Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:28][C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][CH:30]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:28][C:29]2[CH:41]=[CH:40][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2cccs2)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2cccs2)n1Cc1ccc(C(=O)O)cc1
Reaction time: 6 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[(2-thienyl)methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-benzoate (1.28 g, 2.26 mmol) was dissolved in methylene chloride (25 mL) and trifluoroacetic acid (3.3 mL). After stirring for 16 hours an additional amount of trifluoroacetic acid (3 mL) was added. Stirred for a further 6 hours and then the reaction mixture was evaporated in vacuo. pH 7 buffer was added and the mixture extracted with ethyl acetate. This extract was dried over MgSO4 and then evaporated in vacuo and crystallized from ethyl acetate/ether.
Reaction SMILES: [CH:1]1([CH:7]([N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH2:8]OC2C=CC(C(O)=O)=CN=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][O:41][C:42](=[O:52])[C:43]1[CH:48]=[C:47]([F:49])[C:46]([OH:50])=[C:45]([F:51])[CH:44]=1>>[CH3:40][O:41][C:42](=[O:52])[C:43]1[CH:44]=[C:45]([F:51])[C:46]([O:50][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[C:47]([F:49])[CH:48]=1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2ccc(C(=O)O)cn2)C2CCCCC2)c(OC)n1
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Product: COC(=O)c1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethanol (Example 73, intermediate b), 3,5-difluoro-4-hydroxy-benzoic acid methyl ester (commercially available), tri-N-butylposphine and N′N′N′N-tetramethylazodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:tert-butyl methyl ether (100:0 to 50:50). Off-white foam (45%). MS (Turbo Spray): m/z=588.3 [M+H].
Reaction SMILES: C[C:2](CC(OC)(C)C)=[O:3].O=O.[C:12]([N:16]=[N:17][C:18]([O:24][OH:25])([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:19])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]=[N:17][C:18]([O:24][OH:25])([CH2:20][C:21]([O:3][CH3:2])([CH3:22])[CH3:23])[CH3:19])([CH3:13])([CH3:15])[CH3:14]
Reactant: COC(C)(C)CC(C)=O
Reactant: CC(C)CC(C)(N=NC(C)(C)C)OO
Agent: O=O
Product: COC(C)(C)CC(C)(N=NC(C)(C)C)OO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 60 grams of the t-butylhydrazone of pentoxone (4-methoxy-4-methyl-pentanone-2) in 60 grams of odorless mineral spirits was oxidized by passing oxygen through the solution as in Example II. The oxidation was initiated at 30° C by adding 2 drops of a 50% solution of 2-t-butylazo-2-hydroperoxy-4-methylpentane. The oxidation was 1/2 complete after 50 minutes at 30° C. The temperature was lowered to 20° C. and an additional 1 hour was required before the oxidation was complete. It was then cooled to 0° C. by circulating ice water through the jacket and weighed into a cold poly bottle and stored at -30° C. or below. The yield was 126 g (97% of theory). The solution is not sensitive to shock.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]([NH:20][CH:21]3[C:30]4[C:25](=[C:26]([O:31]C)[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH3:19])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]([NH:20][CH:21]3[C:30]4[C:25](=[C:26]([OH:31])[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH3:19])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(NC1CCCc2c(O)cccc21)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene (0.33 g) in CH2Cl2 (7 ml) was added 1M BBr3—CH2Cl2 solution (1.5 ml) at 0° C. After being stirred for 3 hours at the same temperature, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with water and brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.23 g).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[S:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:28][CH:29]2[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:23][S:24][CH:25]2[CH2:26]1)=[O:12]
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
1.18 g of N,N'-carbonyldiimidazole are added to a solution of 1.16 g of 2-dimethylaminophenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 30 minutes at +5° C. and then a solution of 2.0 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 1.83 cm3 of triethylamine in 20 cm3 of dichloromethane is added. The reaction mixture is stirred for 1 hour at 20° C. and is then washed twice with 50 cm3 of water and dried over magnesium sulphate. The solution is filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2.8 cm, height 26 cm), eluting under a nitrogen pressure of 0.6 bar with a cyclohexane and ethyl acetate mixture of (60/40 by volume) and collecting fractions of 60 cm 3 . Fractions 6 to 20 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) and the residue is crystallized from an acetonitrile and diisopropyl oxide mixture. The crystals are drained and dried. 2.16 g of (4aRS,7aRS)-6-[(2-dimethylaminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 163° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[N:13]([C:16]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([C:37]([N:39]6[CH2:44][CH2:43][O:42][CH2:41][CH2:40]6)=[O:38])=[CH:33][N:32]=5)[C:27](=[O:45])[N:26]([CH3:46])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[CH2:12][CH2:11][NH:10][C:9]=2[CH:47]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[BH4-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[N:13]([C:16]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([C:37]([N:39]6[CH2:44][CH2:43][O:42][CH2:41][CH2:40]6)=[O:38])=[CH:33][N:32]=5)[C:27](=[O:45])[N:26]([CH3:46])[CH:25]=4)[C:17]=3[CH2:18][OH:19])[CH2:12][CH2:11][NH:10][C:9]=2[CH:47]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(N3CCNc4cc(C(C)(C)C)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(N3CCNc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reaction time: 0.33 h

