Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][CH3:21])=[C:4]([CH:6]=[C:7]([F:19])[C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]1)[NH2:5].[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[N:40]=[C:41]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[NH:40][C:41]1[N:20]([CH3:21])[C:3]2[C:2]([F:1])=[C:8]([N:9]3[CH2:14][CH2:13][CH:12]([C:15]([F:16])([F:18])[F:17])[CH2:11][CH2:10]3)[C:7]([F:19])=[CH:6][C:4]=2[N:5]=1
Reactant: CNc1c(N)cc(F)c(N2CCC(C(F)(F)F)CC2)c1F
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(F)c(N3CCC(C(F)(F)F)CC3)c(F)c21

Procedure:
The title compound was prepared in analogy to Example 76 using 3,5-difluoro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (186 mg, 0.60 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (3 mL).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][CH:22]([NH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:21][CH:22]([NH:27][C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CC(C)N
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NC(C)CC(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1,3-dimethyl-butylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C18H27NO5 [M−H]−: 336.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:11]=[CH:10][N:9]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(-c3ccccc3)n2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of 3-phenyl-1H-pyrazole (300 mg) in toluene (15 mL) were added tert-butyl 4-hydroxypiperidine-1-carboxylate (838 mg) and (tributylphosphoranylidene)acetonitrile (1.0 g), followed by stirring at 100° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 50/50) and purified again by silica gel column chromatography (hexane/ethyl acetate=100/0 to 70/30) to obtain tert-butyl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (475 mg) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C@@H:8]([CH2:11][Br:12])[CH2:7][C:6]=2[CH:5]=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[Br:12][CH2:11][C@H:8]1[CH2:7][C:6]2[CH:5]=[C:4]([F:13])[CH:3]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[Cl:14])[C:10]=2[O:9]1
Reactant: OB(O)c1ccccc1Cl
Reactant: Fc1cc(Br)c2c(c1)C[C@H](CBr)O2
Product: Fc1cc2c(c(-c3ccccc3Cl)c1)O[C@@H](CBr)C2
Yield: 100.6 %

Procedure:
Treatment of (R)-7-bromo-2-bromomethyl-5-fluoro-2,3-dihydrobenzofuran (0.5 g, 1.6 mmol) and 2-chlorobenzene boronic acid (0.76 g, 4.8 mmol) generally according to the procedure described for Intermediate 37 gave 0.55 g (99%) (R)-2-bromomethyl-7-(2-chloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran as a colorless oil. HRMS EI M+339.9657; [α]D25=+29.6 (c 8.14 in methanol).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:27](O)=[O:28])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)[C:27]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:28])=[CH:22][CH:21]=1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Reactant: O=C(O)C(CN1CCCC1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1SCc2ncnc(N3CCN(C(=O)C(CN4CCCC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (1 g, 3.23 mmol) and 2-(4-chlorophenyl)-3-(pyrrolidin-1-yl)propanoic acid (2 g, 7.88 mmol) in DCM (40 mL) were added HBTU (1.5 g, 3.96 mmol) and triethylamine (2.75 mL, 19.8 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (200 mL) and washed with brine (5×100 mL) and water (3×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give 2-(4-chlorophenyl)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one (0.713 g, 46.7%). 1H NMR (CDCl3, 400 MHz) δ 8.47 (s, 1H), 7.38-7.28 (m, 4H), 4.75 (m, 1H), 4.54 (m, 1H), 4.17 (m, 2H), 3.88-3.25 (m, 14H), 2.12 (m, 4H), 1.43 (m, 3H). MS (APCI+) [M+H]+ 473.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[Br-].[NH4+].I[CH3:16]>[OH-].[Na+].C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]([CH3:16])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Ic1ccc(-c2nnn[nH]2)cc1
Agent: [Br-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Product: CN1NN=C(c2ccc(I)cc2)N1

Procedure:
A mixture of 5-(4-iodo-phenyl)-1H-tetrazole (24) (500 mg) and ammonium bromide (1.18 g) in 1 N aq. NaOH sol. (10 ml) and CH2Cl2 (10 ml) is treated with iodomethane and vigorously stirred 26 h at RT. The organic layer is separated, washed with 1 N aq. NaOH sol., aq. NH4Cl sol. and brine. After drying over MgSO4 the solvent is evaporated and the product is purified by flash chromatography (silica gel, heptane/CH2Cl2 1:1 to pure CH2Cl2).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: OCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: BrCCCOC1CCCCO1
Reaction time: 2 h
Yield: 65 %

