Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1>>[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2([CH2:5][OH:16])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc(F)c(F)cc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4,5-difluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (96%): MS (ES+) m/z 344 (M−17), 384 (M+23).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:5]=1[OH:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:5]=1[OH:13]
Reactant: CCCc1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cccc(N)c1O
Yield: 90.2 %

Procedure:
To a solution of 2-nitro-6-n-propylphenol(2 g, 11.0 mmol) in methanol(100 mL) was added 10% Pd/C (200 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(1.50 g, 80.2%). 1H NMR (CD3OD): d 6.65 (m, 2H), 6.55 (t, 1H), 2.58 (t, 2H), 1.61 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[S:5]1[CH2:11][C:9](=[O:10])[NH:8][C:6]1=S.CCN(C(C)C)C(C)C>>[CH:1]1([NH:4][C:6]2[S:5][CH2:11][C:9](=[O:10])[N:8]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NC2CC2)=N1

Procedure:
Similar procedure as described in example 1f was used, starting cyclopropylamine, rhodanine (2-thioxo-thiazolin-4-one) and DIEA to give 2-cyclopropylamino-thiazol-4-one. LC-MS m/e 157 (MH+).
Reaction SMILES: [C:1]12([CH2:11][C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([N:17](C(F)(F)C(F)C(F)(F)F)CC)C>N>[C:1]12([CH2:11][C:12]([NH2:17])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Agent: N
Product: NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
1-Adamantaneacetic acid (11.7 g, 0.06 mole) was dissolved in N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (13.4 g, 0.06 mole) during which time a highly exothermic reaction occurred. The reaction mixture was allowed to cool to room temperature and cold aqueous ammonia (250 ml) was added slowly. The 1-adamantaneacetamide was isolated as described in example 1 to yield 10.5 g, 90.6 %; mp 173.6-174.0° C. The analytical sample was recrystallized from cyclohexane and sublimed. Anal. Calcd. for C12H19NO: C, 74.63; H, 9.89; N, 7.25. Found: C, 74.36; H, 9.84; N, 7.15.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[N:24]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=5[Cl:38])[N:25]=[CH:26][C:27]=4[CH:28]([CH3:30])[CH3:29])=[CH:17][C:16]=3[CH3:39])=[CH:11][C:8]=2[S:9][CH:10]=1)C.[OH-].[Na+]>O1CCCC1.CO>[Cl:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[N:24]1[C:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:7]4[C:6]([CH2:5][C:4]([OH:40])=[O:3])=[CH:10][S:9][C:8]=4[CH:11]=3)=[C:16]([CH3:39])[CH:17]=2)=[C:27]([CH:28]([CH3:30])[CH3:29])[CH:26]=[N:25]1
Reactant: CCOC(=O)Cc1csc2cc(-c3ccc(OCc4c(C(C)C)cnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of (6-{4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (43 mg; 0.072 mmoles) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) is treated with sodium hydroxide (1.0 mL; 1.0 N). The mixture is stirred at room temperature for 2 hours and quenched with HCl (1.0 mL, 1.0 M). The mixture is extracted with EtOAc (10 mL×2). The combined organic layers are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (eluting with 30-100% EtOAc/Hexanes) and the appropriate fractions are concentrated. The material is dried in vacuo to afford the title compound (28 mg, 68%). ES/MS m/e 564.8; 566.8 (M+1); 562.8; 564.8 (M−1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Li+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)CCNC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)cyclopropylamino)propanoate (0.031 g, 0.064 mmol) in tetrahydrofuran (0.2 mL) and methanol (0.1 mL) was added 1 M lithium hydroxide solution (0.19 mL, 0.19 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulting slurry was diluted with water and neutralized (to pH=˜7) with aqueous 1 N HCl solution. The aqueous suspension was extracted with 15% MeOH/CHCl3; the organic extracts were combined, dried (K2CO3), filtered, and concentrated in vacuo. Purification via reverse phase prep. HPLC afforded the title compound as an off-white amorphous solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([O:12][CH3:13])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[Br:11][C:9]1[CH:8]=[C:7]([O:12][CH3:13])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Br)cc(C(=O)O)n1

