Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C([Li])CCC.CCCCCC.[C:35]1([CH2:41][CH:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:42]([OH:43])[CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:3]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=2)=[CH:18][CH:19]=1
Reactant: O=CCc1ccccc1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
To a solution of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.50 g, 1.0 mmol) in dried tetrahydrofuran (15 mL) under nitrogen at −78° C. was added dropwise a 1.6 M solution of butyl lithium in hexane (1.1 mL, 1.7 mmol). After stirring for 20 minutes, to the reaction mixture was added phenylacetaldehyde (0.228 g, 1.9 mmol). The reaction mixture was stirred additional 1 hour at −78° C. and the temperature was gradually raised to room temperature. It was quenched with water and extracted with dichloromethane. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide the title compound (0.246 g, 44% yield): 1H NMR (CDCl3) δ 7.86 (m, 2H), 7.80 (d, 1H), 7.09–7.47 (m, 9H), 6.98 (dd, 1H), 5.70 (dd, 1H), 5.07 (t, 1H), 4.08 (m, 1H), 3.65 (m, 1H), 3.06 (d, 1H), 2.67 (m, 2H), 2.11 (m, 2H), 1.75 (m, 3H); ES-MS (m/z) 417 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][C:29]=1[C:30]#[N:31]>>[C:30]([C:29]1[CH:32]=[C:33]([O:36][C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:35][C:28]=1[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:26])=[O:2])[CH2:6][O:7][C:8]=2[CH:13]=1)#[N:31]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: N#Cc1cc(OC(F)(F)F)ccc1F
Product: N#Cc1cc(OC(F)(F)F)ccc1Oc1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-5-trifluoromethoxy-benzonitrile following a procedure analogous to that described for Intermediate 12. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.16 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: [Mg].II.[CH2:4]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>CO>[CH2:4]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1NC(=O)C(=Cc2cccc3c2ccn3Cc2ccccc2)S1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CO
Product: O=C1NC(=O)C(Cc2cccc3c2ccn3Cc2ccccc2)S1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To metal magnesium, there was added methanol in an amount sufficient for immersing the magnesium metal and then a small amount of iodine powder was added thereto, under an argon gas atmosphere. The mixture was allowed to stand till foaming was initiated and then stirred till the color of the iodine disappeared. To the mixed liquid, there were added 3.00 g of 5-(1-benzylindol-4-yl)methylene-2,4-thiazolidinedione prepared in Example 2 and 210 ml of methanol, followed by stirring at room temperature and addition of 4.36 g of magnesium powder over 2 hours. After the addition of the magnesium powder, the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 2 l of a 20% ammonium chloride aqueous solution, followed by extraction with dichloromethane (1 l×3). The resulting extract was washed with a 10% citric acid aqueous solution and a saturated common salt solution in this order, followed by drying the extract over anhydrous sodium sulfate and evaporation of the solvent under reduced pressure to give 2.24 g of 5-(1-benzylindol-4-yl)methyl-2,4-thiazolidinedione as yellow crystals. The yield thereof was found to be 74%.
Reaction SMILES: Cl[C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]([F:14])([F:13])[F:12].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>CS(C)=O>[C:15]1([N:3]2[C:2]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:10]3[C:5]([C:6]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:8]=[CH:9]3)=[N:4]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1cccc2c(Cl)n(-c3ccccc3)nc12
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cccc2c(N3CCCCC3)n(-c3ccccc3)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
3-Chloro-2-phenyl-7-trifluoromethyl-2H-indazole (21 mg, 0.07 mmol, compound of formula (XI)) was dissolved in 0.5 ml of DMSO and 100 μl of piperidine (1 mmol) were added. The reaction mixture was stirred overnight at 110° C. After cooling to room temperature, 10 volumes of water were added. The supernatant was removed and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate, 50:50, as eluent) to provide the title compound as a white solid (9 mg, 37%).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[Se:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.BrBr.O.[Br-].[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[C:30]([SeH+]C=2C=1)=[CH:29][C:28](Br)=CC=3>C(O)(=O)C>[Br-:19].[CH2:12]([N:13]([C:3]1[CH:2]=[CH:1][C:14]2[NH:13][C:12]3[C:7]([SeH+:6][C:5]=2[CH:4]=1)=[CH:8][C:9]([N:24]([CH2:23][CH2:22][CH2:21][CH3:20])[CH2:25][CH2:30][CH2:29][CH3:28])=[CH:10][CH:11]=3)[CH2:14][CH2:5][CH2:4][CH3:3])[CH2:11][CH2:10][CH3:9]
Reactant: c1ccc2c(c1)Nc1ccccc1[Se]2
Reactant: Brc1ccc2c(c1)[SeH+]c1cc(Br)ccc1N2
Agent: BrBr
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCN(CCCC)c1ccc2c(c1)[SeH+]c1cc(N(CCCC)CCCC)ccc1N2
Reaction time: 18 h
Yield: 17 %

