Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9])#N.C[Mg]Br.O.Cl.CC[O:21][CH2:22][CH3:23]>C(Cl)Cl.O1CCCC1>[C:8]([NH:7][CH2:6][C:5]1[CH:4]=[C:3]([C:22](=[O:21])[CH3:23])[CH:13]=[CH:12][CH:11]=1)(=[O:10])[CH3:9]
Reactant: CCOCC
Reactant: CC(=O)NCc1cccc(C#N)c1
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCc1cccc(C(C)=O)c1

Procedure:
To a solution of N-(3-cyanobenzyl)acetamide (7.7 g) in methylene dichloride (150 ml) and tetrahydrofuran (50 ml) was added dropwise a solution of methyl magnesium bromide in ether (3 mol/l, 52 ml) at 10° to 20° C. under stirring and the resulting mixture was stirred at the same condition for 6 hours. The reaction mixture was poured into water and the resultant mixture was adjusted to pH 7 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel. The fractions eluted with a mixture of chloroform and ethyl acetate (8:2) were collected and the solvent was evaporated in vacuo to give 3'-(acetylaminomethyl)acetophenone (4.7 g) (oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(CN2CC(CCCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Agent: Cl
Product: COc1cc(CN2CC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-5-oxo-pyrrolidin-3-yl]-propyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:27](I)=[C:11]2[N:12]=[C:13]([CH3:26])[N:14]=[C:15]([N:16]3[CH2:19][C:18]([NH:23][CH2:24][CH3:25])([C:20]([NH2:22])=[O:21])[CH2:17]3)[N:10]2[N:9]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:27]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)=[C:11]2[N:12]=[C:13]([CH3:26])[N:14]=[C:15]([N:16]3[CH2:19][C:18]([NH:23][CH2:24][CH3:25])([C:20]([NH2:22])=[O:21])[CH2:17]3)[N:10]2[N:9]=1
Reactant: CCNC1(C(N)=O)CN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)C1
Reactant: N#Cc1ccc(B(O)O)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: [Na+]
Solvent: C1COCCO1
Product: CCNC1(C(N)=O)CN(c2nc(C)nc3c(-c4ccc(C#N)cc4)c(-c4ccccc4Cl)nn23)C1
Temperature: 68 °C

Procedure:
A mixture of 1-[7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide (I-6A-1a; 50 mg, 0.098 mmol) and 4-cyanophenylboronic acid (22 mg, 0.15 mmol) in dioxane (0.8 ml) and 2M aqueous Na2CO3 (0.2 ml) was purged with nitrogen gas. Tetrakis(triphenylphosphine)palladium (12.5 mg, 0.01 mmol) was added and the mixture was heated at 68° C. for 4 days. After cooling to room temperature, the mixture was extracted from water with chloroform, the combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product. Purification on a Combiflash® using 0.4% methanol/1% aqueous ammonium hydroxide in chloroform as eluant afforded 6A-1 (23 mg, 48%) as a solid: +ESI MS (M+1) 487.1; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.47-7.34 (m, 4H), 7.01 (d, J=4.6 Hz, 1H), 5.39 (d, J=4.6 Hz, 1H), 5.30 (br d, J=9.5 Hz, 1H), 4.80 (br d, J=8.7 Hz, 1H), 4.73 (br d, J=9.5 Hz, 1H), 4.18 (br d, J=8.7 Hz, 1H), 2.64 (t, J=7.0 Hz, 2H), 2.53 (s, 3H), 1.17 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH2:9]([N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]1[SH:23])[CH:10]=[CH2:11]>CN(C=O)C>[CH2:9]([N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]=[C:13]1[S:23][CH3:1])[CH:10]=[CH2:11]
Reactant: C=CCn1c(S)nc(C(F)(F)F)cc1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1c(SC)nc(C(F)(F)F)cc1=O
Yield: 79 %

Procedure:
Next, potassium carbonate (22.5 g, 163 mmol) and methyl iodide (10.2 ml, 164 mmol) were added to DMF (110 ml) solution of 3-allyl-2-mercapto-6-trifluoromethyl-4(3H)-pyrimidinone (32.1 g, 136 mmol) with stirring under ice-cooling, followed by stirring for 23 hours while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, saturated brine (100 ml), water (100 ml) and ethyl acetate (300 ml) were added to the thus obtained residue to separate the organic layer and then the aqueous layer was extracted with ethyl acetate (100 ml×2). The organic layers were combined, washed with saturated brine (50 ml×2) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. The thus obtained crude product was purified, by a silica gel column chromatography (hexane˜hexane:ethyl acetate=9:1) to obtain white solid of 3-allyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (26.9 g, 79%).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CN([P+](ON2N=[N:51][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50]C2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:60][C:61]1C=NC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:60][CH2:61][C:49]4[CH:50]=[N:51][CH:46]=[CH:47][CH:48]=4)=[O:24])=[CH:25][CH:26]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Nc1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Reaction time: 8 h