Procedure:
246 mg (1.00 mmol) 4-bromo-6-methoxy-pyridine-2-carboxylic acid methyl ester was dissolved in 5 mL MeOH and treated with 2.50 mL 4 M aqueous NaOH solution at RT for 12 h. The solvent was removed by distillation. the residue was taken up in water and acidified with 4 M aqueous hydrochlorid acid. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([O:12]CC)=[O:11])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([OH:12])=[O:11])=[O:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CS(=O)Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CS(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 2-(4-fluorobenzylsulfinyl)acetate (1.60 g, 6.55 mmol) in THF (10.0 mL) and MeOH (20.0 mL) was added 1 N NaOH (20.0 mmol). The mixture was stirred at room temperature for 2 h. After removal of organic solvent under reduced pressure, the remaining aqueous solution was neutralized with 1 N HCl (25.0 mL). It was extracted with EtOAc (3×100 mL) and the combined organic layer was dried over MgSO4. The solution was then filtered and concentrated in vacuo to give 2-(4-fluorobenzylsulfinyl)acetic acid (1.25 g, 88% yield). MS (ESI+): m/z 217.05 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([OH:15])([CH2:13][CH3:14])[CH2:11][CH3:12].[CH3:16][C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:21])[CH2:18][CH:19]=O>>[CH2:11]([C:10]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[NH:1][CH2:19][CH2:18][C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:21])[CH3:16])([OH:15])[CH2:13][CH3:14])[CH3:12]
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Reactant: CCC(O)(CC)c1cccc(OC)c1N
Product: CCC(O)(CC)c1cccc(OC)c1NCCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
The product is obtained analogously to intermediate product 1b starting from 3-(2-amino-3-methoxyphenyl)pentan-3-ol and tert-butyl (1,1-dimethyl-3-oxopropyl)carbamate. The crude product is purified by column chromatography (silica gel, cyclohexane/EtOAc, 4:1). Yield: 4.60 g (47%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[NH4+:23].[OH-]>O1CCOCC1.O>[NH2:23][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: [NH4+]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1C
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(NS(=O)(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Temperature: 95 °C

Procedure:
To a suspension of 4-chloro-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide (0.22 g) in dioxane (2 mL) was added NH4OH (3 mL). The reaction mixture was heated to 95° C. for 8 h. The mixture was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The extract was dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 hexane/EtOAc) afforded 4-amino-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([NH2:13])=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[NH2:13][C:10]1[C:11]2[S:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:9]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cc2[nH]nc(N)c2s1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(N)c2sc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 62.8 %

