Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C(=O)CC(=O)C(F)(F)F)=CC=1.NC1C=CNN=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:33]3[N:40]=[CH:41][CH:42]=[C:32]3[N:31]=2)=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+].[I:48]Cl>C(O)(=O)C.O.CCOC(C)=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[N:33]3[N:40]=[CH:41][C:42]([I:48])=[C:32]3[N:31]=2)=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2ccnn12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: Nc1cc[nH]n1
Agent: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of commercially available 1-(4-chlorophenyl)-4,4,4-trifluoro-1,3-butanedione (8.65 g, 34.52 mmol) and commercially available 3-aminopyrazole (2.87 g, 34.52 mmol) in acetic acid (70 mL) was refluxed for 3 h (intermediate 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine). Cooled to 23° C., added sodium acetate (3.54 g, 43.2 mmol) and a solution of iodine monochloride (2.11 mL, 41.4 mmol) in acetic acid (12 mL) was added dropwise, whereupon the reaction mixture solidified 2 min after complete addition. Added acetic acid (50 mL) and the mixture was stirred at 23° C. for additional 1 h. Diluted slowly with water (up to 400 mL), stirred at 23° C. for 30 min, the precipitate was filtered off, washed with water and dried in air at 50° C. to give a yellow solid, which was dissolved in EtOAc, washed with sat. NaHCO3-sol. and sat. Na2SO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum gave 5-(4-chloro-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine as a yellow solid (14.30 g, 98%). MS (EI) 422.9 [(M)+] and 425.0 [(M+2)+]; mp 155° C.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH2:4][C:5]([OH:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].N1C=CN=C1.CN(C)C=O.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>CCCCCC>[I:1]/[CH:2]=[CH:3]/[CH2:4][C:5]([CH3:10])([O:11][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C)(O)C/C=C/I
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCC(C)(C/C=C/I)O[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a stirred mixture of 24.5 g (55.6 mmoles) of 1-iodo-4-hydroxy-4-methyl-trans-1-octene (Example 130), 13.6 g (200 mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g (100 mmoles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 250 ml of hexane. The mixture is washed thoroughly with water followed by brine and dried over magnesium sulfate. After removal of the solvent, the product is distilled to give a colorless liquid, bp 67.5°-68° C. (0.07 mm).
Reaction SMILES: Cl.[CH3:2][C@@H:3]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:4][C:5]([OH:7])=O.[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[CH2:35]([O:34][CH2:33][C@H:15]([NH:14][C:5](=[O:7])[CH2:4][C@@H:3]([CH3:2])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)=CCC[C@H](C)CC(=O)O
Agent: Cl
Product: CC(C)=CCC[C@H](C)CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 46.9 %

Procedure:
Proceeding as in Example 1, but substituting (S)-3,7-dimethyloct-6-enoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 248, (S)—N—((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-3,7-dimethyloct-6-enamide (3 mg, 46.9%). MS (EI) for C32H37FN2O4. found 533.7 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C=O)C.O.CCOCC>[F:17][CH:13]([F:18])[O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(F)cc1OC(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 3.14 g (20.0 mmol) 5-fluoro-2-nitrophenol in 36 mL of DMF are added 6.1 g (40.0 mmol) of sodium chlorodifluoroacetate and 3.31 g (24.0 mmol) of powdered sodium carbonate. The reaction mixture is heated at 100°C. for 4 hours 30 minutes and is then allowed to cool to room temperature. Aqueous 4N HCl solution is added and the mixture is stirred at room temperature for 2 hours. The resulting mixture is diluted with 100 mL of water and 100 mL of ether. The aqueous phase is extracted with ether and the organic phases are then combined, washed with aqueous 1N NaOH solution and then with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. 3.68 g of the expected product are obtained in the form of a yellow oil, which is used as obtained in the following step. Yield=89%.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[N:7][CH:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC>>[CH:6](=[N:7][CH:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:10])[CH3:11])[C:5]1[CH:15]=[CH:16][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)C(N=Cc1ccc(Br)cc1)C(C)C
Agent: [Li]CCCC
Product: CC(C)C(N=Cc1ccccc1)C(C)C

