Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].[CH3:30][CH:31]([OH:33])[CH3:32].[H-].[Na+].O>CN(C=O)C>[CH:31]([O:33][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28])([CH3:32])[CH3:30]
Reactant: CC(C)O
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4ccc(F)c(C(F)(F)F)c4)n3)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of 2-(4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (100 mg) and 2-propanol (35 μl) in DMF (3 ml) was added 60% NaH (12 mg) at 0° C., followed by stirring at room temperature for 9 hours. The reaction solution was added with water (5 ml) to complete the reaction, and extracted with as a mixed solvent of chloroform:CH3OH (8:2). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=98:2 to 93:7), and crystallized with diethyl ether to obtain 2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (25 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.[Cl:32]CCl>>[ClH:32].[CH3:1][NH:2][C:3](=[O:24])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:19]=1)[NH2:5]
Reactant: CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NC)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Product: Cl

Procedure:
N-Tertiary butyloxycarbonyl-O-propyl-L-tyrosine N-methyl amide (370 mg, 1.1 mM) in dichloromethane (8 ml) was treated with trifluoroacetic acid (2 ml) at 20° C. for 2 h. The solvent was removed in vacuo and the residue redissolved in ether saturated with hydrogen chloride and this procedure repeated twice more to afford O-propyl-L-tyrosine-N-methyl amide hydrochloride (1.1 mM) which was used directly in the next step. N-(3-N-(Benzyloxycarbonyl)amino-1-(R)-methoxycarbonylpropyl)-L-leucine hydrochloride (prepared as described in Example 1) (416 mg, 1 mM) in dichloromethane (10 ml) and dimethyl formamide (2 ml) was treated with 1-hydroxybenzotriazole (159 mg, 1.04 mM), O-propyl-L-tyrosine-N-methyl amide hydrochloride (1.1 mM), N-methyl morpholine (315 mg, 3.3 mM) and N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (200 mg, 1.04 mM) at 0° C. The reaction mixture was stirred continuously as it was allowed to warm to 20° C. over 16 h. The reaction was diluted with dichloromethane (30 ml) and washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous citric acid (1M) dried over anhydrous sodium sulphate and concentrated in vacuo to afford N-(3-N-Benzyloxycarbonyl)amino-1-(R)-methoxycarbonylpropyl)-L-leucyl-O-propyl-L-tyrosine-N-methyl amide (0.22 g, 0.36 mM) which crystallised from ethyl acetate/hexane as needles m.p. 135°-140° C. (Found: C,62.8; H,7.8; N,9.2. C32H46N4O7 +0.5 H2O requires: C,63.2; H,7.8; N,9.2%); δ(CDCl3) 0.86 (6H,d,d,J=4 Hz J=4 Hz (CH3)2C); 1.02 (3H,t,J=7 Hz CH3CH2); 1.1-1.98 (9H,m,CH,CH2,CH2,CH2CH2); 2.74 (3H,d,J=4 Hz CH3NH); 2.86-3.48, (5H,m,CH2CH2,CH); 3.64 (3H,s,OCH3); 3.86 (2H,t,J=6 Hz,CH2O); 4.58 (1H,m,NHCHCO); 5.06 (2H,s,CH2C6H5); 5.14 (1H,m,NH) 6.54 (1H,m,NH); 6.76, and 7.06 (4 H,each d, each J=8 Hz,C6H4); 7.32 (5H,m,C6H5); 7.42 (1H,m,NH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#N)=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Li][CH2:29][CH2:30][CH2:31][CH3:32].[BH4-].[Na+].C1C[O:38]CC1>C(Cl)Cl>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([OH:38])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:22][N:21]=2)=[O:18])=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C#N)cn1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCC(O)c1ccc(NC(=O)N2CCCc3ccc(C(OC)OC)nc32)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2H, 50 mg, 0.116 mmol) in THF (2 ml) at −78° C. was treated with n-BuLi (1.5 M in hexane, 217 μl, 0.326 mmol) and stirred for 2 min. The reaction mixture was treated with N,N-dimethylform-13C-amide (45.6 μl, 0.578 mmol) and stirred for 0.5 h. The reaction was quenched by addition of sat. aq. NH4Cl, warmed to room temperature and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (2 ml) and DCM (1 ml), treated with NaBH4 (8.75 mg, 0.231 mmol) and stirred for 10 min. The reaction was quenched by addition of sat. aq. NH4Cl and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product containing fractions were concentrated to give the title compound as a yellow oil. (UPLC-MS 3) tR 1.09 min; ESI-MS 415.2 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[NH:2]1.CN(C)C=O.S(Cl)([Cl:18])=O>ClC1C=CC=CC=1>[Cl:18][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]sc2ccccc12
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: Clc1nsc2ccccc12
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 75.6 g (0.5 mol) of 1,2-benzisothiazol-3-one, 54.8 g (0.75 mol) of N,N-dimethylformamide and 100.0 g of chlorobenzene. While stirring, 71.4 g (0.6 mol) of thionyl chloride was added dropwise thereto over 1 hour at 70° to 80° C., and the mixture was reacted at the same temperature for 8 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was distillated under reduced pressure of 0.93 kPa at 128° C. to give 75.1 g (0.45 mol) of 3-chloro-1,2-benzisothiazole. The yield based on the 1,2-benzisothiazol-3-one was 90%.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[N:24]=[CH:23]1.CO>N1C=CC=CC=1.C(OCC)C>[C:1]([N:22]1[CH:26]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[N:24]=[CH:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CO