Procedure:
The 60:40 mixture from the previous step, with the major component being 2-(8-tert-Butyl-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde, 76 mg, was dissolved in 3 mL THF, and 3 mL absolute ethanol was added. Sodium borohydride (5 mg, 1 eq), was added, and the reaction stirred for 20 minutes, during which time the reaction changed from purple color to colorless. The reaction as quenched with water, and then 1 drop glacial acetic acid was added. The mixture was extracted with ethyl acetate 3×, the organic layers combined and washed with aqueous saturated sodium bicarbonate solution and brine, dried over MgSO4, filtered, and the organic solvent removed under vacuum. The residue was chromatographed over silica gel, eluting first with methylene chloride, and then 3% methanol in methylene chloride, to give the title compound as a white solid, 33 mg, (M+H)+=637.
Reaction SMILES: C(OC([NH:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH:30]C(OCC1C=CC=CC=1)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.[H][H]>C1COCC1.C(O)C.[Pd]>[NH2:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@@H](N)Cc1ccccc1

Procedure:
A solution of 10.432 g (18.36 mmol) of compound 6 in 500 ml THF and 500 ml ethyl alcohol was stirred with 1.043 g of 10% palladium on carbon at room temperature. for 18h over 1 atmosphere hydrogen pressure. The mixture was filtered through celite pad and the filtrate was concentrated to provide 6.06 g yield) of compound 7. The oil was triturated with diethyl ether and the white solid was filtered and washed to provide pure 7 (M. P. 92-94).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[O:12]1[C:17]2=[CH:18][CH:19]=[CH:20][C:16]2=[CH:15][CH:14]=[C:13]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[O:12]1[C:17]2=[CH:18][CH:19]=[CH:20][C:16]2=[CH:15][CH:14]=[C:13]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[S:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:31])=[O:30]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1-c1ccc2cccc-2o1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccccc1-c1ccc2cccc-2o1
Reaction time: 2 h
Yield: 46 %