Procedure:
treating (4-bromobenzylidene)(1-isopropyl-2-methylpropyl)amine with n-butyllithium to give para-lithiated (benzylidene)(1-isopropyl-2-methylpropyl)amine and
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][C:8]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[NH:10][C:9]=32)=[CH:5][CH:4]=1.[OH-].[Na+].I[CH3:22]>C1C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][C:8]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]([CH3:22])[C:9]=32)=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc2c(c1)-c1[nH]c3ccccc3c1C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)-c1c(c3ccccc3n1C)C2
Temperature: 40 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of 37a (592 mg, 2.52 mmol) in benzene (8 mL) was added aqueous sodium hydroxide (50% by mass, 4 mL), tetrabutylammonium iodide (82.7 mg, 0.22 mmol), and iodomethane (1.25 mL, 20.13 mmol). The reaction mixture was stirred vigorously at 40° C. for 16 hours and then at 55° C. for 2 additional hours. Upon cooling to room temperature, the mixture was diluted with benzene (20 mL) and H2O (20 mL), and the aqueous layer was extracted 2×15 mL ethyl acetate. Organic layers were combined, washed 1×25 mL H2O, dried over anhydrous magnesium sulfate and concentrated to yield a brown solid. Crude product was purified by flash column chromatography (20:1 to 10:1 hexanes-ethyl acetate) to give a tan brown solid in 87% yield (545 mg, 2.19 mmol). 1H NMR (600 MHz, CDCl3): δ 7.65 (d, 1H, J=7.8 Hz), 7.42 (d, 1H, J=8.4 Hz), 7.38 (d, 1H, J=7.8 Hz), 7.25-7.27 (t, 1H, J=7.8 Hz), 7.18-7.21 (m, 2H), 6.78-6.79 (dd, 1H, J=8.4 Hz, 2.4 Hz), 3.99 (s, 3H), 3.92 (s, 3H), 3.63 (s, 2H). 13C NMR (150 MHz, CDCl3): δ 158.74, 144.24, 141.77, 140.11, 136.45, 125.63, 123.98, 121.54, 121.16, 119.45, 118.95, 109.63, 109.01, 104.58, 55.50, 30.83, 29.19. FTIR: cm−1 3049, 2900, 1606, 1526, 1469, 1250, 1197, 1037, 742.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:16][CH2:15][N:14]([C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]3[N:14]4[CH2:15][CH2:16][CH:11]([C:6]2=3)[CH2:12][CH2:13]4)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)N1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2S(=O)(=O)c2ccc(Cl)cc2)C2CCN1CC2