Product: O=C(O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trityl chloride (51 g, 0.18 mol) is added to a suspension of (1H-imidazol-4-yl)acetic acid hydrochloride (25 g, 0.15 mol) in pyridine (500 mL). This is stirred at room temperature for 16 h, at the end of which MeOH (150 mL) is added. This solution is stirred at room temperature for 1 h. Solvents are evaporated and the residue is taken up in CH2Cl2 and washed with 1 M aqueous citric acid solution (2×) and brine. The organic phase is dried over anhydrous Na2SO4 and evaporated to give a sticky residue which when taken up in diethyl ether and evaporated gave the product as a white solid that is used without further purification. MS (ESI) m/z 368.9 (M+H) (Procedure adapted from J. Org. Chem. 1993, 58, 4606, also prepared in WO2003013526)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH3:15][C@H:16]([CH2:20][CH2:21][CH:22]=[C:23](C)[CH3:24])[CH2:17]CO.O(C)[Na].O>C1CCCCC1.CCOCC>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH2:13][C@H:23]([CH3:24])[CH2:22][CH2:21][CH:20]=[C:16]([CH3:17])[CH3:15])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)=CCC[C@@H](C)CCO
Reactant: CCOC(=O)C(=O)C1CCC(C)CC1
Agent: CO[Na]
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)=CCC[C@@H](C)CCOC(=O)C(=O)C1CCC(C)CC1
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of ethyl 2-(4-methylcyclohexyl)-2-oxoacetate (5.0 g, 25 mmol), of (R)-3,7-dimethyl-6-octenol (4.74 g, 30 mmol) and NaOCH3 (0.5 ml, 30% in methanol) in cyclohexane (50 ml) was heated with a water separator under reflux for 2 days. After cooling to room temperature, ether was added and the organic phase washed with a saturated solution of NaCl, dried (Na2SO4), filtered and concentrated. Column chromatography (SiO2, heptane/ether 7:3 and heptane/ether 95:5) gave 1.16 g (15%) of the pure product a colorless oil as a mixture of cis/trans isomers (ca. 1:3).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:24])[C:16]2[CH:15]=[C:14]3[C:17]4[C:22]([NH:23][C:13]3=[CH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4.Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[C:28]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]=1>ClCCl>[C:38]1([C:28]2[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:31]=[C:26]([N:23]3[C:13]4[C:14](=[CH:15][C:16]5[C:4]([CH3:24])([CH3:3])[C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=6[C:11]=5[CH:12]=4)[C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC1(C)c2ccccc2-c2cc3[nH]c4ccccc4c3cc21
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2cc3c(cc21)c1ccccc1n3-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g (37.5 mmol) of NaH (60% in oil) are initially introduced in 150 ml of dichloromethane. A solution of 8 g (28 mmol) of 12,12-dimethyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene in dichloromethane is added dropwise at room temperature. After 1 h, 8.5 g (31 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine are added dropwise, and the mixture is stirred at RT for 8 h. The solid which has precipitated out is recrystallised from toluene. The crystals which have deposited are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 11.6 g; 80% of theory; purity: 99.9% according to HPLC.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11]C(C)(C)C)=O)[C:5]([OH:7])=[O:6])[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(C(F)(F)F)=O.[CH3:38][CH:39]([C@H:41]([NH2:60])C(OCCOCN1C2NC(N)=NC(=O)C=2N=C1)=O)[CH3:40]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:38][CH:39]([C@H:41]([NH2:60])[C:9]([NH:8][C@H:4]([C:5]([OH:7])=[O:6])[CH:2]([CH3:1])[CH3:3])=[O:11])[CH3:40]
Reactant: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
Boc-VAL, DCC, DMF, 0° C., 1 hr, ii) DMAP, DMF, 18 hrs, rt iii) TFA, 0° C., 30 min, iv) Boc-Val, DCC, DMF, 0° C., 1 hr, v) TEA, rt, vi) adding Boc-Val amino acid anhydride (step iv) to the neutralized Val-ACV (step v), 5 hrs, rt, vii) TFA, 0° C., 30 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.[CH2:17](S)[CH2:18][CH2:19]C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([S:8][CH2:10][CH2:17][CH2:18][CH3:19])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCS
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCCCSc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, butanethiol and DBU in dioxane. EI-MS m/e (%): 329 (M{81Br}+, 29), 327 (M{79Br}+, 28), 287 ([M{81Br}-C3H6]+, 46), 285 ([M{79Br}—C3H6]+, 45), ), 273 ([M{81Br}—C4H8]+, 98), 271 ([M{79Br}—C4H8]+, 99), 248 ([M—Br]+, 54), 206 (100), 192 (34), 117 (34).
