Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=[S:16])[C:6]=2[CH:17]=1.[OH-].[Na+].[CH3:20]I>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([S:16][CH3:20])[C:6]=2[CH:17]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC1=NCc2nnc(C)n2-c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An ice cold, stirred mixture of 8-chloro-4,5-dihydro-1-methyl-6H-s-triazolo[4,3-a][1,4]benzodiazepine-6-thione (VIIIa) (13.2 g., 0.05 mole) in methanol (75 ml.) was treated with 55 ml. of 0.945 N aqueous sodium hydroxide solution. The ice bath was removed and after 10 minutes methyl iodide (3.11 ml., 0.05 mole) was added to the solution. About 5 minutes after this addition the mixture solidified. It was kept at ambient temperature for one hour, mixed with ice water and stirred for 10 minutes. The solid was collected by filtration, washed with water and dried to give 12.0 g. of the title compound, IXa, melting point 244°-249°. The analytical sample was recrystallized from methylene chloride/ethyl acetate and had melting point 247.5°-249°.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[S:7][C:6]([CH:8]2[O:25][C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:11][N:10]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:9]2)=[N:5][CH:4]=1>ClCCl>[ClH:1].[CH3:2][C:3]1[S:7][C:6]([CH:8]2[O:25][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:11][N:10]([CH2:26][C:27]([F:30])([F:28])[F:29])[CH2:9]2)=[N:5][CH:4]=1
Reactant: Cc1cnc(C2CN(CC(F)(F)F)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)s1
Agent: Cl
Solvent: ClCCl
Product: Cc1cnc(C2CN(CC(F)(F)F)CC3(CCNCC3)O2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
Hydrogen chloride (229 μL of 4 M solution in dioxane, 0.9160 mmol) was added to tert-butyl 10-(5-methylthiazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (95 mg, 0.18 mmol) in anhydrous dichloromethane (1 mL) and the reaction mixture was stirred for 2 hours at room temperature. The excess HCl and solvent were removed under reduced pressure to yield 10-(5-methylthiazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride salt (74 mg, 99%) as a light yellow solid. ESI-MS m/z calc. 335.1. Found 336.5 (M+1)+; Retention time: 0.91 minutes (3 min run).
Reaction SMILES: [CH:1]([CH:3]=O)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([NH2:13])[C:7]=1[NH2:14]>CCO>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]2[C:7]=1[N:14]=[CH:1][CH:3]=[N:13]2
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: O=CC=O
Solvent: CCO
Product: Brc1ccc(Br)c2nccnc12
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A 40% aqueous solution of glyoxal (8.8 M, 6.3 mL, 55.1 mmol, 1.3 equiv) was added to a suspension of 3,6-dibromo-benzene-1,2-diamine (Step 1.6) (11.3 g, 42.4 mmol) in EtOH (280 mL). The reaction mixture was heated to reflux for 3 h and allowed to cool to rt overnight. Vacuum filtration of the reaction mixture afforded 9.7 g of the title compound as a yellow solid: APCI-MS: 286.2/288.1/290.1 [M−1]−; tR=4.40 min (System 1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9]Cl)=[O:7])=[CH:4][CH:3]=1.[Na+].[I-:14]>CC(C)=O>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][I:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(OCCl)c1ccc(F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCI)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 4-fluorobenzoate (3.0g, 15.9 mmol) in 50 mL of dry acetone, NaI (4.8 g, 31.8 mmol) was added and the mixture was stirred overnight. The solvent was removed and Et2O (150 mL) was added to the solid residues and the mixture was stirred for 10 min. After filtration the filtrate was washed with 5% NaHSO3 (aq) (2×25 mL) followed by brine. The organic solution was concentrated by rotary evaporation and purified by silica gel chromatography to give a light yellow oil. Yield 3.7 g (85%). 1H NMR (300 MHz, CDCl3): δ 6.16 (s, 2H), 7.17 (m, 2H), 8.08 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([OH:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH3:40].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:39][CH3:40])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCI
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OC
Temperature: 25 °C
Reaction time: 21 h

