Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[CH3:24][O-:25].[Na+]>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4]([O:25][CH3:24])[CH:3]=1
Reactant: C[O-]
Reactant: Cc1c(Cn2cnc3c(Cl)cc(Cl)nc32)cccc1C(F)(F)F
Agent: [Na+]
Product: COc1cc(Cl)nc2c1ncn2Cc1cccc(C(F)(F)F)c1C
Yield: 55.2 %

Procedure:
5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (200 mg, 0.555 mmol) was suspended in Methanol (1.5 mL), sodium methoxide (0.150 mL, 0.656 mmol) was added and the mixture was irradiated in a microwave oven for 90 min at 110° C. Conversion to desired product was observed by LC/MS (5,7-dimethoxy product, 5-methoxy isomer and 7-OH-5-Cl derivative observed by mass as well). The mixture was diluted with water and the precipitate formed was collected by filtration, washed with water and dried. The solid was purified on silica gel (ISCO 0-60% EtOAc in hexanes) to give 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (125 mg, 0.351 mmol, 63.3% yield) as a white powder. Additional material was prepared from 120 mg of 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine, irradiated in a microwave for 30 min at 110° C. in the presence of NaOMe. After work-up, 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (109 mg, 0.306 mmol, 55.2% yield) was obtained and carried on without further purification to the next step. MS (ES+) m/e 356 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(F)cc3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[CH2:1]([O:19][C:29](=[O:30])[CH2:28][Cl:27])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCO
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCOC(=O)CCl
Temperature: 0 °C

Procedure:
To an ice-cooled solution of z,z,z-octadeca-6,9,12-trienol (2 g, 7.56 mmol) and triethylamine (2.02 g, 20 mmol) in methylene chloride (20 ml) was added dropwise with stirring chloroacetyl chloride (1.13 g, 10 mmol) in methylene chloride (20 ml) under an atmosphere of nitrogen. On completion of the reaction as shown by tlc, the mixture was washed with water (2×100 ml) and saturated sodium chloride solution (100 ml). The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. Toluene (100 ml) was added to azeotropically remove final traces of water. z,z,z-octadeca-6,9,12-trienyl-(2-chloro)acetate was obtained as a dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[C:11]([CH3:10])=[N:15][C:14]([CH3:16])=[N:13]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: Cc1cc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-n2nc(C)nc2C)cc(Cl)n1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloro-6-methylpyridine (24-1, 2.15 g, 13.3 mmol), 3,5-dimethyl-1H-1,2,4-triazole (1.29 g, 13.3 mmol), and cesium carbonate (5.20 g, 16.0 mmol) in DMF (15 mL) was heated at 100° C. for 20 hours and cooled to room temperature. The mixture was diluted with ethyl acetate (250 mL) and washed with brine (4×250 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-90% ethyl acetate in hexanes) to afford 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridine (24-2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 1H), 7.29 (m, 1H), 2.64 (s, 3H), 2.62 (s, 3H), 2.41 (s, 3H). LRMS m/z (M+H) 223 found, 223 required. The regioisomer (24-3) was also obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.71 (m, 1H), 7.10 (m, 1H), 2.83 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H). LRMS m/z (M+H) 223 found, 223 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2S[CH:8]=[CH:7][C:6]=2[CH:10]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:22]([O-:26])([O-])(=[O:24])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:22](=[O:26])(=[O:24])[CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: Brc1ccc2sccc2c1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S1(=O)C=Cc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
5-Bromo-1-benzothiophene (1.50 g, 7.04 mmol) was dissolved in chloroform (47 mL) and allowed to stir vigorously at ambient temperature. m-CPBA (4.34 g, 17.6 mmol) was added in three portions and the resulting mixture was maintained at ambient temperature for 16 hours. The mixture was then diluted with 1M aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was again washed with 1M aqueous sodium thiosulfate, saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-30% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[NH2:13]Cl>CN(C=O)C>[NH2:13][N:4]1[CH:5]=[CH:6][C:2]([Cl:1])=[C:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1[nH]ccc1Cl
Reactant: NCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccn1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a stirred solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (1.00 g, 6.30 mmol) in DMF (15 mL) was added NaH (0.45 g, 18.80 mmol, 99%, dry) and the contents were stirred for 1 h at ambient temperature. NH2Cl (42.0 mL, 0.327 g, 6.30 mmol) was added at −10° C. to the reaction mixture and the contents were stirred for another 30 min at −10° C. The solvents were removed under reduced pressure and the residue was extracted with MTBE. The MTBE layer was passed through anhydrous Na2SO4 and concentrated under reduced pressure to give a brown solid. The crude residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 20% EtOAc/hexanes) to give a methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (0.750 g, 69.0%) as a yellow solid. LCMS Condition B-23: retention time 0.68 min, [M+1]=175.1. 1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 6.11 (d, J=2.8 Hz, 1H), 6.28 (s, 2H), 7.06 (d, J=2.8 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Cl[CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[K+].O>C1(C)C=CC=CC=1>[C:14]1([CH:13]=[CH:12][CH2:11][N:1]2[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCC=Cc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)C1CCN(CC=Cc2ccccc2)CC1
Yield: 86.9 %

