Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NN1CCCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NN1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 1.7 %

Procedure:
A cold (−40° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.35 g) in 1:1 CH2Cl2:EtOAc (200 mL) was treated with 1-aminopyrrolidine HCl (0.134 g). The mixture was then treated with T3P (50% in EtOAc; 0.77 ml, 1.3 eq.) followed by the slow addition of DIPEA (0.51 ml, 3.0 eq.). The reaction mixture was stirred for 30 min at −40° C. before being quenched with ice-water, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous saturated brine, dried with anhydrous Na2SO4 and concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.275 g of crude solid. Purification by column chromatography on silica gel (60-120 mesh size) using MeOH in CH2Cl2 as mobile phase afforded the pure desired (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrrolidin-1-yl)acrylamide (7.0 mg yield: 1.7%): 1H NMR (400 MHz, DMSO-d6) δ, 9.49 (s, 1H), 8.95 (s, 1H), 8.53 (s, 2H), 8.28 (s, 1H), 7.4-7.38 (d, J=7.6 Hz, 1H), 5.87-5.84 (d, J=10.4 Hz, 1H), 2.86-2.81 (m, 4H), 1.74-1.73 (m, 4H); LCMS for C17H16F6N5O [M+H]+ 420.33. found 420.13 (RT 7.76 min, purity: 92.4%).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[OH-].[Na+].[F:12][C:13]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>C(O)C.O>[Cl:21][C:20]1[C:13]([F:12])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: Fc1c(Cl)cccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1cc(O)nc(SCc2cccc(Cl)c2F)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a slurry of 2-mercapto-4,6-pyrimidinediol (64.6 g) in ethanol (387 ml) and H2O (387 ml) was added sodium hydroxide (18 g) in H2O (82 ml) Causing almost a complete solution to form. 2-Fluoro-3-chloro-benzylbromide (100 g) in ethanol (82 ml) was then added dropwise over 30 min causing a thick precipitate to form. Stirring was continued for a further 4 h and the whole then cooled to 0° C. before filtering the white solid formed and then washing with water. The collected solid was dried in vacuo at 50° C. for 48 h leaving the subtitle compound as a white solid. Yield: 125.7 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[O:26])[CH2:20][C@@H:19]1[C:36](O)=[O:37])=[O:17])([CH3:14])([CH3:13])[CH3:12].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[NH:10][C:36]([C@H:19]1[CH2:20][C@H:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[O:26])[CH2:22][CH2:23][N:18]1[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)O
Reactant: Cc1cc(N)c(N)cc1C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(N)c(NC(=O)[C@H]2C[C@H](NC(=O)Nc3ccc(C#N)cc3)CCN2C(=O)OC(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
4,5-dimethylbenzene-1,2-diamine (39 mg, 0.286 mmol) was added to a mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido)piperidine-2-carboxylic acid (100 mg, 0.258 mmol), BOP (120 mg, 0.27 mmol) and DIEA (0.09 mL, 0.52 mmol) in DMF (1 mL), and the resulting solution was stirred at room temperature for 8 hours. Water (10 mL) was added to the reaction mixture and then extracted with ethyl acetate (2×20 mL). The organic layers were dried over MgSO4 and concentrated to give a red solid. Purification was done by Companion (ReadySep, 12 g, silica gel packed) with ethyl acetate/heptane from 50-80% to give the title compound as a white solid 104 mg (80%). LC-MS: 507.3, 505.4 (t=2.4 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[C:8]([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)=[O:10])[CH3:16]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C1CCN(C)CC1