Procedure:
To a stirred solution of phenoselenazine (1.00 g) in glacial acetic acid (170 cm3), under nitrogen and cooled in an ice-bath was added a solution of bromine (10 cm3) in glacial acetic acid (10 cm3). After 10 minutes the reaction mixture was poured into rapidly stirred water (400 cm3). The resultant 3,7-dibromo-phenoselenazin-5-ylium bromide was deposited as a dark solid and was collected by filtration, washed with diethyl ether and dried. A portion of the product (1.24 g) was added to a vigorously stirred solution of dibutylamine (5.00 g) in dichloromethane (200 cm3) under an atmosphere of nitrogen. The reaction mixture was stirred for 18 hours and then washed successively with water, dilute aqueous hydrobromic acid (5% w/w) and finally water. The organic phase was dried (MgSO4) and the solvent removed by rotary evaporation. Flash column chromatography over silica gel 60 A was performed on the crude material using a mobile phase of chloroform with increasing methanol content to a maximum of 2%. 3,7-Bis-(N,N-dibutylamino)-phenoselenazin-5-ylium bromide was isolated as a dark blue solid in 17% yield.
Reaction SMILES: C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([S:27]([NH:30][C:31]2[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:32]=2[O:33][C:34]2[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=2[C:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1>C(OCC)(=O)C.[Pd]>[F:51][C:16]([F:15])([F:52])[C:17]1[CH:18]=[C:19]([S:27]([NH:30][C:31]2[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:32]=2[O:33][C:34]2[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=2[C:36]([OH:38])=[O:37])(=[O:28])=[O:29])[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1
Reactant: O=C([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: OC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Benzhydrol 2-[2-[3,5-bis(trifluoromethyl)phenylsulfonamido]-4-trifluoromethylphenoxy]benzoate (3.7 g, 5 mmol) was dissolved in ethyl acetate (125 mL) and was hydrogenated for 0.75 hour at 50 psi over 10% palladium on carbon (0.5 g). The catalyst was filtered off and the solvent evaporated to give the crude product which was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid). Recrystallization from ethyl acetate/hexane gave the title compound as a white crystalline solid; mp 133°-134° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](/B(O)O)=[CH:14]\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[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>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1CCc1ccccc1
Reaction time: 96 h

Procedure:
Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89 g), tetrakis(triphenylphosphine)palladium(0) (0.50 g), and K3PO4 (2.28 g) were stirred in dioxane (17 mL) at 90° C. for 24 hours. The reaction mixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes. The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd—C and stirred 4 days with H2 in a pressure bottle. The mixture was filtered through a nylon membrane and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:23][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH:24]=2)[N:3]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cscn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cscn1

Procedure:
90 mg (about 0.298 mmol) of 2-amino-6-sulfanyl-4-(1,3-thiazol-4-yl)pyridine-3,5-dicarbonitrile, together with 87 mg (0.382 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 88 mg (1.041 mmol) of sodium bicarbonate, were stirred in 20 ml DMF at room temperature overnight. The reaction mixture was purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 37 mg (24% of theory) of the target compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:20]C1C=C2C(=CC=1)NC=C2>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Br:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Product: Brc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 78 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5-bromoindole (7.84 g, 40 mmol) ) to afford 10.5 g (78%) of the title compound as a white solid; MS EI m/e 333 (M+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][CH:21]1[C:25](=[O:26])[N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[CH2:23][CH:22]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:24]1[C:25](=[O:26])[C@H:21]([NH:20][C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:13])[C@H:22]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23]1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2F)C(=O)[C@@H]1NC(=O)c1cnc2ccccc2c1
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a solution of 3-quinolinecarboxylic acid (118 mg, 0.68 mmol) in CH2Cl (3 ml) was added oxalyl chloride (0.12 ml, 1.36 mmol) and the solution was stirred for 2.5 h. Removal of the solvent in vacuo gave a colorless solid which was redissolved in CH2Cl2 (3 ml). To this solution was added a solution of aminopyrrolidinone of Example W (200 mg, 0.68 mmol) and triethylamine (344 mg, 3.4 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred for 18 h. Removal of the solvent in vacuo and purification of the resulting solid via radial chromatography (4 mm plate) eluting with 2% EtOH/CH2Cl2 gave the title compound (223 mg, 73%) as a solid. 1H NMR (300 MHz, CDCl3) δ9.35 (1H, d), 8.68 (1H, d), 8.19 (1H, d), 7.94 (1H, d), 7.84 (1H t), 7.64 (1H, t), 7.54 (1H, t), 7.32 (1H, m), 7.19 (2H, m), 5.28 (1H, t), 4.21 (1H, m), 3.91 (1H, d), 3.78 (1H, q), 3.49 (1H, s), 1.41 (9H, s).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:27]=[O:28]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]=2[CH:27]=[O:28])=[CH:9][CH:8]=1
Reactant: Cn1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 80 °C