Procedure:
The coupling of 8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (20 mg, 0.09 mmol; Example 211) and 4-chlorobenzenesulfonyl chloride (30 mg, 0.14 mmol; Aldrich) was performed according to the procedure described in Example 69, except that the product was purified by reverse-phase HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.42-1.60 (m, 2H), 1.92-2.13 (m, 2H), 2.40 (s, 3H), 2.45-2.61 (m, 2H), 3.13-3.27 (m, 2H), 4.08 (quintet, J=2.9 Hz, 1H), 7.14 (dd, J=8.6, 1.5 Hz, 1H), 7.35 (s, 1H), 7.46-7.55 (m, 2H), 7.76-7.87 (m, 2H), 8.01 (d, J=8.5 Hz, 1H); MS (ESI) m/z 387 (M+H)+.
Reaction SMILES: [CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)(Cl)(Cl)Cl.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]1=[O:20]
Reactant: CCCCCCCCCCCCN1CCCCCC1=O
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCN1CCCCC(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of 107 g (0.38 mol) of 1-dodecylazacycloheptan-2-one, in CHCl3 was added 159.7 g (0.77 mol) of PCl5, keeping the temperature between 1°-4° C. After 2 hours, a solution of 123.3 g (0.77 mol) of bromine in CHCl3 was added, and the mixture was stirred for 18 hours at room temperature. After removing the solvent and excess bromine by vacuum distillation, the residue was dissolved in CH2Cl2, washed with sat. Na2S2O5, dried over MgSO4, and concentrated in vacuo to give a crude oil. Purification by flash chromatography (silica gel; 1:1 ether/petroleum ether V/V) gave pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:19]3[N:20]=[CH:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(O)(c1cccc(-c2ccc(Cl)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)C(O)(c1cccc(-c2ccc(Cl)cc2)c1)c1c[nH]cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
1-(4′-Chloro[1,1′-biphenyl]-3-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (0.71 g) and pyridine hydrochloride (0.25 g) were dissolved in methanol (20 ml), and the mixture was stirred at 60° C. for 2 h. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was concentrated. Water and ethyl acetate were added and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the obtained residue was purified by silica gel column chomatography (eluent, dichloromethane:methanol=40:1). Recrystallization from hexane-ethyl acetate gave the title compound (0.31 g) as a colorless solid.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:29][S:28](=[O:31])(=[O:30])[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:11]=3[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl-].[I-].[Na+].C([O-])([O-])=O.[K+].[K+].[CH3:50][CH:51]1[CH2:56][O:55][CH2:54][CH2:53][NH:52]1.S(Cl)(Cl)(=O)=O>C(Cl)Cl.CN(C=O)C.O>[CH3:50][CH:51]1[CH2:56][O:55][CH2:54][CH2:53][N:52]1[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:12]2[C:11]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[S:28](=[O:31])(=[O:30])[CH2:29][C:10]=3[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[N:13]2)=[CH:19][CH:18]=1
Reactant: O=C(c1nn(-c2ccc(CO)cc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: CC1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1COCCN1Cc1ccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {4-[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]phenyl}methanol (123 mg; 0.28 mmol; 1 eq.) and DIEA (330 μl; 1.93 mmol; 2.56 eq.) in DCM (13 mL) is added at 0° C. methanesulfonlyl chloride (75 μl; 0.97 mmol; 1.3 eq.). The solution is stirred for 30 min and allowed to warm up to rt. After this time, a suspension of sodium iodide (32 mg; 0.21 mmol; 0.28 eq.), K2CO3 (336 mg; 2.43 mmol; 3.22 eq.) and 3-methylmorpholine (166 μl; 1.51 mmol; 2 eq.) in DMF (50 mL) is added on the sulfonylchloride mixture. The resulting suspension is stirred at 80° C. for 2h after which time water is added after return to RT. The product is extracted with DCM and the combined organic layer is washed with brine, dried over MgSO4 and purified by MD-Autoprep then triturated in a mixture of DCM and pentane to afford the title compound as an orange powder. 1H NMR (DMSO-d6): δ 8.02-7.98 (m, 1H), 7.69-7.43 (m, 6H), 6.87-6.79 (m, 111), 4.91 (s, 211), 4.18-4.03 (m, 111), 4.03-3.88 (m, 2H), 3.79-3.56 (m, 8H), 3.56-3.41 (m, 1H), 3.33-3.24 (m, 2H), 3.24-3.10 (m, 1H), 2.52-2.66 (m, 1H), 2.50-2.36 (m, 111), 2.29-2.09 (m, 1H), 1.03 (d, J=6.3 Hz, 3H). HPLC (max plot) 98.1%; Rt 2.09 min. HPLC (max plot) 76.8%; Rt 2.15 min. MS (ESI+): 523.4.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([CH3:22])=[C:17]([CH3:21])[CH:18]=2)[C:13]1=[O:23])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][C:16]([CH3:22])=[C:17]([CH3:21])[CH:18]=3)[C:13]2=[O:23])[CH:9]=[CH:8][N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1c[n+](Cc2ccccc2C)ccc1CC1Cc2cc(C)c(C)cc2C1=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: CC(=O)C1=CN(Cc2ccccc2C)C=CC1CC1Cc2cc(C)c(C)cc2C1=O

Procedure:
The title compound 166 is prepared according to the procedure reported in Example 39.1 with compound 152 (62.0 mg, 0.13 mmol) and BNAH (33 mg, 1 equiv) as reactants. Yellow solid. (Yield 20.0 mg, 38%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH3:14])[CH:5]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[OH-].[Na+].O>C(O)C>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=[C:6]([CH3:14])[CH:5]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(COc2ccc(S(C)(=O)=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
To a solution of 7.23 g (29.6 mmol) of 4-chloromethyl-2-methylquinoline hydrochloride and 5.61 g (32.6 mmol) of 4-methylsulfonylphenol in ethanol (26 mL) was added 17.1 mL (68.1 mmol) of 4 N aqueous sodium hydroxide, followed by heating under reflux for 5 hours. After standing to cool, water (150 mL) and 4 N aqueous sodium hydroxide (2.5 mL) were added and stirred for 20 minutes at room temperature. The precipitates were collected by filtration, washed thoroughly with water and hexane, and then dried at 40° C. in vacuo in the presence of phosphorus pentoxide to give 9.06 g (yield 93.5%) of 4-(4-methanesulfonylphenoxymethyl)-2-methylquinoline (VI-1). Its physical properties are shown below.
Reaction SMILES: CN(C1C2C(=CC=CC=2)C=CC=1)C1C=CC=CC=1.[CH2:19]([N:21]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20].O=P(Cl)(Cl)Cl.CN(C)[CH:45]=[O:46]>>[CH2:19]([N:21]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:45]=[O:46])=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:20]
Reactant: CCN(c1ccccc1)c1cccc2ccccc12
Reactant: CN(C)C=O
Agent: CN(c1ccccc1)c1cccc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(c1ccccc1)c1ccc(C=O)c2ccccc12