Procedure:
2-Aminobenzenesulfonamide (38 mg, 0.22 mmol) was dissolved in pyridine (2 ml), (E)-2-(4-benzofuran-2-ylphenyl)ethenesulfonyl chloride (70 mg, 0.22 mmol) was added and the mixture stirred for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (46 mg, 46%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:14]
Reactant: Oc1ccc(OCCCBr)cc1
Reactant: CCNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(CCCOc1ccc(O)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Compound 10a (500 mg, 2.2 mmol) and N-ethylaniline (1 g, 5.5 mmol) were reacted in acetonitrile for 30 mins before diisopropylethylamine (284 mg, 2.2 mmol) was added dropwise. The reaction mixture was then heated and stirred at 70° C. for 12 hours. After cooling to room temperature, the solvent was evaporated and the residue was purified by silica gel column chromatography to provide the compound 10 (170 mg, 0.66 mmol, 24% yield) as a pale yellow solid. MS (ESI, positive) m/z calcd. for C17H21NO2 [M+H]+: 272.16, found: 272.00. 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J=7.8 Hz, 2H), 6.88-6.66 (m, 7H), 3.99 (t, J=5.8 Hz, 2H), 3.53 (t, J=7.1 Hz, 2H), 3.41 (q, J=7.2 Hz, 2H), 2.08 (q, J=6.7 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 0.97 mmol 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (CAS: 286961-14-6) in 6 ml dimethylformamide, 2.91 mmol potassium carbonate, 1.02 mmol p-bromobenzotrifluoride, and 0.06 mmol dichlor(1,1′ bis(diphenylphosphino)ferrocene) palladium(II)dichloromethane complex were successively added. The reaction was then stirred at 80° C. for 6 hours, concentrated in vacuo and purified by column chromatography (SiO2, 20 g, heptane), to give the title compound. MS (m/e): 271.1 (M-isobuthylene)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=1.O1CCOCC1.Cl.N>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][C:24]1[NH:25][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: N#CCc1cccc(Cl)c1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.9 %

Procedure:
A mixture of 628 mg of dimethyl aminoterephthalate, 546 mg of 3-chlorophenylacetonitrile and 15 mL of 4N hydrogen chloride dioxane solution was stirred at room temperature for 7 hours. Further continuing the stirring at 30° C. for 63 hours and at 70° C. for 25 hours, ice was added to the reaction mixture, followed by addition of 7 mL of 25% aqueous ammonia. Whereupon precipitated crystals were recovered by filtration, and washed with water, ether and chloroform by the order stated. Subjecting the crystals to through-flow drying under heating, 670 mg of the title compound was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:31][CH2:30][CH2:29][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:32])=[O:8])=[CH:2]1
Reactant: O=C(O)c1cc[nH]c1
Reactant: NCCC(=O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCNC(=O)c1cc[nH]c1)OCc1ccccc1
Reaction time: 24 h

Procedure:
Into a solution of 1.67 g (15 mmol) of 3-pyrrolecarboxylic acid and 6.33 g (18 mmol) of β-alanine benzyl ester p-toluenesulfonate in 20 ml of dimethylformamide, a solution of 2.94 g (18 mmol) of diethyl phosphorocyanidate in 10 ml of dimethylformamide was added dropwise under ice cooling and stirring. A solution of 3.64 g (36 mmol) of triethylamine in 20 ml of dimethylformamide was then added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 24 hours.
Reaction SMILES: [H-].[Na+].Br[C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH:10]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([CH2:16][O:17][C:4]2[N:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCC1CCCCC1
Reactant: Brc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cnc(OCC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
NaH (1.1 equivalent) is added to an equimolar mixture of 2-bromopyrimidine and cyclohexylmethanol in THF. The reaction mixture is stirred at +60° C. for 18 hours, cooled to room temperature, partitioned between H2O and ethyl acetate. Organic portion is separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(cyclohexylmethoxy)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[C@@H:3]1[CH2:9][CH2:10][CH:11](O)[CH3:12].[OH2:15]>C1C=CC=CC=1>[C:9]([CH:3]1[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:14])[CH3:1])(=[O:15])/[CH:10]=[CH:11]/[CH3:12]
Reactant: O
Reactant: CC(O)CC[C@H]1[C@@H](C)CCCC1(C)C
Solvent: c1ccccc1
Product: C/C=C/C(=O)C1C(C)CCCC1(C)C