Procedure:
A mixture of 60.0 g of isonipecotamide (4-piperidinecarboxamide), 75.0 g of (3-chloropropenyl)benzene and 72 g of potassium acid carbonate suspended in 700 ml of toluene are heated with stirring at their reflux temperature for a period of 4 hours. The reaction mixture is cooled, water added thereto and filtered. The crude product is washed with water, ether and recrystallized from a 5:1 ethanol/water mixture to yield 99.4 g of 1-(3-phenyl-2-propenyl)-4-piperidinecarboxamide as light beige needles having a m.pt. of 189.5°-191.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:8]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:9]=2[S:10][C:11]=1C(O)=O)=[O:5])[CH3:2]>O1CCCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:8]2[C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[CH:11][S:10][C:9]=2[CH:15]=1
Reactant: CCOC(=O)Nc1c(C(=O)O)sc2cc(OC)ccc12
Solvent: C1CCOC1
Product: CCOC(=O)Nc1csc2cc(OC)ccc12
Yield: 200 %

Procedure:
11.4 g of 3-[(ethoxycarbonyl)amino]-6-methoxybenzo[b]thiophene-2-carboxylic acid are heated at 220-225° C. A vitreous gum is obtained which is taken up in tetrahydrofuran until dissolved. The solvent is evaporated under reduced pressure and the residue is purified on a silica column with a 10/90 mixture of ethyl acetate and cyclohexane. 19.4 g of product are obtained.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[CH3:27][O:28][C:29]([C@@H:31]1[CH2:35][C@H:34](OS(C)(=O)=O)[CH2:33][N:32]1[S:41]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)(=[O:43])=[O:42])=[O:30]>CN(C=O)C>[CH3:27][O:28][C:29]([C@@H:31]1[CH2:35][C@@H:34]([S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:33][N:32]1[S:41]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)(=[O:43])=[O:42])=[O:30]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
64.2 g (167 mmol) of triphenylmethanthiol was slowly added at room temperature to a solution of 17.9 g (160 mmol) of potassium tert-butylate in 300 ml DMF and stirred mechanically for 30 min. Then 63 g (152 mmol) of (4S, 2S)-4-methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methylester in 300 ml DMF were added at 20° C. by cooling at the end with an ice bath. The reaction was heated for 1.3 h at 100° C., cooled, evaporated to 400 ml and extracted with 250 ml aqueous saturated NH4Cl/EtOAc (3×300). The organic phases were washed with aq. 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography (CH2Cl2/MeOH 99:1) gave 58.6 g (65%, (2S,4R)/(2R,4R)-isomer ca 4:1, 1H-NMR) and 9.2 g (10%, (2S,4R)/(2R,4R)-isomer ca 1:1, 1H-NMR) of (2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid methyl ester, MS: 594 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:12]1)=[O:40]
Reactant: COc1ccc(-c2ccnc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Product: COc1ccc(-c2ccnc(C)c2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 88 (160 mg, 0.36 mmol) is treated with acid chloride 6 (99 mg, 0.40 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:24]([O:42][CH:43]1[CH:48]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:47]([O:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH2:46][CH:45]([C:87](O)=[O:88])[CH2:44]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([NH:1][C:87]([CH:45]2[CH2:46][CH:47]([O:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:48]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:43]([O:42][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:44]2)=[O:88])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2ccc(C(=O)OC)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Methyl 4-amino-2-methoxybenzoate (79 mg, 0.44 mmol) was dissolved in chloroform (1 ml), and HOBt (7 mg, 0.05 mmol) and 3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (201 mg, 0.22 mmol) were added. EDC.HCl (45 mg, 0.23 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, and the residue was precipitated with acetonitrile (10 ml), and then purified by silica gel column chromatography (chloroform/ethyl acetate=10:1) to give N-(3-methoxy-4-methoxycarbonylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (70 mg, 0.06 mmol, yield 27%).
Reaction SMILES: O.[C:2](O)([C:4]([F:7])([F:6])[F:5])=[O:3].[F:9][CH:10]([F:30])[CH2:11][O:12][CH:13]1[C:18](OC)([O:19]C)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:30][CH:10]([F:9])[CH2:11][O:12][CH:13]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:2](=[O:3])[C:4]([F:7])([F:6])[F:5])[CH2:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCC(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)C(F)(F)F)CC1OCC(F)F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Water (5 mL) and TFA (2 mL) were added to a solution of tert-butyl 3-(2,2-difluoroethoxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (121b) (1.5 g, 4.67 mmol) in THF (30 mL), and the mixture was stirred at 70° C. for one hour. Sodium bicarbonate was added to a pH of about 8, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 1.1 g of the title compound as a light brown oily substance (86%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH:18]([CH3:20])[CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH:18]([CH3:19])[CH3:20])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2OC(C)C)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(5-fluoro-2-isopropoxy-phenyl)-methanone (Example 200) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C20H27N5O4SF [(M+H)+] 452.1766, observed 452.1766.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=3)[N:15]=2)[CH:18]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc(C(F)(F)F)cc3)cn2c1