Procedure:
This was prepared using the process described in Stage 3 of Example 1, except that in place of 1-(N-methyl-N-phenylamino)naphthalene there was used 1-(N-ethyl-N-phenylamino)-naphthalene (MW 247, 0.05M, 12.4 g), the amount of POCl3 was reduced to 7.65 g and the amount of dimethyl formamide was reduced to 21.9 g. (N-Ethyl-N-phenylamino)4-formyl-naphthalene (11 g) was obtained as a yellow oil (80% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[CH:24](N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH3:24][O:19][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)O
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.5 %

Procedure:
To a solution of (3S)-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester (1.47 g, 5.0 mmol) in dry DMF (25 mL) at ambient temperature, was added iodomethane (1.2 eq., 6.0 mmol, 0.37 mL) and diisopropylethylamine (1.5 eq. 7.5 mmol, 1.31 mL) in succession, and the reaction mixture was stirred at rt for 3-4 hours, at which point LC/MS analysis showed the presence of product The reaction mixture was poured into 50 mL of water and extracted with DCM (3×50 mL) and the combined DCM extracts were washed with water (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (20-30% ethyl acetate in hexanes) to afford (3S)-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (1.13 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[S:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54]1[N:55]=[CH:56][C:57]([NH2:60])=[N:58][CH:59]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:60][C:57]2[CH:56]=[N:55][C:54]([C:50]3[S:49][CH:53]=[CH:52][CH:51]=3)=[CH:59][N:58]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1cnc(-c2cccs2)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3cccs3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58.9 %

Procedure:
A solution of triphenylphosphine (230.0 mg, 0.877 mmol) in methylene chloride (15 mL) cooled to 0° C. was treated with N-bromosuccinimide (160.0 mg, 0.899 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 232.0 mg, 0.701 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-thiophen-2-yl-pyrazin-2-ylamine (260.0 mg, 1.467 mmol) followed by pyridine (0.24 mL, 2.967 mmol). The resulting reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was back-extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 to 3/2 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-thiophen-2-yl-pyrazin-2-yl)-propionamide (202.3 mg, 58.9%) as a yellow foam: mp 97–99° C. (foam to gel); (ES)+-HRMS m/e calcd for C23H24ClN3O3S2 (M+H)+ 490.1021, found 490.1026.
Reaction SMILES: C([O-])=O.[NH4+:4].C[O:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][CH:15]=O)=O>C(N)=O>[N:14]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:7](=[O:6])[NH:4][CH:15]=1
Reactant: COC(=O)c1sccc1NC=O
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: NC=O
Product: O=c1[nH]cnc2ccsc12
Temperature: 150 °C
Reaction time: 12 h
Yield: 63.4 %

Procedure:
To a solution of ammonium formate (9.4 g, 0.15 mol) in formamide (14 mL) at 150° C. was added 3-(formylamino)-2-thiophenecarboxylic acid methyl ester (81, 5.2 g, 28 mmol) as a solid in small portions. The resulting solution was heated at 150° C. for 4 hours and then allowed to stand at room temperature for 12 hours. The precipitate that formed was collected by vacuum filtration to give 3H-thieno[3,2-d]pyrimid-4-one (2.7 g, 63% yield) as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1cccc(F)c1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cccc(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(2,3-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:34])[CH:22]([N:24]([CH:31]3[CH2:33][CH2:32]3)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23])[N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].C([N:38](C(C)C)CC)(C)C.C(OC(=O)CBr)C>C(#N)C>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:34])[CH:22]([N:24]([CH:31]3[CH2:33][CH2:32]3)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23])[N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)(=[NH:38])[NH2:2]
Reactant: CCOC(=O)CN(C1CC1)C(C)C(=O)N1CCC[C@H]1CCc1cc2ccc(C#N)cc2n1CC
Reactant: CCN(C(C)C)C(C)C
Agent: CCOC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)CN(C1CC1)C(C)C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC
Temperature: 70 °C
Reaction time: 4 h

Procedure:
467 mg of ethyl 2-[[2-[(S)-2-[2-(6-cyano-1-ethylindol-2-yl)ethyl]pyrrolidinyl]-1-methyl-2-oxoethyl]cyclopropylamino]acetate was dissolved in 15 ml of acetonitrile, and diisopropylethylamine and ethyl-2-bromoacetate were added thereto. The reaction mixture was heated to 70° C. and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the residue, which was then purified with silica gel column chromatography [eluent: dichloromethane/methanol (20:1)] to obtain 538 mg of the title compound as a pale yellow oil.