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[N:14]([S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:15]=[CH:16][C:17]=1[C:18]([OH:20])=O)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[CH2:6]([O:5][CH2:4][CH2:3][C@@H:2]1[C:13]2[N:14]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:22])=[O:23])[CH:15]=[CH:16][C:17]=2[C:18](=[O:20])[NH:1]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2[C@H](N)CCOCc2ccccc2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2[C@@H](CCOCc2ccccc2)NC3=O)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of (R)-2-(1-amino-3-(benzyloxy)propyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with TFA (1:1) (504d, 5.43 g, 10.01 mmol) and DIEA (5.22 mL, 30.0 mmol) in EtOAc (50 mL) was added 1-propanephosphonic acid cyclic anhydride (50 wt. % in EtOAc, 5.96 mL, 10.01 mmol) dropwise via syringe. All solids dissolved to give a light brown solution. After 1 h, the reaction was partitioned between sat'd NaHCO3 and EtOAc. The organic layer was washed with sat'd NaHCO3 once, sat'd NaCl once, and the organics were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give (R)-6-(2-(benzyloxy)ethyl)-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (724e) (3.51 g, 8.55 mmol, 85% yield) as a light brown foam. m/z (ESI, +ve) 411.1 (M+Na)+.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:42])[CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(C)c2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 157.9 %

Procedure:
To a solution of 3-butyl-4-[4-cyclohexyloxy-3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.094 mmol, 56.3 mg) in DCM (1 mL) was added formaldehyde solution in water (37%, 0.3 mmol, 0.022 mL), and 2 drops of acetic acid. Sodium triacetoxyborohydride (0.4 mmol, 89 mg, 95%) was added. The reaction mixture was stirred at room temperature for 2 h and partitioned between ethyl acetate (20 mL) and saturated aq. sodium bicarbonate solution (20 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel using 2 M ammonia in MeOH/DCM 1:19, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The yellow solid was dried overnight under high vacuum to provide the title compound (42.8 mg). LCMS: m/z 505 [M+1] 1H NMR (400 MHz, CD3OD) δ 8.14 and 8.16 (1H, s), 8.00-8.01 (1H, m), 7.86 and 7.94 (1H, s), 7.75-7.79 (1H, m), 7.36-7.41 (1H, m), 7.26-7.30 (1H, s), 5.38-5.55 (1H, m), 4.57-4.62 (1H, m), 3.96 (3H, d), 3.14-3.70 (6H, m), 2.95 (3H, d), 1.81-2.58 (6H, m), 1.31-1.66 (12H, m), 0.81 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([N:10]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([OH:22])=[O:21])[CH2:11]2)[CH:3]=1.O[O:24][S:25]([O-:27])=O.[K+].Cl.[CH3:30]O>O>[Cl:1][C:2]1[N:7]=[C:6]([S:25]([CH3:30])(=[O:27])=[O:24])[N:5]=[C:4]([N:10]2[C@H:15]([C:16]([F:18])([F:19])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([OH:22])=[O:21])[CH2:11]2)[CH:3]=1
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C(F)(F)F)n1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of cis-1-[6-chloro-2-(methylthio)-4-pyrimidinyl]-6-(trifluoromethyl)-3-piperidinecarboxylic acid (180 mg, 0.506 mmol) in CH3OH (8 mL) and water (2.5 mL) was cooled in an ice bath and treated slowly with a premixed solution of oxone (778 mg, 1.27 mmol) in water (3 mL). The reaction was stirred at room temperature overnight. The pH was adjusted pH to acidic with 1N HCl and then 5 mL of water was added. The resulting mixture was filtered over fritted funnel to isolate the title compound (79 mg) as a white solid. LC-MS (ES) m/z=388, 390 [M+H]+.