Procedure:
Add to a stirring mixture of 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid (0.188 g, 0.50 m mol), PyBOP (0.0.288 g, 0.50 m mol), and 3-amino-pyridine (0.063 g, 0.59 mmol) in dry CH2Cl2 (10 mL) under N2, Hunigs base (0.148 g, 0.200 mL, 1.11 m mol.). Stir the reaction is overnight at ambient temperature and evaporate on the rotary evaporator. Chromatograph the residue on the ISCO system using a 40 g column and a hexane-EtOAc gradient system (0-100%) to give 0.048 g of the title compound as white foam: Mass spectrum (m/e) (M+H) 460.1697; found 460.1681.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[Cl:20].S(=O)(=O)(O)O.[N+:26]([O-])([O-:28])=[O:27].[Na+]>>[CH3:19][O:18][C:16]([C:4]1[C:3]([Cl:20])=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:26]([O-:28])=[O:27])[C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=1)=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2F)cc(N)c1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)cc(N)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
Methyl 4-amino-3-chloro-6-(4-chloro-2-fluorophenyl)pyridine-2-carboxylate (1.0 g, 3.2 mmol) was added as a solid to well stirred concentrated sulfuric acid (16 mL) at 0° C. Sodium nitrate (0.29 g, 3.5 mmol) was added to the mixture and the resulting yellow solution was stirred at 0° C. for 1.5 hours then diluted with a large quantity of ice and allowed to warm to room temperature. The solution was filtered to remove some solids then the filtrate extracted with 3 portions of ethyl acetate and the combined ethyl acetate layers washed with saturated aqueous NaHCO3 and dried (Na2SO4). Filtration and concentration gave 4-amino-3-chloro-6-(4-chloro-2-fluoro-5-nitrophenyl)pyridine-2-carboxylic acid methyl ester (0.96 g, 2.7 mmol) as a yellow solid: mp 161-163° C.: 1H NMR (CDCl3): δ 8.73 (d, 1H), 7.36 (d, 1H), 7.24 (d, 1H), 4.93 (bs, 2H), 4.02 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:16]=2[CH2:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:63][C:64]1[CH:80]=[CH:79][CH:78]=[CH:77][C:65]=1[CH2:66][C:67]1([CH2:74][O:75][CH3:76])[CH2:72][CH2:71][CH2:70][N:69]([NH2:73])[CH2:68]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:63][C:64]1[CH:80]=[CH:79][CH:78]=[CH:77][C:65]=1[CH2:66][C:67]1([CH2:74][O:75][CH3:76])[CH2:72][CH2:71][CH2:70][N:69]([NH:73][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[CH2:68]1
Reactant: Cc1cc(C2=C3CC(C(=O)O)=CC=C3N(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)ccn1
Reactant: COCC1(Cc2ccccc2F)CCCN(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(Cc2ccccc2F)CCCN(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-4H-indazole-5-carboxylic acid (271 mg, 0.546 mmol), HATU (256 mg, 0.67 mmol) and 3-(2-fluorobenzyl)-3-(methoxymethyl)piperidin-1-amine (122 mg, 0.42 mmol) was dissolved in dimethylformamide (2 mL). Diisopropylethylamine (0.366 mL, 2.1 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 h. Upon completion, the reaction was quenched with water (10 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude product was progressed to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:23])=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=2)=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:23][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:7][C:6]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)=[O:9]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(N)ccc2Cl)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(NCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A solution of ethyl (4-{[(5-amino-2-chlorophenyl)carbonyl]amino}phenyl)acetate (300 mg, 0.90 mmol) in DMF (5 ml) was treated with potassium carbonate (152 mg, 1.1 mmol, 1.2 eq) and benzyl bromide (215 ul, 1.8 mmol, 2 eq) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate (150 ml) and washed with water (2×80 ml) and brine (80 ml). Organic layer dried over magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography (Biotage SP4, 40 g silica column) eluting with 0-25% ethyl acetate in hexanes to afford the title compound as a white solid (90 mg). MS (ES+) m/z 423 [M+H]+ (C24H2335ClN2O3). 1H-NMR (400 MHz, d6-DMSO) δ 1.18 (3H, t, J 7.2), 3.61 (2H, s), 4.07 (2H, q, J 7.2), 4.30 (2H, d, J 6), 6.62-7.65 (13H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1CCCCC=1>C(OCC)(=O)C.[Pd]>[F:16][C:10]1([CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:3][CH:2]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCOCC2)c(Br)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1=CCCCC1
Product: NS(=O)(=O)c1ccc(OCC2(F)CCOCC2)nc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide (200 mg) and cyclohexene (0.549 mL) in ethyl acetate (10 mL) was added 10% palladium on carbon (57.6 mg). The suspension was stirred for 60 minutes at 120° C. The reaction mixture was filtered and concentrated. The product was purified by reverse-phase flash chromatography (C18, 15 g, 10%-100% acetonitrile/H2O/trifluoroacetic acid 0.1%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[N+:16]([O-])([OH:18])=[O:17].Cl>CC(OC(C)=O)=O.CC(O)=O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C1(c2ccc(OC)c([N+](=O)[O-])c2)CC1
Yield: 98.1 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) in Ac2O (300 mL) was added a solution of HNO3 (14.1 g, 146 mmol, 65%) in AcOH (75 mL) at 0° C. The reaction mixture was stirred at 0˜5° C. for 3 h before aq. HCl (20%) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (200 mL×3). The organic layer was washed with sat. aq. NaHCO3 then brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (36.0 g, 98%), which was directly used in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, J=2.1 Hz, 1 H), 7.54 (dd, J=2.1, 8.7 Hz, 1 H), 7.05 (d, J=8.7 Hz, 1 H), 3.97 (s, 3 H), 3.65 (s, 3 H), 1.68-1.64 (m, 2 H), 1.22-1.18 (m, 2 H).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][C@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][C@H:58]5[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]5)=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@H]5COC(C)(C)O5)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of 115 mg (0.177 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.5 ml of N,N-dimethylformamide, 111 mg (0.388 mmol) of (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate and 73.5 mg (0.532 mmol) of potassium carbonate were added, and the mixture was stirred at 90° C. for 4 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20-59/41 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 113.3 mg of the title compound as a white solid (yield: 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=O)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:20]1([CH:26]([CH3:35])[CH2:27][S:28][C:29]2[S:33][C:32]([NH2:34])=[N:31][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[C:20]1([CH:26]([CH3:35])[CH2:27][S:28][C:29]2[S:33][C:32]([NH:34][C:14](=[O:16])[CH:13]([NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:17][CH2:18][CH3:19])=[N:31][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(CSc1nnc(N)s1)c1ccccc1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(SCC(C)c2ccccc2)s1
Temperature: 25 °C