Procedure:
13.9 g (0.1 mol) of 3-bromopropan-1-ol are mixed with 400 ml of dry dichloromethane and 45.7 ml (0.5 mol) of dihydropyran are added. While stirring and if needed cooling in an ice bath 190 mg (1 mmol) of p-toluenesulfonic acid monohydrate are added in such a way that the temperature of the reaction solution does not exceed 25° C. Subsequently the reaction mixture is left for 2 hours at room temperature and extracted with half-saturated aqueous sodium hydrogen carbonate solution, the dichloromethane phase is washed twice with water, dried with magnesium sulfate and filtered to remove the drying agent and the solvent is distilled off in vacuo. The remaining oil is fractionally distilled in vacuo via a 20 cm Vigreux column. 14.2-16.4 g (65-75%) of colorless oil are obtained, which boils at from 60° to 65° C. (0.5-1 mbar).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[C@H:23]([C@@H:24]2[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]2)[CH2:22][C:21]1=[O:31])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH:32](=[O:34])[CH3:33]>CCCCCC.O1CCCC1>[Si:13]([N:20]1[C@H:23]([C@@H:24]2[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]2)[C@@H:22]([C@H:32]([OH:34])[CH3:33])[C:21]1=[O:31])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC1(C)OC[C@@H]([C@@H]2CC(=O)N2[Si](C)(C)C(C)(C)C)O1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]1COC(C)(C)O1
Reaction time: 0.5 h

Procedure:
16.2 ml of a 1.7M solution of butyl lithium in hexane is added dropwise within 5 minutes to a solution (cooled to -65°) of 2.78 g (27.5 mmol) of diisopropylamine in 100 ml of tetrahydrofuran. The resulting mixture is then cooled to -76° and treated after 15 minutes with a solution of 7.14 g (25 mmol) of (S)-1-(t-butyldimethylsilyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone in 6 ml of tetrahydrofuran. The mixture is stirred at -76° for 30 minutes and then a solution of 2.65 g of acetaldehyde in 5 ml of tetrahydrofuran is added dropwise within 10 minutes thereto. The mixture is stirred for 15 minutes, the cooling bath is removed, the reaction solution is treated with 20 ml of 14 percent (by volume) aqueous ammonium chloride solution and extracted with 100 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residual oil is taken up in 10 ml of hexane and the solution is left to stand at -20°. Colourless crystals of melting point 80°-90° are obtained. After repeated recrystallization from ethyl acetate/hexane there is obtained (3S,4S)-1-(t-butyldimethylsilyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-[(R)-1-hydroxyethyl]-2-azetidinone of melting point 95°-96°; [α]D20 =16.6° (c=1, ethyl acetate).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=[O:4])=[O:3].Br[C:13](C)(C)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1S(C)(=O)=O