Procedure:
reacting 1-methylpiperidine-4-carboxylic acid with thionyl chloride and diethyl amine to yield N,N-diethyl-1-methylpiperidine-4-carboxamide;
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][N:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]1=[O:24].C1C=CC2N(O)N=NC=2C=1.[CH3:35][O:36][C:37]1[N:42]=[C:41](/[CH:43]=[CH:44]/[C:45](O)=[O:46])[CH:40]=[CH:39][C:38]=1[N:48]1[CH:52]=[C:51]([CH3:53])[N:50]=[CH:49]1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:13]2[CH2:14][CH2:15][CH2:16][N:11]([NH:10][C:45](=[O:46])/[CH:44]=[CH:43]/[C:41]3[CH:40]=[CH:39][C:38]([N:48]4[CH:52]=[C:51]([CH3:53])[N:50]=[CH:49]4)=[C:37]([O:36][CH3:35])[N:42]=3)[C:12]2=[O:24])=[CH:22][CH:21]=1
Reactant: COc1nc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN1CCCN(c2ccc(Cl)cc2)C1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1nc(/C=C/C(=O)NN2CCCN(c3ccc(Cl)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
IPEA (0.65 mL), 1-amino-3-(4-chlorophenyl)tetrahydropyrimidin-2-one (139 mg), EDC (177 mg) and HOBT (125 mg) were added to a solution of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid (300 mg) in DMF (6 mL) at room temperature. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 287 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:23]#[N:24])([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].C(OCC)(=O)C>>[ClH:25].[C:23]([C:11]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:24]
Reactant: Cc1ccccc1OCC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1OCC1(C#N)CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
After adding 10 ml of 4N hydrogen chloride/ethyl acetate to 273 mg of 1-(tert-butoxycarbonyl)-4-cyano-4-(2-methylphenoxymethyl)piperidine, the mixture was stirred for 6 hours at room temperature. The solvent was distilled off under reduced pressure to obtain 336 mg of 4-cyano-4-(2-methylphenoxymethyl)piperidine hydrochloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12]>C1COCC1.O>[OH:13][C:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:16][CH2:15]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1nccs1)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (740 mg, 8.72 mmol) in THF (87 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 3.84 mL, 9.59 mmol) and the solution was stirred for 30 minutes at −78° C. A solution of benzyl (trans-4-acetylcyclohexyl)carbamate (1.20 g, 4.36 mmol) in THF (5 mL) was added and the reaction was stirred for one hour at −78° C. The reaction was diluted with water and warmed to room temperature. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography on silica gel (0-10% methanol gradient in dichloromethane) afforded benzyl {trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexyl}carbamate MS ESI calc'd. for C19H25N2O3S [M+H]+ 361. found 361. 1H NMR (500 MHz, DMSO-d6) δ 7.67 (d, J=3.2, 1H), 7.51 (d, J=3.2, 1H), 7.40-7.20 (m, 4H), 7.12 (d, J=8.0, 1H), 5.70 (s, 1H), 4.95 (s, 2H), 3.19-2.98 (m, 1H), 1.88-1.66 (m, 3H), 1.65-1.49 (m, 1H), 1.47-1.33 (m, 4H), 1.28-1.14 (m, 1H), 1.14-0.89 (m, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[NH:13][C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[NH:13][C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(OCc3ccccc3)ccc2N1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CC1=NS(=O)(=O)c2cc(O)ccc2N1

Procedure:
The product of Example 307A (1.42 g, 3.79 mmol) in tetrahydrofuran (60 mL) was reacted with 10% palladium on carbon (0.2 g) under hydrogen atmosphere for 16 hours at 25° C. The reaction mixture was filtered and concentrated under reduced pressure to an oil. The residue was purified on silica gel eluting with ethyl acetate to give the title compound as of a white solid (0.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([Si:14]1(C2C=CC=CC=2)[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH:12]=[CH2:13]>>[CH2:9]([Si@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:21])[CH2:18][CH2:19]1)[CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1ccc(F)cc1
Product: C=CCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(F)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using (4-fluorophenol and 4-(4-pentenyl)-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.CN(C)C(=O)C(F)(F)F>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27](=[O:32])[C:28]([F:31])([F:29])[F:30])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(C(=O)C(F)(F)F)o1
Agent: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Agent: CN(C)C(=O)C(F)(F)F
Product: O=C(CCCCCCc1ccccc1)c1ncc(C(=O)C(F)(F)F)o1
Yield: 58 %