Procedure:
To an ice-cooled suspension of 3-amino-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (35.5 mmol, 7.0 g) and N,N′-diisopropylethylamine (0.21 mol, 36.5 mL) in 71 mL of tetrahydrofuran were added, dropwise, 3.5 mL of ethyl chloroformate (36.6 mmol). After 1.5 hours, the cold suspension was concentrated under vacuum and diluted with dichloromethane. The organic phase was washed with buffer pH 4, sodium hydroxide 1 N, brine and dried over Na2SO4. The filtrate was evaporated to dryness and triturated with dichloromethane to give 6 g 1-ethyl 5-methyl 3-amino-1H-thieno[3,2-c]pyrazole-1,5-dicarboxylate (7)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:22])[C@@H:9]([NH:14]C(OC(C)(C)C)=O)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.[ClH:23]>ClCCl.O1CCOCC1>[ClH:23].[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:22])[C@@H:9]([NH2:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccnc1)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](N)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid 3-pyridylamide (1.6 g, 5.21 mmol) in dichloromethane (10 mL) cooled at 0° C. is added 4 M HCl in dioxane (10 mL). The resulting solution is allowed to warm to 25° C. and is stirred for 3 h. The reaction mixture is concentrated and the solid is filtered to provide (2S)-2-amino-3,3-dimethylbutanoic acid 3-pyridylamide dihydrochloride (1.40 g, 94% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][CH2:9]2)([O-:3])=[O:2].[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+].ClCCl>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][CH2:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1cccc2c1CCNC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c(c([N+](=O)[O-])c1)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Nitro-1,2,3,4-tetrahydroisoquinoline (1.0 g, 5.6 mmol) in conc. sulfuric acid (3 ml) was treated with conc. nitric acid (1 ml) and the mixture stirred at room temperature for 1 h. The mixture was cooled, basified with 40% aqueous NaOH and work-up with dichloromethane gave the title compound (1.14 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:27]4[CH2:28][CH:22]5[NH:30][CH2:29][CH:26]4[CH2:25][CH2:24][CH2:23]5)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of 0.53 g (2.0 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.44 g (2.2 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 10 ml of pyridine was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature and the solid was filtered and washed with ethanol to yield 0.39 g of the title compound, mp 273°-276° dec.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=O)[N:16]=3)=[C:9]([F:30])[CH:8]=1.[CH3:31][Si](C[Mg]Cl)(C)C.CC(C)([O-])C.[K+]>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH2:31])[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a slurry of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridine-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (0.408 g, 0.952 mmol) in 20 mL THF at ambient temp was added trimethylsilylmethylmagnesium chloride, 1.1 M solution in THF (1.472 mL, 1.619 mmol) dropwise via syringe. The reaction mixture became clear and dark brown. After 10 min, the reaction mixture became light orange and was cooled to 0° C. and was quenched by careful dropwise addition of sat'd aq NH4Cl. The reaction mixture was partitioned between satd NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an orange solid. The crude was taken up in 10 mL THF and potassium tert-butoxide (0.128 g, 1.143 mmol) was added. The reaction mixture became dark brown. After 2 h, additional potassium tert-butoxide (0.128 g, 1.143 mmol) was added. After 2 h, the reaction mixture was partitioned between sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The solid was suspended in a minimum amount of MeOH and filtered, rinsing with MeOH to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)vinyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 426.1; Observed: 427.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH2:9])[CH2:3]1.CN(C)/[CH:12]=[C:13](/[C:19](=[O:28])[C:20]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:21]=1F)\[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>O>[I:26][C:24]1[CH:25]=[C:20]2[C:21](=[CH:22][CH:23]=1)[N:9]([CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]2=[O:28]
Reactant: CN1CCCC(CN)C1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(CC2CCCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
1-(1-Methylpiperidine-3-yl)methanamine (500 mg, 3.9 mmol) was added to the solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 10.4 mL, 2.25 mmol) and the mixture was heated at 50° C. for 3 h. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (7 mL) and potassium carbonate powder (695 mg, 5.1 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (30 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 1.12 mg (69% yield) of ethyl 6-iodo-1-((1-methylpiperidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13](=[O:15])[CH3:14].[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14]
Reactant: CC(=O)CCc1c[nH]c2ccc(F)cc12
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)CCc1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
A solution of 4-(5-fluoro-1H-indol-3-yl)-butan-2-one (11.1 g, 54.1 mmol) in THF (200 mL) at 0° C. is treated with MeMgBr (54.1 mL, 3 M in THF, 162.3 mmol) and stirred at 0° C. for 2 h, and warmed to rt overnight. The mixture is then poured over ice, treated with solid NH4Cl (3 g), and extracted with EtOAc (3×120 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-60% EtOAc in heptane to afford 4-(5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (3.07 g, 26%). MS: 222 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.94 (s, NH, 1H), 7.22 (m, 2H), 7.03 (s, 1H), 6.93 (m, 1H), 2.81 (m, 2H), 1.90 (m, 2H), 1.33 (s, 6H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:18]=4[CH:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:26][C:27]1([CH3:34])[CH2:32][C:31](=[O:33])[O:30][C:28]1=[O:29]>C(Cl)Cl>[Cl:25][C:24]1[C:18]2[CH:17]=[C:16]([C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:6][CH2:5][N:4]([C:31](=[O:33])[CH2:32][C:27]([CH3:34])([CH3:26])[C:28]([OH:30])=[O:29])[CH2:3][CH2:2]4)=[N:12][CH:11]=3)=[O:15])[S:20][C:19]=2[CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1cc2c(Cl)cccc2s1
Solvent: ClCCl
Product: CC(C)(CC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1)C(=O)O
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-benzo[b]thiophene-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide (50 mg, 0.13 mmol), CH2Cl2 (5 mL), and TEA (40 mg, 0.39 mmol) was stirred at room temperature. 2,2-Dimethylsuccinic anhydride (36 mg, 0.28 mmol) was added slowly. The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up into 50 mL of EtOAc and washed with 50 mL of saturated ammonium chloride, brine and dried over anhydrous sodium sulfate. The solvent was removed and the product was triturated with diethyl ether and hexanes followed by filtration, to afford the product 4-(4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid (58 mg, 89% yield). LCMS for C24H25ClN4O4S calcd. (m/e) 500, observed 499 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[O:20][C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1.S(Cl)([Cl:32])(=O)=O>C(Cl)(Cl)Cl>[Cl:32][C:17]1([C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:14]=[CH:13][C:12]=2[CH2:15][CH3:16])[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[O:20][C:19]([CH3:27])([CH3:26])[C:18]1=[O:28]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1(Cl)C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a solution of 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.220 g, 0.525 mmol) in dry chloroform (4 ml) is added sulfuryl chloride (0.085 ml, 1.05 mmol), followed by stirring at room temperature for 4 hours. After dilution with diethyl ether (150 ml) the organic phase is washed with saturated sodium carbonate (150 ml) then dried over magnesium sulphate and the filtrate concentrated in vacuo to afford 4-chloro-4-(2′,4′-dichloro-4-ethylbiphen-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.229 g, 96%) as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[O:16]1[CH2:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[O:16]1[CH2:17][CH:18]=[C:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH:13]([OH:15])[CH3:14])[CH2:20][CH2:21]1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1C1=CCOCC1
Yield: 25.7 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A2, 0.50 g, 1.86 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.51 g, 2.42 mmol), Pd(PPh3)4 (0.11 g, 0.093 mmol) and Cs2CO3 (0.30 mg, 0.93 mmol) to afford the title compound (0.13 g, 26%) as a orange oil.