Procedure:
To a solution of 2-(methylsulfonyl)phenol (200 mg, 1.16 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (232 mg, 1.39 mmol) and K2CO3 (690 mg, 5 mmol) at 25° C. The mixture was refluxed for 16 h and then quenched by addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.C([Mg]Br)(C)C.[O:19]1CCC[CH2:20]1.CN(C)C=O.Cl>O1CCCC1>[CH2:7]([C:5]1[S:6][C:2]([CH:20]=[O:19])=[CH:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc(Br)sc1CC
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C=O)sc1CC
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (10.0 g) synthesized in Example 69 (4) in tetrahydrofuran (100 was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (45.6 mL) at −45° C., and the mixture was stirred for 2 hr under an argon atmosphere. N,N-Dimethylformamide (8.80 mL) was added, and the mixture was stirred at −45° C. for 1 hr, and then at room temperature for 2 hr. 1N Hydrochloric acid was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to give the title compound (7.82 g, 97%) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:33])/[CH:5]=[C:6](/[CH:8]=[CH:9]/[C@@H:10]1[CH2:12][C@@:11]1([C:14]1[CH:15]=[C:16]([CH2:25][CH2:26][CH:27]([OH:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C:17]2[O:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]=2[CH:24]=1)[CH3:13])\[CH3:7])C.CO.O1CCCC1.[OH-].[Na+]>C(#N)C.O>[OH:32][CH:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH2:25][C:16]1[C:17]2[O:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]=2[CH:24]=[C:14]([C@@:11]2([CH3:13])[CH2:12][C@H:10]2/[CH:9]=[CH:8]/[C:6](/[CH3:7])=[CH:5]/[C:4]([OH:33])=[O:3])[CH:15]=1
Reactant: CCCCC(O)CCc1cc([C@@]2(C)C[C@H]2/C=C/C(C)=C/C(=O)OCC)cc2c1OCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CCCCC(O)CCc1cc([C@@]2(C)C[C@H]2/C=C/C(C)=C/C(=O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure H and using (E)-3-((E)-2-{(1S,2S)-2-[7-(3-hydroxy-heptyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl]-2-methyl-cyclopropyl}-vinyl)-but-2-enoic acid ethyl ester (Compound 37, 0.007 g, 0.015 mmol), methanol (1.5 mL), tetrahydrofuran (1.5 mL) and 1M aqueous sodium hydroxide (0.5 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the eluent, the title compound was obtained (0.0044 g, 67%).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[CH2:5]([O:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([O:26]C)[N:16]2[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[C:12]([NH2:28])[N:11]=1)[CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.CS(C)=O>CN(C=O)C>[NH2:28][C:12]1[N:11]=[C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:26])[N:16]2[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH:2]([CH3:4])[CH3:3])[CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1
Reactant: CC(C)I
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(C(C)C)C3)c2n1
Reaction time: 18 h
Yield: 30.6 %

Procedure:
2-Iodopropane (0.1 mmol) was weighed into a vial and an aliquot (0.3 ml, 0.1 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-(3-piperidinylmethyl)-9H-purin-6-amine (802 mg, 2.398 mmol) suspended in DMF (7.2 ml) was added. DIPEA (40 μl, 0.229 mmol) was added and the tube was capped and shaken to aid dispersion then allowed to stand at room temperature (18 hours). DMSO (400 uL) was added and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.5 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The material was redissolved in methanol (0.5 ml), and applied to a 0.5 g aminopropyl SPE (preconditioned with methanol, 2 CV). The cartridge was eluted with methanol (2 ml), the solvent was removed to give the title compound (11.1 mg). LCMS (System A): tRET=0.62 min; MH+ 363
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:23]([C:33]([F:36])([F:35])[F:34])=[N:24][N:25]([CH:28]([CH3:32])[C:29](O)=[O:30])[C:26]=1[CH3:27]>>[Cl:21][C:22]1[C:23]([C:33]([F:35])([F:34])[F:36])=[N:24][N:25]([CH:28]([CH3:32])[C:29]([N:18]2[CH2:19][CH2:20][CH:15]([C:12]3[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:11]=3)[CH2:16][CH2:17]2)=[O:30])[C:26]=1[CH3:27]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)O
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) is reacted analogously to Example I-63 with 2-[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]propanoic acid (282 mg). After chromatographic purification, this gives 2-[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}propan-1-one (165 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[N:10][C:9]=2[CH2:13]O)=[CH:4][CH:3]=1.Cl.[C:16]([OH:19])(=[O:18])[CH3:17]>O1CCCC1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][N:11]=[N:10][C:9]=2/[CH:13]=[CH:17]/[C:16]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: OCc1nnsc1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1nnsc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
[5-(4-Fluorophenyl)-1,2,3-thiadiazol-4-yl]methanol (0.75 g) was dissolved in tetrahydrofuran (30 ml) and activated manganese dioxide (3 g) was added. The mixture was stirred at room temperature for 16 hrs. The reaction mixture was filtered and the filtrate was concentrated. Ethyl diethylphosphonoacetate (0.50 g) and N,N-dimethylformamide (10 ml) were added to the residue. To this mixture was added sodium hydride (60% in oil, 80 mg) at 0° C. and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into an aqueous dilute hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a yellow oil. A 6N aqueous hydrochloric acid solution (10 ml) and acetic acid (5 ml) were added to this yellow oil and the mixture was stirred for 3 hrs. with heating under reflux. The reaction mixture was concentrated, poured into water, and the precipitated solids were filtered, washed with water and dried to give (2E)-3-[5-(4-fluorophenyl)-1,2,3-thiadiazol-4-yl]acrylic acid (190 mg, yield: 21%) as pale-yellow crystals.
Reaction SMILES: C(OC([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[O:17][CH2:18][C:19]([CH3:22])([CH3:21])[N:20]=3)=[CH:13][CH:14]=2)[C:9]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:8][CH:7]1P(OC)(OC)=O)=O)C.[OH-].[Na+]>C(O)C>[CH3:21][C:19]1([CH3:22])[CH2:18][O:17][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:6]=[CH:7][CH:8]=[C:9]3[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[N:20]1
Reactant: CCOC(=O)N1c2ccc(C3=NC(C)(C)CO3)cc2C(Cc2ccc(-c3ccccc3)cc2)=CC1P(=O)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)COC(c2ccc3nccc(Cc4ccc(-c5ccccc5)cc4)c3c2)=N1
Yield: 27.8 %

