Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:30]I>>[CH3:30][N:25]([C:23]1[CH:22]=[CH:21][C:3]([C:4]([N:6]2[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)=[O:5])=[C:2]([Cl:1])[CH:24]=1)[C:26](=[O:29])[CH2:27][CH3:28]
Reactant: CI
Reactant: CCC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Product: CCC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1

Procedure:
In a manner analogous to that described in Example 5, 0.8 g of 1-[2-chloro-4-(N-propionylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine is methylated with 0.29 g of methyl iodide to form 1-[4-(N-methyl-N-propionylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine and converted into the hydrochloride having a melting point of 135°.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]=1[CH3:12])(=[O:5])[CH3:4].I[CH2:14][CH3:15]>CS(C)=O>[C:3]([C:6]1[S:10][C:9](=[O:11])[N:8]([CH2:14][CH3:15])[C:7]=1[CH3:12])(=[O:5])[CH3:4]
Reactant: CC(=O)c1sc(=O)[nH]c1C
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1c(C)c(C(C)=O)sc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
KOH (1.476 g, 26.31 mmol) was added to a solution of 5-acetyl-4-methyl-3H-thiazol-2-one (4.134 g, 26.31 mmol) in DMSO (10 mL), and stirred at room temperature for 30 min. Iodoethane (2.525 mL, 31.57 mmol) was added and the resulting mixture stirred for 72 h. The reaction mixture was extracted into CH2Cl2 (5×30 mL) from H2O (30 mL) and the combined organic layers were dried over MgSO4, before passing through a short SiO2 gel column. Pooling of the desired fractions yielded the title compound (3.104 g, 64%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH:12]([CH2:23][NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=2)[CH2:11]1>[OH-].[OH-].[Pd+2]>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH:12]([CH2:23][NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=2)[CH2:11]1
Reactant: COc1ccccc1N1CCN(Cc2ccccc2)C(CNC(=O)c2ccc(NS(C)(=O)=O)cc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: COc1ccccc1N1CCNC(CNC(=O)c2ccc(NS(C)(=O)=O)cc2)C1

Procedure:
In a manner similar to Example 1, react N-[[4-(2-methoxyphenyl)-1-(phenylmethyl)piperazin-2-yl]methyl]-4-[(methylsulfonyl)amino]benzamide hydrochloride (8.7 g, 16 mmol) with H2 over Pd(OH)2 (0.2 g) catalyst to give the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:43][C:44](=[O:50])[C@@H:45]1[CH2:49][CH2:48][CH2:47][NH:46]1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([N:46]3[CH2:47][CH2:48][CH2:49][C@H:45]3[C:44]([OH:43])=[O:50])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N3CCC[C@H]3C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and L-Proline methyl ester hydrochloride (33 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.66-13.14 (br.s, 1 H), 8.95 (s, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.22 (dd, 1 H), 4.03 (d, 4 H), 3.46 (m, 2 H), 2.91 (s, 3 H), 2.58 (t, 2 H), 2.39 (s, 3 H), 2.27 (t, 2 H), 1.97-2.24 (m, 2 H), 1.70-1.95 (m, 4 H); MS (APCI+) m/z 656 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:22][C:23]1(C)[C:27](C)(C)OB(C(C)=C)O1>C1(C)C=CC=CC=1.O.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].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[C:8]1([C:4]2[CH:3]=[C:2]([C:23]([CH3:27])=[CH2:22])[CH:7]=[CH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccnc(-c2ccccc2)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1ccnc(-c2ccccc2)c1
Yield: 93.7 %