Procedure:
After dissolving 1.0 g of {2-(3-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 10 ml of DMF, 473 mg of potassium carbonate and 219 μl of iodoethane were added and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (983 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:22])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.C(OC1C=C2C(=C(F)C=1)N=C(C1C=CC(C(OC)=O)=CC=1)C=C2)(=O)C.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([OH:22])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH:8]=[CH:7]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)cc(F)c3n2)cc1
Agent: COC(=O)c1ccc(-c2ccc3cc(OC(C)=O)cc(F)c3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc3cc(O)cc(F)c3n2)cc1

Procedure:
A mixture of methyl 4-(8-fluoro-6-hydroxyquinolin-2-yl)benzoate and methyl 4-(6-acetoxy-8-fluoroquinolin-2-yl)benzoate (120 mg) was hydrolyzed with 2N NaOH (4 mL) in MeOH (4 mL). The desired product-4-(8-fluoro-6-hydroxyquinolin-2-yl)benzoic acid (65 mg) was collected by filtration after acidification with 12N HCl. 1H NMR (DMSO-d6 300 MHz TMS): δ 8.36-8.33 (3H, m), 8.18 (1H, d, J=9 Hz), 8.09 (2H, d, J=9 Hz), 7.24 (1H, dd, J=12 and 3 Hz), 7.09 (1H, d, J=3 Hz) ppm, MS (ESI): m/z 284, [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[S:22][CH:23]=1)(=[O:10])[CH3:9].Br[CH:33]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[F:45])[C:34]([CH:36]1[CH2:38][CH2:37]1)=[O:35].C(N(CC)CC)C>C(#N)C>[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[C:34]([CH:36]2[CH2:37][CH2:38]2)=[O:35])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[S:22][CH:23]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)SC1CCNC/C1=C\c1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1csc(NC(=O)OC(C)(C)C)n1
Yield: 48.5 %

Procedure:
Following a procedure similar to that described in Example 132-(g), (E)-4-(acetylsulfanyl)-3-{[2-(t-butoxycarbonylamino)-1,3-thiazol-4-yl]methylidene}piperidine hydrogen trifluoroacetate (420 mg) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (340 mg) and triethylamine (310 μl) in acetonitrile (5 ml). The product obtained by usual extraction was purified by silica gel chromatography (eluent: hexane/ethylacetate=2/1˜2/3) to afford (E)-4-(acetylsulfanyl)-3-{[2-(t-butoxycarbonylamino)-1,3-thiazol-4-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (230 mg) as a pale yellow amorphous solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:21][C:16]4=[N:17][CH:18]=[CH:19][N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[K+].[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]Cl)[CH2:26][CH2:25]1>O>[N:27]1([CH2:30][CH2:31][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[NH:21][C:16]5=[N:17][CH:18]=[CH:19][N:20]=[C:15]5[CH:14]=4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1
Reactant: ClCCN1CCOCC1
Reactant: c1cnc2[nH]c(-c3ccc(N4CCNCC4)cc3)cc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1cnc2[nH]c(-c3ccc(N4CCN(CCN5CCOCC5)CC4)cc3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(4-piperazin-1-ylphenyl)-5H-pyrrolo[2,3-b]pyrazine (Example 49) and water (5 mL) was treated with potassium hydroxide (71 mg) and after complete solution this mixture was then treated with morpholinoethyl chloride (59 mg) and the resulting slurry was stirred at room temperature overnight. The reaction mixture was treated with water (100 mL). and then extracted three times with ethyl acetate (100 mL). The combined extracts were washed with brine and then evaporated. The residual orange solid was treated with ethyl acetate and methanol and this solution was then acidified by addition of hydrochloric acid (2N) in methanol and then concentrated on a steam bath to give after treatment with ethyl acetate and dichloromethane the title compound (55 mg) as an orange solid. LC-MS: Method A: RT=2.09 minutes, 393 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C:4](=[O:14])[N:3]=1>CN(C(OC)OC)C>[F:8][C:7]1[C:2](/[N:1]=[CH:4]/[N:5]([CH3:9])[CH3:6])=[N:3][C:4](=[O:14])[N:5]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]=1
Reactant: Nc1nc(=O)n(-c2ccsc2)cc1F
Agent: COC(OC)N(C)C
Product: CN(C)/C=N/c1nc(=O)n(-c2ccsc2)cc1F
Yield: 85.3 %

