Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([Cl:21])[C:19]([Cl:20])=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[C:11]3[N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:7]1=[O:27])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:21][C:18]1[C:19]([Cl:20])=[C:12]2[C:11]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:10][CH:9]=[C:8]3[C:13]2=[C:14]([CH:17]=1)[C:15](=[O:16])[N:6]([OH:5])[C:7]3=[O:27]
Reactant: CC(C)(C)ON1C(=O)c2ccc(N3CCCC3)c3c(Cl)c(Cl)cc(c23)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccc(N3CCCC3)c3c(Cl)c(Cl)cc(c23)C(=O)N1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A mixture of 2-tert-butyloxy-5,6-dichloro-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (50.0 mg, 0.12 mmol, from Example M3-B) and TFA (1.0 mL) was stirred at room temperature for 2 hours and poured into ice water. The solid was washed with water and ether, and dried to give 26 mg of the title compound, mp 200-201 ° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[O:24]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25]1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:26]3[CH:27]=[CH:28][O:24][CH:25]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ccoc1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ccoc3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in dimethylformamide (2 mL) was added 3-furaldehyde (80.7 mg, 0.840 mmol) and oxone (258 mg, 0.420 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (171 mg, 69% yield) as pale yellow crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[O:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:4][C:5]1[C:10]2[O:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:9]=2[CH:8]=[C:7]([NH2:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc([N+](=O)[O-])cc2c1OC(C)(C)C2
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Oc1cc(N)cc2c1OC(C)(C)C2
Yield: 87.2 %

Procedure:
A mixture of 3.5 grams (0.014 mole) of 2,2-dimethyl-5-nitro-2,3-dihydrobenzo[2,3-b]furan-7-yl acetate (known compound) and a catalytic amount of 10% palladium on carbon in 125 mL of ethanol was subjected to hydrogenation conditions using a Parr Hydrogenator. Upon completion of the uptake of the theoretical amount of hydrogen, the reaction mixture was filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride, followed by 5% methanol in methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]([CH3:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Cs+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C)C=O>[OH:22][C:17]1[CH:16]=[C:15]([CH2:14][C@@:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:23])[C:11]([O:13][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:12])[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: CC(C)(C)OC(=O)NNC(C)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COC(=O)[C@](C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a stirred solution of 102 (650 mg, 2 mmol) in anhydrous N,N-dimethylformamide (7 mL) in a 50 mL capacity screwcap-septum vial was added cesium hydrogencarbonate (480 mg, 2.5 mmol). After having stirred at room temperature for 30 min, a solution of tert-butyl α-bromoacetate (2.5 mmol) was introduced into the reaction mixture. The resulting mixture was stirred at room temperature for 3 h and then, at 45° C. overnight (˜12 h). The reaction mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate (25 mL×4). The combined filtrates were washed with water (25 mL×2), dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed over silica gel using a gradient of 10–100% ethyl acetate and hexane to afford 710 mg (81%) of the title compound as a light yellow thick liquid. MS (ESI) m/z 463.16 (M+Na+) and 439.02 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[OH:30])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:32][Si](C=[N+]=[N-])(C)C>CO>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[O:30][CH3:32])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Yield: 99 %

Procedure:
N-(2-Chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-hydroxybenzamide (0.050 g, 0.113 mmol) was dissolved in methanol (5 ml) and after adding thereto 10% trimethylsilyldiazomethane (hexane solution) (3.5 ml), the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the obtained residue was recrystallized from a mixed solvent of ether and hexane (1:1) to obtain the titled compound (0.051 g, 0.112 mmol, 99%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
To 10 mL of a methylene chloride solution containing 280 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 150 mg of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde, 0.05 mL of acetic acid was added, and stirred at room temperature for 1.5 hours. To the reaction mixture, 280 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=5:1] to give 233 mg of 7-methoxy-1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][C:13]=1[O:26][CH3:27].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=1[O:26][CH3:27]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetate (2.27 g, 5.34 mmol) in CH2Cl2 (50 ml) was added TFA (20 ml) at room temperature. After 2 h string, the mixture was concentrated in vacuo. The residue was triturated by the addition of water, to give 4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetic acid (1.50 g, 76%) as a colorless powder. mp 246-249° C. (dec.); 1H-NMR (DMSO-d6) δ3.49 (s, 2H), 3.88 (s, 3H), 6.75 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.97 (d, J=8.0 Hz, 1H), 8.40 (s, 1H), 8.86 (s, 1H), 12.23 (br, 1H); MS (ESI) m/z 369 (M++1), 371 (M++3), 373 (M++5).
Reaction SMILES: [CH:1]([C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=O.O.NN.C(O)CO.[OH-].[K+]>O.CO>[CH3:1][C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccoc2C=O)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Solvent: CO
Product: Cc1occc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
A mixture of tert-butyl 9-(2-formyl-3-furyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (750 mg, 2.18 mmol), hydrazine monohydrate (0.300 ml, 6.18 mmol), ethylene glycol (15 ml) and methanol (5 ml) was stirred at 85° C. for 10 min. After cooling to room temperature, potassium hydroxide (500 mg, 8.91 mmol) was added, and the mixture was stirred at 100° C. for 0.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (300 mg, 41.8%) as an oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([OH:28])([CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1)[CH2:4][C:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])([CH3:7])[CH3:6].[BH4-].[Na+]>CO.C1COCC1>[OH:28][C:3]([C:2]([F:30])([F:1])[F:29])([CH2:4][C:5]([C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][OH:12])[CH:9]=1)([CH3:7])[CH3:6])[CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(CO)c1
Reaction time: 0.75 h
Yield: 31.5 %