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid (25.4 mg, 0.2 mmol), 5-(2-phenyl-propylsulfanyl)-[1,3,4]thiadiazol-2-ylamine (50 mg, 0.2 mmol), HBOT (29 mg, 0.21 mmol), EDC HCl (46 mg, 0.24 mmol.) and triethylamine (0.12 ml) in methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a light yellow solid (26 mg), LC-MS M+1=505.0
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]([NH2:40])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:34]1([CH2:33][CH2:32][CH2:31][CH:30]([NH:40][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-tert-Butoxycarbonyl-3-(3-pyridyl)-alanine (1.00 g; 3.76 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.37 g; 4.51 mmol), N,N-diisopropylethylamine (1.55 g; 12.0 mmol) and PyBOP (2.34 g; 4.51 mmol) are added sequentially. The reaction is stirred for 2.5 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (60%→80% ethyl acetate in hexanes) affording the desired product (84) as a solid. ESMS: MH+ 516.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3Br)[N:18]=2)=[CH:8][C:7]=1[CH3:26].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[CH:28]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:17]2[N:18]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:27])=[C:7]([CH3:26])[CH:8]=3)[S:15][CH:16]=2)[CH2:30][CH2:29]1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3ccccc3Br)cs2)cc1C
Reactant: OB(O)C1CC1
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: CCO
Solvent: COCCOC
Solvent: O
Product: COC(=O)COc1ccc(OCc2nc(-c3ccccc3C3CC3)cs2)cc1C

Procedure:
{4-[4-(2-Bromo-phenyl)-thiazol-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid methyl ester (30 mg, 0.067 mmol), cyclopropylboronic acid (6.9 mg, 0.080 mmol) and sodium carbonate (21 mg, 0.20 mmol) are dissolved in water (120 μL), ethanol (90 μL) and 1,2-dimethoxyethane (360 μL). Pd(PPh3)4 (10 mol %) is added, and the mixture is subjected to microwave (180° C.) for 5 min in a sealed tube to give crude methyl 2-(4-((4-(2-cyclopropylphenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate, which is used without further purification in Step B.