Procedure:
4-Chloro-2-phenylpyridine (14 g, 73.8 mmol) and potassium phosphate (51.0 g, 221 mmol) were dissolved in 300 mL of toluene and 30 mL of water. The reaction was purged with nitrogen for 20 minutes and then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (16.65 mL, 89 mmol), Pd2(dba)3 (1.35 g, 1.48 mmol) and S-Phos (2.42 g, 5.91 mmol) were added. The reaction was brought to reflux for 18 h. After cooling, 100 mL of water was added, separated and the aqueous layer extracted twice with 100 mL of ethyl acetate. The organic layers were passed through a plug of silica gel, eluting with DCM. After evaporation of the solvent, the crude product was subjected to column chromatography (SiO2, 5% EtOAc in hexane to 10% EtOAc in hexane) to get 13.5 g (90%) of 2-phenyl-4-(prop-1-en-2yl)pyridine.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[CH:8]=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C1C=C(C(C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)(O[Si](C(C)(C)C)(C)C)[C@H]2CCCN2)C=C(C(F)(F)F)C=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C1(C)C=CC=CC=1.[Br:71][C:72]1[CH:73]=[N:74][NH:75][CH:76]=1>>[Br:71][C:72]1[CH:73]=[N:74][N:75]([C@@H:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:7][CH:8]=[O:9])[CH:76]=1
Reactant: O=C/C=C/C1CCCC1
Reactant: Brc1cn[nH]c1
Agent: CC(C)(C)[Si](C)(C)OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=CC[C@H](C1CCCC1)n1cc(Br)cn1
Temperature: 0 °C
Reaction time: 22 h
Yield: 85 %

Procedure:
A solution of (2E)-3-cyclopentylacrylaldehyde (28, 654 mg, 5.0 mmol, 5.0 equiv), (2R)-2-(bis[3,5-bis(trifluoromethyl)phenyl][tert-butyl(dimethyl)silyl]oxymethyl)pyrrolidine ((R)-35, 64 mg, 0.10 mmol, 0.10 equiv) and 4-nitrobenzoic acid (17 mg, 0.10 mmol, 0.10 equiv) in anhydrous toluene (4.0 mL, 38 mmol) was stirred at rt for 10 min, then cooled to 0° C. before 4-bromo-1H-pyrazole (39, 148 mg, 1.0 mmol) was then added. The resulting reaction mixture was stirred at 0° C. for 22 h. When LCMS showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by CombiFlash (SiO2) with 0-30% EtOAc/hexane gradient elution to give (3R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropanal ((R)-40, 230.5 mg, 271.2 mg theoretical, 85% yield) as a pale yellow viscous oil. For (R)-40: C11H15BrN2O (MW, 271.15), LCMS (EI) m/e 271/273 (M++H).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]([CH:19](OC)OC)[CH3:18]>>[CH:1]1([CH2:4][C:5](=[O:15])/[C:6](/[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:16]\[N:17]([CH3:19])[CH3:18])[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CSc1nccc(CC(=O)CC2CC2)n1
Product: CSc1nccc(/C(=C/N(C)C)C(=O)CC2CC2)n1
Yield: 69.2 %

Procedure:
A solution of 1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one (2) (216.3 mg, 0.973 mmol) in DMF-DMA (1303 μl, 9.73 mmol) was stirred at 80° C. for 2 hours. The reaction was partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [25 g ISOLUTE column, 100% DCM to 10% MeOH/DCM] to obtain the desired product as a orange-yellow solid (186.8 mg, 69.2% yield). MS (ES+): m/z=278.2/279.2 (100/50) [MH+]. HPLC: tR=0.99 minute over 3 minutes. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH2:14])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=Cc1cc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1cc(Cl)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 65.9 %