Procedure:
A solution of 320 g (1.5 moles) of the ketol prepared in Example 2 in 1000 ml of benzene containing 2 g p-toluene-sulphonic acid is heated in an apparatus for azeotropical water separation (Dean-Stark) till no more water separates. The reaction mixture is washed with a solution of sodium bicarbonate till neutral reaction and dried over anhydrous sodium sulfate. The solvent is removed by distillation at reduced pressure and the residue is distilled through a short Vigreux column. The product, cis, E-1-crotonoyl-2,2,6-trimethyl-cyclohexane (III, contains about 10% of the trans isomer) is collected at 76° C/1 mm; yield 273 g (94%). Recrystallization from pentane gives cis, E-1-crotonoyl-2,2,6-trimethylcyclohexane in high purity (m.p. 27°-28° C).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([NH:13][C:14](=[O:39])[CH:15]([NH:20][C:21](=[O:38])[CH:22]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]([C:40]([O:42]C(C)(C)C)=[O:41])[CH2:9]1)=O)(C)(C)C.[S:47](Cl)(Cl)(=[O:49])=[O:48]>ClCCl>[C:10]([O:42][C:40]([CH:10]1[CH:11]([NH:13][C:14](=[O:39])[CH:15]([NH:20][C:21](=[O:38])[CH:22]([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:12][N:8]([S:47]([C:35]2[CH:36]=[CH:37][C:32]([CH3:22])=[CH:33][CH:34]=2)(=[O:49])=[O:48])[CH2:9]1)=[O:41])([CH3:40])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CC1NC(=O)C(NC(=O)C(NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC(NC(=O)C(NC(=O)C(NC(=O)c3cnccn3)C3CCCCC3)C(C)(C)C)C(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 8 h
Yield: 93 %

Procedure:
The product from Example 23, Part B (100 mg, 0.17 mmol) was dissolved in dichloromethane (1.7 ml). TEA (84 ul, 0.6 mmol) was added followed by the sulfonyl chloride (65.6 mg, 0.34 mmol). The reaction was stirred overnight then loaded onto a silica plug and eluted with ethyl acetate to give the title compound as a white solid (112 mg, 93% yield). MS (APCI) m/z 699 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)[N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([NH2:30])=[O:21])[N:16]=1)=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(-c3nc(CCC(=O)O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3nc(CCC(N)=O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-4-yl)propanoic acid (0.11 g), 1H-1,2,3-benzotriazol-1-ol (40 mg) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (57 mg) at room temperature. The mixture was stirred for 20 min, and 28% aqueous ammonia (0.08 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.04 g, yield 36%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (4:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 200-201° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[OH:22].[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[C:14]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:24])[F:25])=[O:23])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Yield: 6.6 %

Procedure:
Using N-[2,5-bis(trifluoromethyl)phenyl] 5-chloro-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH3:22][N+:23]([CH3:25])=[CH2:24].[I-].O>C1COCC1>[CH3:22][N:23]([CH2:25][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19])[CH3:24]
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Reactant: C=[N+](C)C
Agent: CC(C)[N-]C(C)C
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1M of solution of lithium diisopropylamide in a 3:5 mixture of hexanes/THF (8.25 ml) is added dropwise to (3R,7aS)-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (1.51 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) in THF (5 ml) at −78° C. After stirring 30 minutes at −78° C. Eschenmoser's salt (2.78 g) is added. The reaction mixture is then allowed to warm to −40° C. with vigorous stirring over 1 hour and maintained for 2 hours at −40° C. Water is then added and the aqueous layer extracted with dichloromethane, the combined organic layers dried over sodium sulphate and evaporated. The residue is then purified by mormal phase chromatography eluting with a gradient from dichloromethane to 20% ethyl acetate in dichloromethane to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH:8][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CCCC=O
Product: CCCCNc1cccc(C(C)(C)C)c1
Yield: 87.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3-tert-butylaniline (500 mg, 3.35 mmol) and butyraldehyde (300 μL, 3.35 mmol) were converted to the title compound (600 mg, 80%). 1H NMR (CDCl3) δ 7.15 (t, J=7.8 Hz, 1H), 6.79-6.74 (m, 1H), 6.66 (t, J=2.1 Hz, 1H), 6.47 (ddd, J=8.0, 2.3, 0.7 Hz, 1H), 3.61 (br s, 1H), 3.14 (t, J=7.0 Hz, 2H), 1.69-1.55 (m, 2H), 1.53-1.42 (m, 2H), 1.32 (s, 9H), 0.99 (t, J=7.3 Hz, 3H).