Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([CH3:17])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:7]2.[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].O>C(Cl)(Cl)Cl>[CH2:19]([NH:23][C:24]([NH:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([CH3:17])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:7]2)=[O:25])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN1CCc2c(C)cc(C)c(N)c21
Reactant: CCCCN=C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCN1CCc2c(C)cc(C)c(NC(=O)NCCCC)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.1 %

Procedure:
7-Amino-4,6-dimethyl-1-hexylindoline (800 mg) was dissolved in chloroform (20 ml) and butyl isocyanate (400 mg) was added, which was followed by stirring at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent : chloroform-methanol=1:0-50:1) and recrystallized from ethanol to give 450 mg of the title compound.
Reaction SMILES: CS[C:3]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[S:5](=[O:12])(=[O:11])[N:4]=1.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])=[CH:19][CH:18]=1)[CH3:15]>C(O)C>[CH3:15][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:24][CH2:25][NH:26][C:3]2[C:7]3=[CH:8][S:9][CH:10]=[C:6]3[S:5](=[O:11])(=[O:12])[N:4]=2)=[CH:19][CH:18]=1)[CH3:13]
Reactant: CSC1=NS(=O)(=O)c2cscc21
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)c3cscc32)o1
Reaction time: 1.5 h

Procedure:
To a suspension of 1.8 g. (0.0082 m.) of 3-(methylthio)thieno[3,4-d]isothiazole-1,1-dioxide in 10 ml. of ethanol is added 1.76 g. (0.0082 m.) of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamine with stirring at room temperature. The reaction mixture is heated to reflux and heating is continued for 1.5 hours. At this time the reaction mixture is filtered to remove insoluble material and then evaporated to dryness. The product is purified using a silica gel column with methanol as the eluant. The desired fraction was evaporated to dryness and then triturated with ether to give 120 mg. a white solid with a m.p. 100°-103° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([CH2:37]O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:37][C:30]2[C:31]([C:33]([F:35])([F:34])[F:36])=[N:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:40])([F:18])[F:39])=[CH:26][CH:25]=3)=[CH:28][CH:29]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: OCc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with [6-(4-trifluoromethoxy-phenyl)-2-trifluoromethyl-pyridin-3-yl]-methanol in the presence of N,N,N′,N′-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.Cl>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: COCCO
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: Cl
Agent: [Na]
Solvent: O
Product: COCCOc1ccc2c(=O)[nH]cnc2c1
Yield: 58 %

Procedure:
Sodium (400 mg, 17 mmol) was added carefully to 2-methoxyethanol (10 ml) and the mixture heated at reflux for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (750 mg, 4.57 mmol) was added to the resulting solution and the mixture heated at reflux for 15 hours. The mixture was cooled and poured into water (250 ml). The mixture was acidified to pH4 with concentrated hydrochloric acid. The resulting solid product was collected by filtration, washed with water and then with ether, and dried under vacuum to give 7-(2-methoxyethoxy)-3,4-dihydroquinazolin4-one (580 mg, 58%).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[CH:13]1([CH2:18][CH2:19][OH:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:18][CH2:19][O:20][NH2:2])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCC1CCCC1
Product: NOCCC1CCCC1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and 2-cyclopentylethanol (Lancaster). 13C-NMR (CDCl3) δ 75.7, 37.0, 34.6, 32.8, 25.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.C[O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18](O)[CH:17]=1>>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([OH:25])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: OCCc1cccc(CCO)c1
Product: COc1ccc(C(=O)O)cc1OCCc1cccc(CCO)c1

Procedure:
2-[3-(2-Hydroxy-ethyl)-phenyl]-ethanol and 3-hydroxy-4-methoxybenzoic acid methyl ester were coupled in analogy to step 1 of example 1 and the methyl ester was hydrolyzed in analogy to step 2 of example 1 to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]([CH:11]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]([O:14][CH3:15])=[O:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C(=O)OC)c1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
To a solution of methyl (4-fluoro-2,6-dinitrophenyl)acetate from Step B (9.51 g, 36.8 mmol) and ethyl bromoacetate (8.17 mL, 73.6 mmol) in DMF (100 mL) was added cesium carbonate (18.0 g, 55.2 mmol). The reaction mixture was stirred for 16 h and then poured onto H2O (500 mL). The aqueous layer was extracted with EtOAc (3×250 mL). The combined organic layers were washed with H2O (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=345 (M+1).
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:7])(=O)=O.[Na+].[CH2:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:7])[C:5]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCOC(C)(COS(=O)(=O)[O-])OCCCCCC
Reactant: CCCCCCO
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Yield: 84 %