Procedure:
To a solution of the 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzaldehyde (20.0 mg, 0.05 mmol) in methanol (0.50 mL) and THF (0.50 mL) was added NaBH4 (20.0 mg, 0.48 mmol). The reaction vessel was sealed and stirred for 45 minutes. The solvent was evaporated in vacuo and the off-white solid was re-dissolved in EtOAc and water and transferred to a separatory funnel. The aqueous layer was extracted with two 10 mL portions of EtOAc and the combined organic layers were washed with one 10 mL portion of brine, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give a white foam. The material was chromatographed (6% MeOH/CH2Cl2, 0.5% NH4OH) to give the desired compound, 1-[2-hydroxy-4-(3-hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one as a white foam (6.6 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=3[CH3:24])=[O:16])=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=2)=[C:4]([CH3:28])[CH:3]=1.Cl[CH2:30][CH2:31][CH2:32][OH:33].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH2:30][CH2:31][CH2:32][OH:33])[CH:20]=[CH:19][C:18]=3[CH3:24])=[O:16])=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(O)ccc2C)c([N+](=O)[O-])c1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(OCCCO)ccc2C)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
Compound 505 (0.05 g, 0.13 mmol) and 3-chloro-propanol (0.022 mL, 0.26 mmol) were dissolved in CH3CN (3 mL). K2CO3 (0.1 g, 0.72 mmol) and NaI (0.005 g, 0.03 mmol) were added and the suspension was heated in a microwave oven at 100° C. for 20 minutes. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/CH2Cl2 1:9 as the eluent. This afforded the title compound. 1H NMR (CDCl3) δ 7.36 (d, 1H), 7.22 (dd, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 7.06-6.89 (m, 3H), 6.83 (dd, 1H), 6.79 (d, 1H), 5.88 (bs, 1H), 4.04 (t, 2H), 3.82 (t, 2H), 2.47 (s, 3H), 2.25 (s, 3H), 1.99 (m, 2H)
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([O:10][C@@H:11]([CH3:15])[C:12]([O:14][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:13])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)O)cc1
Reactant: C=C(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 2(S)-(p-toluenesulfonyloxy)propionic acid (4.4 g) to a cold solution of 10ml of isobutylene and 0.4 ml of concentrated sulfuric acid in 30 ml of methylene chloride in a pressure vessel, seal, and agitate at room temperature for 48 hours. Pour into 50 ml of 15% sodium carbonate solution, dry over magnesium sulfate and concentrate to obtain t-butyl 2(S)-(p-toluenesulfonyloxy)propionate as an oil (NMRδ1.37). Distilled material (Kugelrohr, 120°) has [α]D26 =-45.9° (EtOH, c=1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[NH:20][N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:36]=1[CH2:37]Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[N:20]([CH2:37][C:36]4[C:35]([Cl:34])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:43])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=c1n(S(=O)(=O)c2ncn[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: Clc1cccc(Cl)c1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1n(S(=O)(=O)c2ncnn2Cc2c(Cl)cccc2Cl)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
37 mg (0.10 mmol) of the compound from Example 93A were dissolved in 3 ml of dichloromethane, and 21 μl (0.13 mmol) of N,N-diisopropylethylamine were added. 30 mg (0.13 mmol) of 2,6-dichlorobenzyl bromide dissolved in 1 ml of dichloromethane were then added, and the mixture was stirred at RT for 20 h. For work-up, the mixture was concentrated under reduced pressure and the crude product was purified chromatographically [Method 19]. This gave 39 mg (74% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([F:33])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][NH:40][C:39]1=[O:43].C(N(CC)CC)C>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([F:33])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:35][CH2:36][CH2:37][N:38]4[CH:42]=[CH:41][NH:40][C:39]4=[O:43])[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCn1cc[nH]c1=O
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4cc[nH]c4=O)ncc3F)sc12
Temperature: 130 °C
Yield: 44.9 %