Procedure:
78.5 ml. (0.84 mole) of phosphorus oxychloride is added dropwise over a 20 min. period to 213 ml. of dimethylformamide stirred at 0° C. under nitrogen, the temperature of the reaction mixture not being allowed to exceed 10° C. The reaction mixture is heated to 80° C., a solution of 163.5 g. (0.727 mole) of 3-(4'-fluorophenyl)-1-methylindole in 270 ml. of dimethylformamide is added at a rate such that the temperature of the reaction mixture is maintained at 81°-83° C., the reaction mixture is maintained at 80°-81° C. for 5 hours and cooled to 10° C., and 1 l. of 15% sodium hydroxide solution is added dropwise at a rate such that the temperature of the reaction mixture is maintained at 35°-40° C., the reaction mixture being stirred under nitrogen throughout. The reaction mixture is cooled to 25° C., and the solids are collected by filtration, washed three times with 500 ml. portions of water and dissolved in 500 ml. of methylene chloride. The methylene chloride solution is filtered through 500 ml. of silica gel (70-230 mesh A.S.T.M.) and the silica gel is carefully washed with 2 l. of methylene chloride. The methylene chloride solutions are combined and concentrated to a volume of 300 ml. at reduced pressure, 300 ml. of absolute ethanol is added, and the reaction mixture is distilled until the internal temperature reaches 78° C. The reaction mixture is cooled to 0° C. and the precipitated bright yellow product is collected by filtration and vacuum dried at room temperature (153.9 g. (84%)), m.p. 80.5°-81.5° C. A slightly less pure second crop may be obtained from the mother liquor.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([C:22]([O:33][CH3:34])=[O:32])[CH:31]=[CH:30][C:28]=1[O:29][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2) (500 mg, 1.72 mmol) was dissolved in dry dichloromethane (15 ml) and treated sequentially with methyl vanillate (313 mg, 1.72 mmol), molecular sieves (4A, 1.0 g), copper acetate (467 mg, 2.58 mmol) and triethylamine (1.20 ml, 8.60 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, filtered through celite and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic portion was dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of (0.1:9.9) to afford the title compound (240 mg). MS (ES+) m/e 328 [(M+H)—CO2tBu]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)(C)(C)C>>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:30])[NH:5][C:4]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([I:1])[CH:3]=3)=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: Cc1ccc(N)cc1I
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1I

Procedure:
4-[4-(3-Iodo-4-methyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from 3-iodo-4-methyl aniline and 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, above. The product was isolated after a silica gel purification with 10-30% Et2O in toluene. HRMS m/z calcd for C23H28N3O3I [M+H]: 522.1248. Found: 522.1246.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:24][OH:25])[CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].[C:26]([O:31][CH3:32])(=[O:30])[C:27]([CH3:29])=O.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:29][C:27]1([C:26]([O:31][CH3:32])=[O:30])[O:1][CH2:2][CH:3]([CH2:4][C:5]2[CH:23]=[CH:22][CH:21]=[C:7]([CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])[CH:6]=2)[CH2:24][O:25]1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC(CO)CO)c1
Reactant: COC(=O)C(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C1(C)OCC(Cc2cccc(Cc3nc(-c4ccccc4)oc3C)c2)CO1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
To 5 ml of acetonitrile, 297 mg of 4-{3-[2,2-bis-(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole and 369 mg of methyl pyruvate were added. To the mixture was added 544 mg of boron trifluoride etherate (about 47%) with stirring at room temperature, and stirred for 14 hours at room temperature. The reaction solution was poured into an ice-cold water solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=3:1) to provide 185 mg of a mixture (cis:trans=2.5:1, based on NMR integral value) as colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.BrC1C=CN=CC=1NC.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:44]1[CH2:47][CH:46]([NH:48][C:49](=[O:66])[CH2:50][NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([C:62]([F:65])([F:64])[F:63])[CH:60]=3)[N:55]=[CH:54][N:53]=2)[CH2:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][CH:12]([N:44]2[CH2:45][CH:46]([NH:48][C:49](=[O:66])[CH2:50][NH:51][C:52]3[C:61]4[C:56](=[CH:57][CH:58]=[C:59]([C:62]([F:63])([F:65])[F:64])[CH:60]=4)[N:55]=[CH:54][N:53]=3)[CH2:47]2)[CH2:11][CH2:10]1
Reactant: CNc1cnccc1C1CCC(=O)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: CNc1cnccc1Br
Product: CNc1cnccc1C1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 4-(3-(methylamino)pyridin-4-yl)cyclohexanone (prepared by the reaction of 4-bromo-N-methylpyridin-3-amine with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH2:6]([O:13][C:14]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@@H:17]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][C@H:19]([C:30](OC)=[O:31])[CH2:18]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S([O-])(O)(=O)=O.[Na+]>C(O)C.C1COCC1>[CH2:6]([O:13][C:14]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:17]1[CH2:18][C@@H:19]([CH2:30][OH:31])[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:22]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CN(C(=O)OCc1ccccc1)[C@H]1C[C@@H](CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
Powder calcium chloride (0.49 g) was suspended in ethanol (10 ml), sodium borohydride (0.34 g) was added while cooling to 0° C., and the mixture was stirred at 0° C. for 30 min. A solution (10 ml) of 1-tert-butyl 3-methyl(3R,5S)-5-{[(benzyloxy)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (1.00 g) in THF was added to the reaction suspension, and the mixture was stirred at 0° C. for 8 hr. 5% Aqueous sodium hydrogen sulfate solution was added to the reaction mixture for neutralization and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (0.88 g) as an oil.