Procedure:
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) is added 1-hexanol 2 (40.1 g, 392 mmol) and p-Ts0H (186 mg, 0.98 mmol). The mixture is heated to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The reaction is quenched with saturated NaHCO3 (100 mL), and the reaction mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf (15% EtOAc/hexane)=0.53; IR (thin film, cm−1) 2956, 2930, 2860, 1746 (C═O), 1467, 1280, 1137, 1062. 1H NMR (600 MHz, CDCl3) δ 4.14 (t, J=7.2 Hz, 2H), 3.48 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.35 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m, 4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J=7.2 Hz, 9H); 13C NMR (150 MHz, CDCl3) δ 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0, 13.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH2:23][C@@H:24]([N:26]([CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH2:27][CH3:28])[CH3:25])=[CH:22][C:17]=2[CH2:16][CH2:15]1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:29][N:26]([C@@H:24]([CH3:25])[CH2:23][C:21]2[CH:20]=[CH:19][C:18]3[O:14][CH2:15][CH2:16][C:17]=3[CH:22]=2)[CH2:27][CH3:28])[CH2:31][CH2:32]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC1CCNCC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Solvent: ClCCl
Product: CCN(CC1CCN(C(=O)CCNC(=O)OC(C)(C)C)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of N-tert-butoxycarbonyl-β-alanine (0.31 grams, 165 mmole) in dichloromethane (5 ml) was added N,N′-carbonyldiimidazole (0.3 grams, 185 mmole). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a solution of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(piperidine-4-ylmethyl)amine (0.5 grams, 1.65 mmole) in dichloromethane (2 ml). The reaction mixture was stirred for 16 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using 2% methanol in dichloromethane containing 0.1% ammonium hydroxide. Appropriate fractions were combined and concentrated to give (S)-3-tert-butoxycarbonylamino-1-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-ethylamino}methyl)piperidin-1-yl]propan-1-one as a solid (0.76 grams, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:8]=[C:4]2[CH:3]=1.[CH3:28][N:29]1[C:34]([CH3:36])([CH3:35])[CH2:33]C(O)[CH2:31][C:30]1([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16][CH:17]3[CH2:33][C:34]([CH3:36])([CH3:35])[N:29]([CH3:28])[C:30]([CH3:39])([CH3:38])[CH2:31]3)=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Product: CN1C(C)(C)CC(OC(=O)CCc2cc(-n3nc4ccc(Cl)cc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C

Procedure:
Methyl 3-(5-chlorobenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate (10.0 g, 0.026 mol) and 1,2,2,6,6-pentamethyl-4-hydroxypiperidine (3.98 g, 0.023 mol) are reacted together according to the procedure of Example 1. The title compound is obtained in a yield of 3.23 g (26%) as an off-white solid, melting at 150-158° C., whose structure is consistent with 1Hnmr and mass spectrometry. The compound has a molar absorptivity of 17,092 l/mole cm.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:25])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([NH:23][CH3:24])[CH:17]=3)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])C.C(O)(=O)C.C(O)(=O)C.[F:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41].CN1CCCC1>C1COCC1>[F:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH:41][C:5]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:25])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([NH:23][CH3:24])[CH:17]=3)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])=[O:4]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3nc2C)c(C)cc1F
Reactant: CC(C)(F)CCN
Agent: CN1CCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1cc2nc(C)c(-c3cc(NC(=O)NCCC(C)(C)F)c(F)cc3C)cc2cn1
Yield: 70.9 %