Procedure:
24 g (0.077 mole) of 1-bromo-2-(4-trifluoromethylphenyl)-2-ethanone, 8.4 g (0.077 mole) of 2-amino-5-methylpyridine and 13 g of sodium bicarbonate are mixed in 210 ml of 95% strength ethanol, and this suspension is heated under reflux until the evolution of gas has ceased. The solvent is then evaporated off under reduced pressure and the evaporation residue is taken up with water and dichloromethane. The organic phase is decanted and dried over magnesium sulphate, and the solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([CH:13]3[CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[NH:15]1[CH2:14][CH:13]([C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH2:6][CH2:7]2)=[O:12])[CH2:16]1
Reactant: O=C(OCc1ccccc1)N1CC(C(=O)N2CCN(C3CCC3)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: O=C(C1CNC1)N1CCN(C2CCC2)CC1
Reaction time: 23 h
Yield: 74.6 %

Procedure:
To a stirred solution of benzyl 3-[(4-cyclobutylpiperazin-1-yl)carbonyl]azetidine-1-carboxylate (130 mg, 0.36 mmol) in EtOH (10 mL) was added 10% Pd/C (13 mg, 10% wt/wt). The flask was evacuated and the vacuum purged with N2 gas. The flask was evacuated again and the vacuum purged with H2 gas. After 16 hours the reaction mixture was filtered through Celite® and charged with 10% Pd/C (13 mg, 10% wt/wt). The flask was evacuated and the vacuum purged with N2 gas. The flask was evacuated again and the vacuum purged with H2 gas. After 23 hours, the reaction mixture was filtered through Celite® and the filtrate concentrated at reduced pressure to give the final compound (60 mg, 74%) which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([OH:12])=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CCO>[Br:11][C:9]1[CH:10]=[C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:2]=2)[C:6]([OH:12])=[N:7][CH:8]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1cc(Br)cnc1O
Solvent: CCO
Product: Oc1ncc(Br)cc1-c1cn2ccccc2n1
Yield: 67.6 %

Procedure:
A mixture of 2-bromo-1-(5-bromo-2-hydroxypyridin-3-yl)ethanone (300 mg, 1.02 mmol) and 2-aminopyridine (100 mg, 1.06 mmol) in EtOH (10 mL) was stirred at reflux overnight. The reaction mixture was cooled and filtered to provide 5-bromo-3-(imidazo[1,2-a]pyridin-2-yl)pyridin-2-ol (200 mg, yield: 67%). 1H-NMR (DMSO, 400 MHz) δ 12.75 (br s, 1H), 9.02 (s, 1H), 8.94 (d, J=6.8 Hz, 1H), 8.42 (d, J=2.8 Hz, 1H), 7.89˜7.96 (m, 3H), 7.45 (d, J=4.8 Hz, 1H). MS (M+H)+: 290/292.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:10]=2)=[CH:4][CH:3]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:11]3[N:10]=[C:9]([S:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[CH2:30][C:28]#[N:29])=[CH:3][CH:4]=4)[CH:14]=[CH:13][N:12]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Product: N#CCC(=O)Nc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Yield: 67.2 %

Procedure:
In a procedure analogous to Example 15, reaction of 4-(4-aminophenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (60 mg, 0.16 mmol) and cyanoacetic acid (46 mg, 0.32 mmol) furnished the product (48 mg, 68%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=O)=O.O>CS(C)=O>[C:1]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C1
Reaction time: 18 h
Yield: 61.8 %

Procedure:
Potassium cyanide (5.80 g, 89.0 mmol) was added to a solution of tert-butyl (3S)-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate (preparation 78) (9.35 g, 35.3 mmol) in dimethylsulphoxide (100 ml), and the reaction stired at room temperature for 18 hrs, and then at 100° C. for a further 24 hrs. The cooled mixture was poured into water and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (20:80) as eluant to give the title compound as an oil, (4.28 g, 62%).
Reaction SMILES: [C:1]([O:14][CH2:15]Cl)([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[I-:17].[Na+].O>CC(C)=O>[C:1]([O:14][CH2:15][I:17])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: [I-]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCCl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCI

Procedure:
C4F9OCH2Cl (50 g, 0.175 mole, isomer ratio n/i=95:5) was combined with sodium iodide (52.5 g, 0.38 mole) in acetone (200 g) and heated to reflux overnight. Water was added and the acetone distilled from the reaction vessel using a Dean-Stark apparatus. The product was washed with water to remove residual acetone. Glc of the residue (52.6 g) revealed it to be 82.6 wt. % of the desired product C4F9OCH2I, which was further purified by distillation. The distillation fraction boiling at 110-115° C. was found to be 97.8 wt. % of the desired product with a 96/4 normal to iso ratio.