Procedure:
3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester (10.4 g, 46 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (13.8 g, 69 mmol) were set stirring in CH2Cl2 (230 mL). Sodium triacetoxyborohydride (14.6 g, 69 mmol) was added in portions over 10 min. Acetic acid (1.3 mL, 25 mmol) was then added and the mixture left to stir. After 18 h saturated NaHCO3 was added and the organics separated. The organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 20-50% EtOAc/hexanes) to obtain 12.4 g (66%) of a light beige solid. TLC (silica, 25% EtOAc/hexanes): Rf=0.5. MS (electrospray): exact mass calculated for C21H29ClN2O4, 408.18. m/z found, 409.1 [M++H]. 1H NMR (400 MHz, CDCl3): 7.64 (d, J=15.65 Hz, 1H), 7.29 (d, J=2.35 Hz, 1H), 7.14 (dd, J=6.26 Hz, 2.54 Hz, 1H), 6.59 (d, J=9.00 Hz, 1H), 6.28 (d, J=15.65 Hz, 1H), 4.23 (dd, J=7.04 Hz, 7.04 Hz, 2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.46-3.36 (m, 1H), 2.89 (t, J=11.74 Hz, 2H), 2.04-1.95 (m, 2H), 1.44 (s, 9H), 1.42-1.33 (m, 2H), 1.30 (t, J=7.24 Hz, 3H).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:11])[CH2:8][C:9]#[CH:10].[C:12](=[O:14])=[O:13].O>CCCCCC.O1CCCC1.CO>[CH3:6][N:7]([CH3:11])[CH2:8][C:9]#[C:10][C:12]([OH:14])=[O:13]
Reactant: C#CCN(C)C
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CN(C)CC#CC(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (96 mL, 2.5 M in n-hexane) was slowly added to 1-dimethylamino-2-propyne (20 g, 240 mmol) in 100 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 h at −78° C., then dry carbon dioxide was pass through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 15.6 g of 4-dimethylamino-but-2-ynoic acid: mass spectrum (m/e): M−H 126.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[N:15]([S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:19]=1)(=[O:26])=[O:25])[S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:29])([F:28])[F:16])[CH:19]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc2cc(C3=NCCS3)[nH]c12
Solvent: c1ccncc1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(c1cccc2cc(C3=NCCS3)[nH]c12)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a mixture of 2-(4,5-dihydro-1,3-thiazol-2-yl)-1H-indole-7-amine (100 mg) and pyridine (3 mL) was added 3-(trifluoromethyl)benzenesulfonyl chloride (140 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (93 mg, yield 32%) as pale-yellow crystals. M+1=634.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Si:10]([O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].Cl.NCCC(O)=O>C(O)C>[Si:10]([O:17][CH2:18][CH:19]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCOC(=O)/C=C/CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: NCCC(=O)O
Solvent: CCO
Product: CCOC(=O)CCNC(CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Ethyl 3-aminopropanoate HCl salt (4.6 g, 39.2 mmol, 1.4 eq) was added to a solution of (E)-ethyl 4-(tert-butyldimethylsilyloxy)but-2-enoate in 50 mL of ethanol. The mixture was stirred at RT overnight and then heated to reflux overnight. Another 9.2 g of 3-aminopropanoate HCl salt was added. The reaction was continued to heat at reflux for 2 hr. Solvents were removed; the yellow oily residue was dissolved in DCM, filtered through a pad of SiO2 (˜80 g), and washed with 800 mL EtOAc. The filtrate was concentrated to give the product 7.8 g (76%) as a light yellow liquid. HPLC retention time: T=1.844 min (analytical-3); ESI-MS:m/z 362.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.CCOC(C)=O>[N:36]1([C:21]2[CH:20]=[C:19]([C:17]3[S:18][C:14]4[C:13]([C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=5)=[C:12]([C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:27]([CH3:28])=[CH:26][C:15]=4[N:16]=3)[CH:24]=[CH:23][N:22]=2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[N:37]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ncc5ccccc54)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 160 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30 mg, 0.057 mmol) and 1H-indazole (6.0 mg, 0.052 mmol) in DMF (0.5 mL) was added K2CO3 (16.0 mg, 0.117 mmol) and 18-crown-6 (0.1 mg, 5.1×10−4 mmol). The reaction mixture was heated in a microwave at 160° C. for 1 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 60% ethyl acetate/hexanes) and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O3S: 611.2; found: 611.3.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Br[CH:15]([CH3:17])[CH3:16].[OH-].[K+]>CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[CH3:16][CH:15]([CH3:17])[CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]#[N:13]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: CC(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C(C#N)c1ccc2ccccc2c1
Yield: 0 %