Procedure:
Combine prop-1-en-2-yl(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)carbamate (2.5 g, 6.6 mmol), 3-fluoro-3-methylbutan-1-amine diacetate (1.8 g, 7.9 mmol), and N-methylpyrrolidine (2.7 mL, 26.0 mmole) in THF (50 mL) and heat at 50° C. overnight. Evaporate under reduced pressure and partition between NaHCO3 and EtOAc. Wash the organic layer with brine, dry over Na2SO4, concentrate in vacuo, and purify by silica gel chromatography (50-100% EtOAc/DCM) to obtain the title compound (2.0 g, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.33 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.83 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.73 (m, 1H), 6.56 (m, 1H), 6.52 (s, 1H), 3.15 (m, 2H), 2.82 (d, J=5 Hz, 3H), 2.27 (s, 3H), 1.94 (s, 3H), 1.73 (m, 2H), 1.30 (d, J=21.6 Hz, 6H); MS (ESI) m/z: 428.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5]2.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5]2
Reactant: BrCc1ccccc1
Reactant: CCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of the title compound of Example 3 Step A (1.35 g, 5.73 mmol) in DMF (25 mL) was added NaH (252 mg, 60% suspension if mineral oil, 6.30 mmol). After 20 min, benzyl bromide (0.750 mL, 6.30 mmol) was added, and the mixture was allowed to stir for 15 h, whereupon it was quenched by addition of sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 15%, then 15 to 100% EtOAc in hexanes) provided the title compound: LCMS A, tr=4.36 min, m/z 326.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=1.0 Hz, 1H), 7.34-7.22 (m, 6 H), 7.04 (d, J=7.0 Hz, 2H), 5.88 (s, 2H), 2.99 (t, J=7.5 Hz, 2H), 1.76-1.70 (m, 2H), 1.44-1.36 (m, 2 H), 0.97 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28](=[O:30])[CH3:29]>CN(C=O)C>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:27][C:28](=[O:30])[CH3:29])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Temperature: 60 °C
Yield: 32.4 %

