70 mmol) and pyridine (0.214 g., 2.55 mmol) in 30 ml dry tetrahydrofuran at 0 degrees was added lauroyl chloride (0.408 g., 1.86 mmol). This solution was allowed to warm to room temperature, stirred 30 minutes, and partitioned between ethyl ether and 5% sodium bicarbonate solution. The organic portion was washed with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to a colorless oil. This material was purified by flash chromatography (silica, 5% ethyl ether/petroleum ether) to give the desired ester.
Reaction SMILES: C(OC([NH:8][N:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:35])=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][N:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([C:23]2[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:35]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1N
Reaction time: 1 h
Yield: 92 %

Procedure:
To the compound obtained in Example 67 (200 mg) is added a 4M solution of hydrogen chloride in ethyl acetate (10 ml) and the mixture is allowed to stand at room temperature for one hour. The reaction mixture is concentrated under reduced pressure, and to the residue is added ethyl acetate. The mixture is washed with a saturated aqueous sodium hydrogen carbonate solution, dried, and concentrated under reduced pressure to give 2-amino-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (146 mg) as listed in Table 6.