Procedure:
4-Amino-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (140 mg, 0.66 mmol) was dissolved in DMF-DMA (5 mL). The reaction mixture was stirred at reflux overnight. The residual DMF-DMA was removed in vacuo, and the residue was purified by preparative thin layer chromatography to give (E)-N′-(5-fluoro-2-oxo-1-(thiophen-3-yl)-1,2-dihydropyrimidin-4-yl)-N,N-dimethylformimidamide (75 mg, 43%) as a yellow solid: mp 211-213° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.22 (d, J=6.4 Hz, 1H), 7.75 (dd, J=3.2, 1.4 Hz, 1H), 7.60 (dd, J=5.2, 3.2 Hz, 1H), 7.34 (dd, J=5.2, 1.4 Hz, 1H), 3.26 (s, 3H), 3.13 (s, 2H); ESIMS m/z 267 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5](Br)=[C:4]([F:12])[C:3]=1[F:13].[CH2:14]([C:26]1[CH:27]=[C:28]([Sn](C)(C)C)[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>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.C1(C)C=CC=CC=1>[CH2:14]([C:26]1[CH:27]=[C:28]([C:2]2[C:7]3=[N:8][S:9][N:10]=[C:6]3[C:5]([C:28]3[S:29][CH:30]=[C:26]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:27]=3)=[C:4]([F:12])[C:3]=2[F:13])[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Reactant: Fc1c(F)c(Br)c2nsnc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1csc(-c2c(F)c(F)c(-c3cc(CCCCCCCCCCCC)cs3)c3nsnc23)c1
Temperature: 105 °C
Yield: 89.1 %

Procedure:
4,7-Dibromo-5,6-difluoro-benzo[1,2,5]thiadiazole (0.33 g, 1 mmol), (4-dodecyl-thiophen-2-yl)-trimethyl-stannane (1.04 g, 2.5 mmol), and Pd(PPh3)4 (20 mg) were combined in a 50-mL Schlenk flask. The system was vacuumed and backfilled with argon for three cycles before 20 mL of anhydrous toluene was added. The mixture was heated at 105° C. for 3 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was further purified by silica gel column with toluene/hexane (v/v, 1/4) as the eluent and recrystallization from a hexane/iso-propoanol mixture. The final product (0.60 g, 89.5% yield) was obtained as red needle crystals after drying in vacuo. 1H NMR (CDCl3, 500 MHz): δ 8.15 (d, 2H, J=1.0 Hz), δ 7.23 (d, 2H, J=1.0 Hz), δ 2.74 (t, 4H, J=7.5 Hz), δ 1.73 (m, 4H), δ 1.29 (m, 18H), δ 0.90 (t, 6H, 7.0 Hz). 13C NMR (CDCl3, 500 MHz): δ 150.8, 148.9, 143.7, 132.3, 131.2, 124.0, 111.7, 31.97, 30.607 30.52, 29.74, 29.72, 29.70, 29.67, 29.53, 29.42, 29.39, 22.75, 14.19.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12]>C(Cl)(Cl)Cl.CO>[CH3:1][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([NH2:7])[CH:9]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(N)c1
Reaction time: 8 h

Procedure:
To a chilled solution of methanol (100) was added thionyl chloride (21.25 ml, 0.29 mol). The solution was stirred for a further 30 minutes after which time m-aminobenzoic acid (10 g, 73 mmol) was added. The reaction was allowed to proceed overnight at room temperature and the solvents were then removed under reduced pressure. The product was obtained on tituration of the residue with diethyl ether. Yield 12.2 g (89%), m.p. 216°-218° C. The product was judged homogeneous by tlc in chloroform/methanol (4:1) (Rf 0.688) or chloroform/methanol (1:1) (Rf 0.597). (Found: C, 50.16; H, 5.27; N, 7.29. C8H10O2N1Cl1 requires C, 50.26; H, 5.23; N, 7.33%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]2)=[N:27]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CO>[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH:35][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)=[O:13])[CH2:32]2)=[N:27]1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NC(=O)c3ccc5c(c3)OCCO5)C4)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.1 %