Procedure:
3.00 g (17.9 mmol) of 2-naphthylacetonitrile was dissolved in 10 ml of dimethyl sulfoxide, and 2.43 g (19.7 mmol) of 2-bromopropane, 330 mg (0.90 mmol, cat) of tetra-n-butylammonium iodide and 10 ml of 50% potassium hydroxide were successively added thereto. After completion of the reaction, brine was added, and the mixture was extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to 150 g of silica gel (ethyl acetate:hexane=1:10), to give 2.42 g (11.6 nmol, 64.6%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]([NH2:18])=O)[O:13][N:12]=2)[CH2:7][CH2:6]1.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]#[N:18])[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: NC(=O)c1cc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carboxamide (1.6 g, 4.2 mmol) and Et3N (1.5 mL, 10.8 mmol) in CH2Cl2 (20 mL) was added TFAA (0.8 mL, 5.7 mmol) at ice-water bath temperature. A homogeneous solution resulted. After addition, the cooling bath was removed and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water (10-15 mL), followed by saturated aqueous NaHCO3 (15-20 mL) and extracted with CH2Cl2 (2×30 mL). The combined CH2Cl2 extracts were washed with diluted brine (40 mL), dried (Na2SO4) and concentrated. Chromatography over silica gel and elution with hexanes:EtOAc (4:1) gave the title compound as a colorless gum.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:12]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1>O1CCOCC1>[O:7]([C:11]1[C:12]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccc3ncnc(Oc4ccccc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To a solution of phenol (94 mg, 1 mmol) in dioxane (5 ml) was added sodium hydride (40 mg of a 60% dispersion in mineral oil, 1.0 mmol). The mixture was stirred at room temperature for 10 minutes. Then, 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (52 mg, 0.2 mmol) was added to this solution. The resulting mixture was stirred at room temperature for another 30 minutes. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:60, yielding the title compound (60 mg, yield 95%) as a white solid which was characterised by its mass spectrum as follows: MS (m/z): 318 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]=[CH2:4].[F:7][C:8]([F:37])([F:36])[C:9]1[CH:10]=[C:11]([C@H:19]([O:21][C@@H:22]2[C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:26]([CH:34]=[O:35])[CH2:25][CH2:24][O:23]2)[CH3:20])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[CH2:1]([CH:34]([C@@H:26]1[CH2:25][CH2:24][O:23][C@H:22]([O:21][C@@H:19]([C:11]2[CH:10]=[C:9]([C:8]([F:36])([F:7])[F:37])[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=2)[CH3:20])[C@H:27]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:35])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Mg]Br
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCC(O)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
3-Butenylmagnesium bromide (0.5M in tetrahydrofuran, 75 mL, 37.5 mmol) was added slowly to a stirred, cooled −78° C. solution of (2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde (WO 00/56727A1; 11.1 g, 24.9 mmol) in tetrahydrofuran (125 mL). The mixture was stirred at −78° C. for 3 hours, then at room temperature for 1.5 hour. Saturated aqueous ammonium chloride (20 mL) was added slowly, followed by ethyl acetate (300 mL). The layers were separated and the organic layer was washed with brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL), the combined organic layers were dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (97:3 increasing to 80:20), to give the title compound (8:1 mixture of alcohol diastereoisomers) as a colorless oil (10 g, 80%).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][SiH:16]([Cl:18])[Cl:17]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Si:16]([Cl:18])([Cl:17])[Cl:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)Cc1ccc(-c2ccccc2)cc1
Yield: 75.1 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.22 g (0.75 mmol) of tetrabutylphosphonium chloride, 1.52 g (7.5 mmol) of 4-phenylbenzyl chloride, 10 ml of dried benzene, and 3.05 g (22.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.70 g of (4-phenylbenzyl)trichlorosilane (yield; 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH:13]([NH:16][CH2:17][C:18]2[CH:34]=[CH:33][C:21]([O:22][C:23]([CH3:32])([CH3:31])[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:20][CH:19]=2)[CH2:14][CH3:15])=[O:12])=[C:5]([CH3:35])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH:13]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]([CH3:32])([CH3:31])[C:24]([OH:26])=[O:25])=[CH:33][CH:34]=2)[CH2:14][CH3:15])=[O:12])=[C:5]([CH3:35])[CH:4]=1
Reactant: CCC(NCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)C(=O)Nc1cc(C)c(OC)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(NCc1ccc(OC(C)(C)C(=O)O)cc1)C(=O)Nc1cc(C)c(OC)cc1C
Yield: 98.5 %

Procedure:
Similarly to the procedure of Example 1-9, 115 mg (0.237 mmol) of tert-butyl 2-(4-{[(1-{[(4-methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate (Example 1-8) are reacted with 0.46 ml (5.93 mmol) of trifluoroacetic acid in 3 ml of dichloromethane to give 100 mg (93%) of 2-(4-{[(1-{[(4-methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionic acid.