Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([NH2:33])[C@@H:25]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:33][C@@H:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:24][C@H:25]5[OH:34])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 140 °C
Yield: 14.7 %

Procedure:
A stirred mixture of 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (130 mg, 0.332 mmol) from Step 4 of Example 78, (1R,2R)-(−)-trans-1-amino-2-indanol (198 mg, 1.33 mmol), and DIEA (214 mg, 1.66 mmol) in anhydrous DMA (2 mL) in a sealed reaction vessel was heated in a Biotage microwave synthesizer at 140° C. for 1.5 h. LCMS indicated that the reaction was incomplete. Additional (1R,2R)-(−)-trans-1-amino-2-indanol (50 mg, 0.335 mmol) was added, and the mixture was heated in a Biotage microwave synthesizer at 140° C. for a further 45 min. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-1-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (24 mg, 15%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.47 (d, J=7.9 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.11-7.28 (m, 5H), 5.45-5.54 (m, 3H), 5.18 (t, J=7.1 Hz, 1H), 4.24-4.35 (m, 1H), 3.16 (dd, J=6.9, 15.5 Hz, 1H), 2.74 (dd, J=7.1, 15.5 Hz, 1H). LCMS (ESI) m/z 492 and 494 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([CH:11]([OH:13])[CH3:12])[CH:9]=[CH2:10].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCCCCC>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:11](=[O:13])[CH3:12])[CH:9]=[CH2:10]
Reactant: C=CC1(C(C)O)CCC(C)=CC1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: C=CC1(C(C)=O)CCC(C)=CC1C
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of (2,4-dimethyl-1-vinylcyclohex-3-enyl)ethanol (20 mmol) in CH2Cl2 (40 ml) at room temperature was added PCC (40 mmol). The mixture was stirred at room temperature over night and was then diluted with hexane, filtered through a pad of celite and concentrated in vacuo. The residue was purified by chromatography to give 1-(2,4-dimethyl-1-vinylcyclohex-3-enyl)ethanone (83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 8.8 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (574.6 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.64 ml) and 1-methyl-2-chloropyridinium iodide (907.5 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (113 mg).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[NH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15])=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].O>C(OCC)(=O)C>[S:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:1]1[C:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[NH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Nc1ccccc1S
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
In 10 ml of ethyl acetate were dissolved 0.50 g (2.16 mmol) of methyl 3-formyl-4,7-dimethylindole-2-carboxylate and 0.27 g (2.16 mmol) of o-aminothiophenol. The reaction mixture was stirred at room temperature overnight. After addition of 0.30 g of o-aminothiophenol, the reaction mixture was stirred for 1 day and then poured into water. The reaction mixture was extracted with diethyl ether, washed with water and concentrated. The crude crystals were purified by silica gel column chromatography (toluene) and recrystallized from methanol-water to provide 0.15 g of beige powder. Yield: 20%
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=4)[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:30]I.O>C1COCC1>[CH3:30][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[CH:22]=[C:14]1[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:27])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1
Reactant: CI
Reactant: COC(=O)c1ccc2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n(C)c2c1
Reaction time: 2 h

Procedure:
1.40 g (3.8 mmol) of the ester produced in Example 13, are dissolved in 20 ml of dry THF, and treated with 0.14 g (4.6 mmol) of sodium hydride (80% in oil). This mixture is stirred for 1 hour, at which point 0.65 g (4.4 mmol) of methyl iodide is added. The resulting mixture is stirred for 2 hours and then poured into water (100 ml) and extracted with dichloromethane (3×100 ml). The organic phase is dried and the solvent evaporated. The resulting residue is recrystallized in hexane, yielding methyl 1-methyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-indole carboxylate. (1.30 g, 91%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[C:18]1([CH3:37])[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([NH:27][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:37])=[CH:19][CH:20]=3)(=[O:26])=[O:25])=[CH:36][CH:35]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)cc1OC
Reaction time: 1 h

Procedure:
6.4 g of (+/-)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene are dissolved in 150 ml of methylene chloride and 9 ml of triethylamine. A solution of 11.2 g of 4-p-toluenesulfonamidobenzoyl chloride in 200 ml of methylene chloride is added dropwise at RT in the course of 3 h, and the mixture is extracted after stirring for 1 h with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again. The organic phase is dried using sodium sulfate, concentrated and crystallized from ethyl acetate. 3.9 g (28.2% of theory) of the title compound of m.p. 174-176° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])([O-])=O.C(O)(=O)C.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13]