Procedure:
To a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (44 mg, 0.24 mmol) and 2-(6-methoxy[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (48 mg, 0.16 mmol) in DMF (1 mL) was added HOBT (1-hydroxybenzotriazole; 33 mg, 0.24 mmol) and EDC; 47 mg, 0.24 mmol). The reaction mixture was stirred for 1.5 h at RT. The reaction mixture was diluted with CH3OH and purified directly by basic reverse phase HPLC to provide 22 mg (30%) of the title compound. MS (ESI): exact mass calculated for C25H23N5O4, 457.18; m/z found, 458.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.14 (s, 1H), 8.76 (d, J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.16 (d, J=5.1, 1H), 7.31-7.28 (m, 1H), 7.26-7.23 (m, 1H), 7.17 (d, J=9.1, 1H), 6.86 (d, J=8.4, 1H), 6.13 (d, J=7.7, 1H), 4.54-4.51 (m, 1H), 4.27-4.24 (m, 4H), 4.07 (s, 3H), 3.19 (dd, J=15.5, 5.1, 1H), 2.99-2.96 (m, 2H), 2.66 (dd, J=15.5, 7.7, 1H), 2.21-2.16 (m, 1H), 2.10-2.03 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].[O:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:8][C:6]1[CH:7]=[C:2]([CH:20]([CH:19]2[CH2:17][CH2:18]2)[OH:16])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C1CCOC1
Agent: CC(C)[Mg+]
Agent: [Cl-]
Agent: [Li+]
Product: OC(c1cncc(Br)c1)C1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
3,5-Dibromo-pyridine (1 g, 4.22 mmol) was dissolved in 5 mL of tetrahydrofuran and cooled to 0° C. A solution of isopropyl magnesium lithium chloride (15% in tetrahydrofuran, 5.07 mL, 5.06 mmol) was added dropwise and the solution was stirred for 15 min at 0° C. The resulting solution was added to a solution of cyclopropyl aldehyde (0.31 mL, 4.22 mmol) in 2 mL of tetrahydrofuran at 0° C. and the mixture was stirred for another 30 min at 0° C. The reaction was quenched with a saturated solution of ammonium chloride (10 mL) and water (10 mL). The crude mixture was passed through a Varian Chemelut cartridge (ethyl acetate as eluent) and concentrated to afford 623 mg of (5-Bromo-pyridin-3-yl)-cyclopropyl-methanol as an oil (2.73 mmol, 65% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.57 (m, 2H), 7.99 (t, J=2 Hz, 1H), 5.49 (d, J=5 Hz, 1H), 4.02 (m, 1H), 1.04 (m, 1H), 0.47 (m, 1H), 0.4 (m, 3H). MS: m/z 228.0/230.0 (M+H+).
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=c1c(Br)coc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(-c2ccc(F)cc2)coc2ccccc12
Yield: 22.5 %

Procedure:
Prepared according to general procedure using 3-bromochromone (338 mg, 1.5 mmol), 4-fluorophenylboronic acid (231 mg, 1.65 mmol), K2CO3 (622 mg, 4.5 mmol), PdCl2(PPh3)2 (45 mg, 0.045 mmol), THF (3 mL) and water (1.5 mL). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford afford 37 (81 mg, 23%) as a white solid. Analytical data for isoflavone 37: 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=9 Hz, 1H), 8.04 (s, 1H), 7.72 (app t, J=9 Hz, 1H), 7.58-7.56 (m, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.47 (app t, J=8 Hz, 1H), 7.16 (app t, J=9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 176.5, 164.0, 162.0, 156.5, 153.2, 134.0, 131.0, 128.0, 126.7, 125.6, 124.8, 118.3, 115.8; LCMS: Mass calculated for C15H9FO2, [M+H]+, 241. Found 241.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25]C(=O)C)[CH:20]=1.C(OCC)(=O)C.O>CO>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1
Reactant: COCCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 75 °C
Yield: 91 %