Procedure:
Combine (1-{4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-6-fluoro-pyridin-3-yl}-ethyl)-carbamic acid tert-butyl ester (150 mg, 0.3 mmol), 1-(2-amino-ethyl)-1,3-dihydro-imidazol-2-one (70 mg, 0.55 mmol) and triethylamine (80 mg, 0.8 mmol) in N-methylpyrrolidone (1.0 mL) in a pressure tube. Heat the reaction mixture at 130° C. for 1 hour in a microwave reactor and then cool to room temperature. Dilute the reaction mixture with ethyl acetate, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over MgSO4. After filtration, evaporate the organic solvent to give the crude. Purify the crude by column chromatography (10% methanol in dichloromethane) to afford the desired product (80 mg, 74%). MS (ES) m/z 538 [M+t-Bu]+, 494 [M-Boc]−, 616 [M+Na]+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2cnc3ccccc32)cc1

Procedure:
To a flask were added 2 g benzimidazole, 3.5 g potassium carbonate, 20 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 3.2 g Benzyl chloride were added and the mixture was heated to 50 C for 16 hrs. The reaction was quenched with 40 ml water and 7 ml 3M hydrochloric acid and cooled to 5 C. The product was filtered and washed with water. The product was recrystallized by dissolving in 10 ml 2-propanol at reflux, hot filtered and 30 ml hexane were added. After cooling to 5 C, the product was filtered, washed with hexane and dried giving 1.6 g.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.I([O-])(=O)(=O)=[O:18].[Na+]>CO.O>[CH3:1][S:2]([CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:18]
Reactant: CSCCOc1ccc2c(c1)CCC(=O)N2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)CCOc1ccc2c(c1)CCC(=O)N2
Reaction time: 1.5 h

Procedure:
1.42 gm (0.006 mol) of 6-(2-methylmercapto-ethoxy)-3,4-dihydro-carbostyril were suspended in 12 ml of methanol, and a solution of 1.71 gm (0.008 mol) of sodium metaperiodate in 8 ml of water was added. The reaction mixture was stirred for 1.5 hours; at the beginning a distinct warming of the reaction mixture was noted. Subsequently, the mixture was diluted with a little water and exhaustively extracted with chloroform. The evaporation residue of the chloroform extract was recrystallized from ethyl acetate by addition of a little ethanol.
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]=1.[ClH:15]>Cl([O-])=O.[Na+]>[Cl:15][C:5]1[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:4]=1[I:3]
Reactant: Ic1cnc(-c2ccccn2)[nH]1
Reactant: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Product: Clc1nc(-c2ccccn2)[nH]c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To 5% aqueous sodium chlorite solution (180 mL) was added sodium hydroxide (737 mg) and completely dissolved. To the reaction solution was added 2-(5-iodo-1H-imidazol-2-yl)pyridine (5.00 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was adjusted to pH 3 to 4 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=30:70-100:0, volume ratio) to give the title compound (3.57 g, yield 63%) as colorless crystals. melting point 188-189° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[C:13]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[C:13]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2cc(OC)ccc2c1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)c(C)cc2c1
Temperature: 50 °C
Yield: 78.5 %

Procedure:
To a solution of ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)acetate (16.2 mg, 0.037 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 2.5 mL) was added lithium hydroxide (4 mg, 0.183 mmol) and the reaction was heated at 50° C. overnight. The reaction was purified by reverse phase HPLC (Gemini, 20-90% ACN/H2O+0.1% TFA) to give a white powder (12 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 7.60 (s, 1H), 7.55 (m, 3H), 7.30 (m, 1H), 7.17 (d, J=2.8 Hz, 1H), 7.13 (d, J=9.6 Hz, 1H), 6.94 (dd, J=9.2, 2.8 Hz, 1H), 5.15 (s, 1H), 3.90 (s, 3H), 2.58 (s, 3H), 0.98 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C24H24ClO4: 411.14; found: 411.14.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:28][N:27]=2)=[CH:21][CH:20]=1
Reactant: ON=C(Cl)Cc1ccc(CCc2ccccn2)cc1
Reactant: C#Cc1cccnc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(CCc3ccccn3)cc2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine (39 mg, 0.33 mmol) described in Manufacturing Example 1-2-3 was added (4-(2-pyridin-2-yl-ethyl)-phenyl)-acetohydroximoyl chloride hydrochloride (310 mg, 1.0 mmol) described in Manufacturing Example 93-1-8 under nitrogen atmosphere at room temperature. Triethylamine (0.42 mL, 3.0 mmol) was then added dropwise, and stirred for 2 hours at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:7 then 4:6), and the resulting crude product was further purified by silica gel thin-layer chromatography (ethyl acetate) to obtain the title compound (21.2 mg, 18%).