Reactant: [H][H]
Reactant: C[C@@H](CO)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](CO)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
A 1-L round bottomed flask containing (S)-2-(2-nitrophenylamino)propane-1-ol (6.9 g, 35.2 mmol) and equipped with a magnetic stir bar was charged with methanol (138 mL), acetic acid (6.04 mL, 106 mmol), and 10% palladium on carbon (0.700 g, 0.658 mmol). The flask was fitted with a three-way stopper with a balloon of hydrogen attached. A vacuum line was connected, and the flask was gently evacuated, then back filled with hydrogen, twice. The reaction mixture was then stirred under a hydrogen atmosphere at rt. After 4 h, the reaction mixture was filtered through a pad of Celite, and the filter cake and catalyst were rinsed with fresh methanol. The filtrate was concentrated under reduce pressure to a dark syrup. The material was redissolved in toluene (ca. 200 mL), which was then removed under reduced pressure. The residue was then dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (75 mL) followed by 5 wt % aqueous sodium chloride (50 mL). The ethyl acetate extract was then concentrated under reduced pressure to afford (S)-2-(2-aminophenylamino)propane-1-ol (5.12 g, 88%) as a dark purple solid. MS (ESI, pos. ion) m/z 167 [M+1]+.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])C.Cl>C1COCC1>[O:11]=[C:12]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)Cc1c(C)cc(C)cc1C
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(CC(=O)CC#N)c(C)c1
Temperature: -78 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (0.506 mL) in 25 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then treated in dropwise fashion with 6.0 mL of a 1.6 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 1 h and subsequently treated in dropwise fashion with a solution of 5 gms. of (2,4,6-trimethyl-phenyl)-acetic acid ethyl ester in 25 mL of anhydrous THF. The resulting solution is then stirred 5 h at room temperature. Subsequently, the reaction mixture is acidified (pH 7-8) with dropwise addition of conc. HCl and a 1 M HCl(aq) solution. The quenched reaction mixture is then partitioned between water and ethyl acetate. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the desired 3-oxo-4-(2,4,6-trimethyl-phenyl)-butyronitrile as a yellow-white solid in the amount of 1.41 gms. (72% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:15][NH2:16].[BH4-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
1-(4-Methoxyphenyl)propan-2-one (2.9 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (3.03 g) were condensed and subsequently reduced with sodium borohydride (3.55 g) by an analogous procedure to that described in Example 1. The crude product was recrystallised from diethyl ether-hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, mp 80°-7° C., as a 45:55 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5](F)=[CH:4][N:3]=1.[Cl:10]C1N=C(Cl)C(F)=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: Cc1nc(Cl)ncc1F
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1nc(Cl)ncc1Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 55, substituting 2,4,5-trichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine. 1H NMR (500 MHz, CDCl3): 8.47 (s, 1H), 2.61 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>C(Cl)Cl>[C:16]([Si:20]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(OCc2ccccc2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A mixture of 4-benzyloxyphenol (100 g, 360 mmol), t-butylchlorodiphenylsilane (72.8 g, 360 mmol), and imidazole (24.5 g, 360 mmol) in 1 L of methylene chloride was stirred overnight at ambient temperature. The reaction mixture was washed with water, sat'd NaHCO3 and brine. After drying (Na2SO4), the solvent was evaporated to provide, 155 g of the title compound
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:35]2[CH:36]=[CH:31][CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=2)=[CH:16][CH:17]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CNC(=O)Cc1cccc(Br)c1
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: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)Cc1cccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