Procedure:
A 2 M sodium hydroxide solution (30 mL) was added to a solution of N-(4-((6-(3-methoxypropoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 32-6 (2.8 g, 7.88 mmol) in methanol (30 mL) under nitrogen atmosphere at room temperature. The liquid mixture was stirred under reflux under a thermal condition of 75° C. for 2 hours. The reaction liquid was allowed to stand to cool to room temperature, and then ethyl acetate and water were added. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=1:9-0:1-ethyl acetate:methanol=49:1) to obtain the title compound (2.24 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH2:17])[CH3:16])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[OH:20][C@@H:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22](O)=[O:23]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH:17][C:22](=[O:23])[CH:21]([OH:20])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:16])[N:10]=[CH:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: COC(=O)CC(C)(C)n1cnc(NC(=O)C(C)N)c1
Product: COC(=O)CC(C)(C)n1cnc(NC(=O)C(C)NC(=O)C(O)C(C)(C)C)c1

Procedure:
3-[4-(2-Amino-propionylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 19.2, 26.2, 28.1, 28.2, 35.2, 47.1, 48.6, 51.9, 56.4, 79.7, 105.1, 112.4, 131.0, 137.7, 169.7, 170.0, 173.0; MS 383.3 m/z (M+1).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+].[F:35][C:36]([F:72])([F:71])[C:37]1[CH:38]=[C:39]([CH:64]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:66]=1)[CH2:40][N:41]([C:58]1[N:59]=[N:60][N:61]([CH3:63])[N:62]=1)[C@H:42]1[CH2:48][CH2:47][CH2:46][NH:45][C:44]2[CH:49]=[C:50]([C:54]([F:57])([F:56])[F:55])[C:51]([CH3:53])=[CH:52][C:43]1=2.[CH3:73][O:74][C:75](=[O:83])[C:76]1[CH:81]=[CH:80][C:79](I)=[CH:78][CH:77]=1>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:73][O:74][C:75](=[O:83])[C:76]1[CH:81]=[CH:80][C:79]([N:45]2[CH2:46][CH2:47][CH2:48][C@H:42]([N:41]([CH2:40][C:39]3[CH:64]=[C:65]([C:67]([F:70])([F:68])[F:69])[CH:66]=[C:37]([C:36]([F:71])([F:35])[F:72])[CH:38]=3)[C:58]3[N:59]=[N:60][N:61]([CH3:63])[N:62]=3)[C:43]3[CH:52]=[C:51]([CH3:53])[C:50]([C:54]([F:55])([F:56])[F:57])=[CH:49][C:44]2=3)=[CH:78][CH:77]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)cc1
Temperature: 100 °C
Yield: 40.2 %

Procedure:
Combine tris(dibenzylideneacetone)dipalladium (0) (16 mg, 0.018 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (14 mg, 0.036 mmol) and sodium t-butoxide (43 mg, 0.452 mmol) in toluene (5 mL) and purge this suspension with nitrogen at room temperature for 5 min. Add (S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (Example 3, Step 18) (100 mg, 0.181 mmol) followed by methyl-4-iodobenzoate (47 mg, 0.181 mmol) and heat this mixture at 100° C. under nitrogen for 2 h. Cool the mixture to room temperature, dilute with dichloromethane, filter through Celite®, and concentrate under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (20:1 to 1:2), to provide the title compound as an off-white solid (50 mg, 40%). mp 101-105° C.; TLC Rf 0.50 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.72-1.89 (m, 1H), 2.00-2.32 (m, 3H), 2.29 (s, 3H), 3.33-3.40 (m, 1H), 3.89 (s, 3H), 3.99-4.09 (m, 1H), 4.19 (s, 3H), 4.69-5.33 (m, 3H), 6.68-6.73 (m, 2H), 7.15 (s, 1H), 7.45 (s, 1H), 7.62-7.72 (m, 2H), 7.79 (s, 1H), 7.96-8.05 (m, 2H); ESI MS m/z 687 [C31H27F9N6O2+H]+.