Reaction SMILES: [CH3:1][Mg+].[Br-].CC[O:6][CH2:7][CH3:8].C(OC([C:14]1[N:15]=[C:16]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:18]=1)=O)C>C1COCC1>[Br:33][C:30]1[CH:29]=[CH:28][C:27]([C:16]2[N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:18]=[C:14]([C:7]([OH:6])([CH3:8])[CH3:1])[N:15]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2Cl)c(-c2ccc(Br)cc2)n1
Reactant: C[Mg+]
Reactant: CCOCC
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1cn(Cc2ccccc2Cl)c(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a 3.0 M solution of MeMgBr in Et2O (1.0 mL, 3.0 mmol) at 0° C. added slowly a solution of 2-(4-bromophenyl)-1-(2-chlorobenzyl)-1H-imidazole-4-carboxylic acid ethyl ester (235 mg, 0.56 mmol) in THF (3 mL, anhyd). After addition was completed the flask was removed from the ice-water bath and allowed to warm to ambient temperature. At 40 min the reaction mixture was quenched by addition of satd NH4 Cl, extracted with EtOAc, dried (MgSO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to give the title compound (135 mg, 59%) as a pale amber solid. 1H-NMR (DCM-d2): δ 7.54 (d, 2H), 7.38-7.45 (m, 3H), 7.24-7.33 (m, 2H), 6.89 (d, 1H), 6.82 (s, 1H), 5.25 (s, 2H), 2.86 (br s, 1H), 1.54 (s, 6H); MS (ES): 405, 407 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:31]3[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)CC1
Reaction time: 24 h
Yield: 62 %

Procedure:
A suspension of 4-(4-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (3.11 g), 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.51 g), and polymer supported triphenylphosphine (6.25 g; loading: 3 mmol/g) in DCM (100 mL) was treated with di-tert-butylazodicarboxylate (3.78 g). After 24 h, the resulting mixture was filtered, and the filtrate was evaporated. Chromatography of the residue (15–30% ethyl acetate/hexanes) gave the title compound as a white solid (3.20 g).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][C:6]([F:15])([F:14])[C:7]1[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:12]([C:10]1[N:11]=[C:7]([C:6]([F:5])([F:14])[F:15])[S:8][CH:9]=1)[OH:13])#[CH:2]
Reactant: O=Cc1csc(C(F)(F)F)n1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1csc(C(F)(F)F)n1

Procedure:
11 cm3 of a molar solution of ethynyl magnesium bromide is added to a solution of tetrahydrofuran containing 2 g of 2-(trifluoromethyl) 4-thiazolecarboxaldehyde. The reaction mixture is maintained under agitation for 30 minutes at about 20° to 25° C. It is poured into a solution of ammonium chloride, followed by extraction with methylene chloride, drying, filtering and bringing to dryness. 2.1 g of desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:37](I)[CH3:38]>CN(C)C=O.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26]([O:28][CH2:37][CH3:38])=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CCI
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)O)ccc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)OCC)ccc1OC
Product: Cl
Reaction time: 1 h

Procedure:
1 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2methoxyphenyl)-N-propylamino]thiazole (EXAMPLE 3) is dissolved at room temperature and under argon in 3 ml of dimethylformamide and then 0.66 g of Cs2CO3 and 0.5 ml of ethyl iodide are added. The reaction mixture is stirred for one hour and then diluted with ethyl acetate. It is washed with water, dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column eluted with a cyclohexane/ethyl acetate 5/1 (v/v) mixture. The expected product is obtained in the form of a colourless oil.
Reaction SMILES: O.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.Cl.[C:10](=O)([O-])[O-:11].[Na+].[Na+].C[CH:17]([C:21](Cl)=[O:22])[C:18](Cl)=[O:19]>O.ClCCl>[CH3:10][O:11][C:21](=[O:22])[CH2:17][C:18](=[O:19])[N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)Cl)C(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC(=O)N1CCC(=O)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-piperidone monohydrate, hydrochloride (30.7 g; 0.2 mol), sodium carbonate (42 g; 0.4 mol) in water (160 mL) was added dichloromethane (500 mL). The mixture was stirred at room temperature and a solution of methyl malonylchloride (26 ml; 1.2 eq) in dichloromethane (100 mL) was added dropwise at room temperature, keeping the temperature of the reaction mixture below 30° C. The pH was maintained at 8 at the end of the addition. The mixture was stirred 4 hours at room temperature. The residue was extracted twice with dichloromethane, dried over magnesium sulfate and evaporate to yield the title compound (37.4 g).