Procedure:
A mixture of 1-ethoxycarbonyl-6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-2-dimethoxyphosphoryl-4-(4-phenylbenzyl)-1,2-dihydroquinoline (738 mg), ethanol (20 ml) and 1N aqueous sodium hydroxide solution (4 ml) was refluxed under heating for 2 hr. The reaction mixture was concentrated to dryness under reduced pressure. Water was added and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the objective compound (140 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=1)[CH2:4][CH:5]([OH:7])[CH3:6].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]([CH:3]([N:2]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:4][CH:5]([OH:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH3:18]
Reactant: CCOc1cc(C(N)CC(C)O)ccc1OC
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 85 °C
Yield: 64.8 %

Procedure:
A mixture of 4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol hydrochloride (0.5 g, 1.81 mmol), 3-acetamidophthalic anhydride (0.37 g, 1.81 mmol) and triethylamine (0.18 g, 1.81 mmol) in dimethylformamide (10 mL) was heated at 80-90° C. for 7 hours. The mixture was concentrated in vacuo to an oil. The oil was dissolved in ethyl acetate, washed with water, brine, dried, filtered and concentrated to an oil. This oil was purified by chromatography (silica gel, methylene chloride/ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (0.5 g, 65%); mp 132-134° C.; 1H NMR (CDCl3) δ9.54 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.4 Hz, 1H), 7.46 d, J=7.3 Hz, 1H), 7.12-7.08 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 5.46 (t, J=7.8 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.80 (m, 1H), 2.59-2.42 (m, 2H), 2.25 (s, 3H), 1.65 (s, 1H), 1.45 (t, J=7.0 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3) δ170.36, 169.20, 167.96, 149.04, 148.26, 137.29, 135.70, 131.50, 131.35, 124.60, 120.61, 117.85, 113.10, 111.25, 66.00, 64.39, 55.89, 52.43, 40.19, 24.92, 24.33, 14.73; Anal. Calcd. For C23H26N2O6: C, 64.78; H, 6.15; N, 6.57. Found: C, 64.86; H, 6.10; N, 6.46.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[C:17]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[C:29]([Cl:37])[CH:28]=4)[O:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>CS(C)=O.C(Cl)Cl>[Cl:37][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[CH:14][N:13]=[C:12]4[NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])[N:26]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N[C@H](C(=O)O)C(C)C)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of L-valine (36.6 mg, 0.312 mmol) and sodium hydride (60%; 9.99 mg, 0.250 mmol) in dimethyl sulfoxide (DMSO) (2 ml) were stirred at room temp for 30 min. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was stirred at 120° C. under nitrogen for 48 hr. The cooled reaction mixture was loaded onto an SCX column. The column was flushed with acetonitrile and then the desired product was eluted with 20% ammonia in acetonitrile. The solvent was removed in vacuo from the appropriate fractions to give an orange solid which was dissolved in DCM and washed with water. The organics were passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (22 mg). MS (ES) C25H2535ClN4O4 requires 480. found 481 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][C:7]=1[Cl:15]
Reactant: CCOc1ccc(N)c(C(=O)OC)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOc1cc(Cl)c(N)c(C(=O)OC)n1
Temperature: 80 °C
Yield: 5.3 %

Procedure:
To a stirred solution of the compound prepared in Example 426 (0.048 g) in N,N-dimethylformamide (1.2 mL) was added N-chlorosuccinimide (0.0343 g). The resulting mixture was heated at 80° C. for 18 hours. The solvent was evaporated and the residue dissolved in dichloromethane and purified by column chromatography on silica gel (20% ethyl acetate in hexanes) to obtain the title compound (0.003 g) having the following physical data.