A solution of (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11), 2-(3-bromophenyl)-N-methyl -acetamide (0.21 g, Example 12a)), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml) was heated at 100° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml). The suspension was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ether and water. The aqueous layer was neutralised and extracted with dichloromethane (2×50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.15 g).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([CH2:18][CH:19]([CH3:21])[CH3:20])([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[CH2:18]([C:12]1([C:15]([OH:17])=[O:16])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC1(C(=O)O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of hydrochloric acid (12N, 1.2 mL) in 1,4-dioxane (2.4 mL) is added to 4-isobutylpiperidine-1,4-dicarboxylic acid monotertbutyl ester (0.7 g, 0.0025 mol) and stirred at room temperature for 1 hr. The reaction mixture is concentrated under reduced pressure and the residue is treated with saturated solution of sodium bicarbonate (0.5 mL) to adjust the pH to ˜7. It is again concentrate under reduced pressure to get crude 4-isobutylpiperidine-4-carboxylic acid.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])(=O)=O>CN(C=O)C.CCOC(C)=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=3)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)COc1cccc(OCCCOS(C)(=O)=O)c1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(OCCCn2nc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 6-(diphenylmethyl)pyridazin-3(2H)-one (158 mg) in DMF (2 mL) was added NaH (60% in oil, 26 mg) at 5° C. After stirring for an hour at ambient temperature, to the reaction mixture was added a solution of ethyl (3-{3-[(methylsulfonyl)oxy]propoxy}phenoxy)acetate (200 mg) in DMF (0.5 mL), and the resulting mixture was stirred at ambient temperature for 12 hours and then was stirred at 50° C. for 5 hours. After cooling, the reaction mixture was diluted with EtOAc (5 mL) and washed with water (5 mL) and brine (5 mL) two times. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (EtOAc:n-hexane=3:1) to give ethyl (3-{3-[3-(diphenylmethyl)-6-oxopyridazin-1(6H)-yl]propoxy}phenoxy)acetate (230 mg) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].O.[OH-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O:5][CH2:4][CH:3]1[O:6][CH2:2]1)(=[O:18])=[O:17]
Reactant: OCC(O)CCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of 10 g of 3-chloro-1,2-propanediol (0.09 mol) and 40 ml of water, was added dropwise at 24-26° C. 16.6 g of 24% sodium hydroxide (0.1 mol). The solution was stirred for one hour. The solution was cooled and thereto 0.17 g of N,N-dimethylaminopyridine (0.0014 mol) and 17.2 g of p-toluenesulfonyl chloride (0.09 mol) in 50 ml of toluene, and then 16.6 g of 24% sodium hydroxide (0.1 mol) were added under stirring at 0-5° C. And the solution was stirred for one hour. After separation with a separating funnel, the organic layer was washed with 50 ml of 1% hydrochloric acid and 50 ml of water. The excess solvent was removed under vacuo. The chemical purity by HPLC at that time was 98.3%. The residue was recrystallized from isopropyl alcohol/hexane=1/1 (V/V) to give 14.0 g of glycidyl tosylate. Chemical purity: 99.6% (yield: 68%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][CH:16]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CSc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2nc(C)nc3ccccc23)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol), 4-methylthio-aniline (139.2 mg, 1.0 mmol) and sodium acetate (98.4 mg, 1.20 mmol) in 4 mL of solvent (THF:water=1:1) was stirred at 60-70° C. for 3 h. The reaction mixture was diluted with 30 mL of ethyl acetate. It was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was rinsed with ethyl acetate and dried, yielding 273 mg of title compound (97.2%). 1H NMR (CDCl3): 7.86-7.82 (m, 2H), 7.79-7.73 (m, 3H)), 7.50-7.45 (m, 2H), 7.34-7.26 (m, 2H), 2.7 (s, 3H), 2.51 (s, 3H),
Reaction SMILES: Br[CH2:2][P:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH:5]([CH3:7])[CH3:6].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13](=[O:16])([S:15][CH2:2][P:3]([O:8][CH:9]([CH3:11])[CH3:10])([O:4][CH:5]([CH3:7])[CH3:6])=[O:12])[CH3:14]
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Reactant: CC([O-])=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCP(=O)(OC(C)C)OC(C)C
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of diisopropyl bromomethylphosphonate (5.00 g, 19.3 mmol) in N,N-dimethylformamide (15.4 mL) was added potassium thioacetate (3.75 g, 32.8 mmol) followed by tetrabutylammonium iodide (0.36 g, 0.97 mmol). The reaction mixture was stirred at 85° C. for 2.5 hours. The reaction mixture was cooled and partitioned between water and EtOAc (3×) and the layers were separated. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (24 g column, eluent: 0 to 90% EtOAc/hexanes) provided the title compound as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9](B(O)O)=[CH:8][CH:7]=1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:9]4[S:10][C:6]([CH2:5][NH:4][CH2:3][CH:2]([CH3:1])[CH2:14][CH3:15])=[CH:7][CH:8]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCC(C)CNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 20 %

Procedure:
To a CEM microwave tube containing the crude (5-{[(2-methylbutyl)amino]methyl}-2-thienyl)boronic acid (43 mg, 0.188 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), dioxane (1.5 mL), H2O (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C., and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give 16.2 mg of the title compound (17%).