Procedure:
To a solution of 6-(tert-butylsulfonyl)-4-chloroquinolin-7-ol (500 mg, 1.668 mmol) in DMF (8162 μl) was added K2CO3 (692 mg, 5.00 mmol) followed by 1-chloropropan-2-one (178 μl, 2.502 mmol). This was heated to 60° C. for 30 min. The crude sample was purified via Biotage normal phase chromatography (25 g SNAP column, 0%-65%, 65%. hex/EtOAc). The pure product containing-fractions were combined and concentrated leading to the product as an off-white solid: 1-((6-(tert-butylsulfonyl)-4-chloroquinolin-7-yl)oxy)propan-2-one (192 mg, 0.540 mmol, 32.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 2.27 (s, 3H) 5.21 (s, 2H) 7.64 (s, 1H) 7.76 (d, J=4.80 Hz, 1H) 8.67 (s, 1H) 8.93 (d, J=4.80 Hz, 1H). MS: m/z: 356.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][CH2:18][C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(-c2n[nH]c3ccc(NCc4ccncc4)cc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
To a solution of N-[3-(4-fluorophenyl)(1H-indazol-5-yl)]-4-pyridylcarboxamide (50 mg, 0.12 mmol) in THF (3 mL) was added lithium aluminum hydride (LAH) (9 mg, 0.24 mmol). The solution was stirred for 3 hours when an additional equivalence of LAH was added. The reaction was stirred for another 3 hours when it was quenched with ethyl acetate and water (100 mL) was added. The layers were separated and the water layer extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4) and concentrated to an oil. The oil was taken up in methanol (10 mL) and 6N HCl (10 mL) and heated to 80° C. for 2 hours when it was quenched with NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound (7.5 mg, 20% yield). 1H NMR (CDCl3) δ 8.6 (br s, 1H), 7.76 (dd, 2H), 7.35 (d, 2H), 7.24 (d, 2H), 7.15 (t, 2H), 6.9–6.8 (m, 2H) 4.43 (s, 2H); ES-MS (m/z) 319[M+1]+.
Reaction SMILES: N[C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@H](Br)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
(S)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) was dissolved in a mixture of 48% hydrogen bromide (13 ml, 198 mmol, 8 equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g, 79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C. for 1.5 h. The reaction was degassed in vacuo and extracted with ether. The organic layer was further washed with water and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—1%-10% ethyl acetate/hexanes) to afford the (R)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40% yield).). 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H); 5.95 (s, 1H); 7.36-7.42 (m, 3H); 7.54 (d, 2H, J=1.6 Hz); 7.56 (d, 1H, J=2 Hz). MS for C9H9BrO2 m/z 229.98 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]2)[CH2:3][CH2:2]1.N1C2C(=CC=CC=2)C=CC=1>CCCCCC.[Pd]>[CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]2)[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(CCC#CCC2CC2)O1
Agent: [Pd]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CC1(C)OCC(CCC=CCC2CC2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(5-Cyclopropyl-pent-3-ynyl)-2,2-dimethyl-[1,3]dioxolane (1.92 mmol, 0.40 g) in hexane (5 mL) was added quinoline (0.192 mmol, 24.8 mg), followed by addition of 5% Pd on BaSO4 (0.384 mmol). Stirred at room temperature under H2 atmosphere for 4 hrs. TLC showed reaction completed. Filtered through celite and concentrated. Diluted with hexane, washed with NH4Cl, brine and dried over MgSO4. Silica gel chromatography (2˜7% EtOAc/Hexane) 4-(5-Cyclopropyl-pent-3-enyl)-2,2-dimethyl-[1,3]dioxolane as clear oil 1H NMR (400 MHz, CDCl3): δ 5.52–5.45 (m, 1H), 5.40–5.34 (m, 1H), 4.11–4.04 (m, 1H), 4.02 (dd, 1H, J1=8.0 Hz, J2=6.0 Hz), 3.51 (t, 1H, J=7.5 Hz), 2.17–2.04 (m, 2H), 1.97 (t, 2H, J=7.0 Hz), 1.74–1.66 (m, 1H), 1.58–1.49 (m, 1H), 1.41 (s, 3H), 1.35 (s, 3H), 0.73–0.68 (m, 1H), 0.43–0.39 (m, 2H), 0.08–0.04 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:28][C:29]1[C:34]([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)c1
Reactant: OB(O)c1cccnc1F
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
tert-butyl ({5-bromo-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (459 mg), (2-fluoropyridin-3-yl)boronic acid (169 mg), sodium carbonate (254 mg), and tetrakis(triphenylphosphine)palladium (173 mg) were suspended in 1,2-dimethoxyethane (10 mL) and water (4 mL), and the mixture was stirred at 105° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 303 mg, 64%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CCCCCC.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>C1COCC1>[C:7]1([N:6]2[C:5]3[CH:13]=[CH:14][C:2]([B:32]([OH:35])[OH:33])=[CH:3][C:4]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Into a solution of 19.6 g (60.7 mmol) of 3-bromo-9-phenylcarbazole, prepared in Step 1 of the Embodiment 2, in THF (100 mL) was added dropwise 66.8 mL (42.3 mmol) of an n-butyllithium hexane solution (1.58 mol/L) at −78° C. under nitrogen, which was followed by stirring for 3 hours at the same temperature. Thereafter, 13.5 mL (140 mmol) of trimethyl borate was added, and stirring was continued for 24 hours while gradually raising the reaction temperature to room temperature. 200 mL of 2.0 mmol/L hydrochloric acid was added to the solution, and additional stirring was conducted for 1 hour at room temperature. After the solution was extracted with ethyl acetate, the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated: The resulting solid was recrystallized with a mixed solvent of chloroform and hexane, giving 10.2 g of 9-phenylcarbazole-3-ylboronic acid as white powder in 58% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3=[CH:27][S:28][CH:29]=[C:23]3[NH:22][C:21]2=[O:30])[CH2:11][CH2:10]1.CN([CH:34]=[O:35])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3=[CH:27][S:28][CH:29]=[C:23]3[N:22]([CH2:5][CH2:4][C:3]([O:35][CH3:34])=[O:2])[C:21]2=[O:30])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCCCn2c(=O)[nH]c3cscc3c2=O)CC1
Reactant: CN(C)C=O
Product: COC(=O)CCn1c(=O)n(CCCCCN2CCN(c3ccccc3OC)CC2)c(=O)c2cscc21
Yield: 23 %

Procedure:
The title compound was produced following the procedure of Example 1 using 9.91 g (23 mmol) of 3-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentyl]thieno[3,4-d]-pyrimidine-2,4-dione in DMF for several days to produce methyl 3-[3-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate in 23% yield (2.8 g). A portion of this material was converted to its brown hydrochloride salt using 2-propanol/HCl.