Procedure:
1-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)-2,2,2-trifluoroethanone. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazole (100 mg, 0.268 mmol) and N,N-dimethyltrifluoroacetamide following General Procedure K. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (73 mg, 58%): 1H NMR (CDCl3, 600 MHz) δ 8.01 (s, 1H), 7.28-7.26 (m, 2H), 7.18-7.16 (m, 3H), 4.90 (t, 1H, J=7.0 Hz), 2.60 (t, 2H, J=7.5 Hz), 1.96-1.88 (m, 2H), 1.63-1.60 (m, 2H), 1.44-1.35 (m, 6H), 0.90 (s, 9H), 0.09 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 172.8, 169.2 (q, J=39 Hz), 145.1, 143.5, 140.6, 1292, 129.1, 126.5, 116.6 (q, J=287 Hz), 69.5, 37.1, 36.8, 32.2, 30.0, 29.9, 26.5, 25.7, 19.1, −4.2, −4.3.
Reaction SMILES: OCC[N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].CC1(C)NC(C)(C)CC(=O)C1>O>[CH3:13][C:5]1([CH3:14])[CH2:6][CH:7]([OH:12])[CH2:8][C:9]([CH3:11])([CH3:10])[NH:4]1
Reactant: CC1(C)CC(O)CC(C)(C)N1CCO
Agent: CC1(C)CC(=O)CC(C)(C)N1
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)N1

Procedure:
Accordingly, the invention relates to a process for the preparation of 1-(2-hydroxyethyl)-2,2,6,6-tetramethyl-4-piperidinol from triacetoneamine, which comprises reducing triacetoneamine in a manner known per se by catalytic hydrogenation in water or in a polar organic solvent or in a mixture thereof with water, to give 2,2,6,6-tetramethyl-4-piperidinol, adding a catalytic amount of an inorganic or organic acid to the solution of 2,2,6,6-tetramethyl-4-piperidinol as obtained or after concentrating the solution by distillation, without further purification and/or isolation of the intermediate, with the proviso that, if the solution of the intermediate is concentrated, the addition of acid is made before or after the distillation, and that the concentrated solution or melt may be diluted again with the same solvent or with another solvent, and subsequently reacting said solution or melt of 2,2,6,6-tetramethyl-4-piperidinol with ethylene oxide in a molar excess of 1-35% in the temperature range from 60°-170° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:8]1>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](c2ccccn2)C1
Solvent: CCO
Product: N[C@H]1CC[C@H](c2ccccn2)C1
Yield: 91.8 %

Procedure:
A mixture of (1S,3S)-N-[3-(2-pyridyl)cyclopentyl]phthalimide (4.12 g, 14.1 mmol), and hydrazinemonohydorate (2.0 mL, 41.2 mmol) in EtOH (100 mL) was stirred at reflux for 3 h. After cooling, the reaction mixture was filtered followed by the removal of solvent. The residue was suspended in EtOAc and stirred at reflux for 1 h. After cooling, the precipitate was filtered followed by the removal of solvent to yield (1S,3S)-3-(2-pyridyl)cyclopentylamine (2.10 g, 92%) as yellow oil.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>>[CH2:1]([S:19][CH2:20][CH:21]([OH:22])[CH2:23][OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: OCC1CO1
Product: CCCCCCCCCCCCCCCCCCSCC(O)CO

Procedure:
The octadecyl mercaptan is then condensed with 4 moles glycidol per mole octadecyl mercaptan, by first introducing a first molar equivalent of glycidol to obtain 3-octadecylthio-propane-1,2 diol at 80° C, the rest of the glycidol then being introduced at 155° C in the course of 2 hours 20 minutes.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[CH2:15][OH:16])=[CH:5][CH:4]=1)[CH3:2].O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([CH3:31])[C:19]=1[CH3:32].C(C1C=CC(C2C=C(C)SC=2COC2C(F)=CC(CCC(OCC)=O)=CC=2F)=CC=1)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[CH2:15][O:16][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH3:31])[C:19]=2[CH3:32])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2cc(C)sc2CO)cc1
Agent: CCOC(=O)CCc1cc(F)c(OCc2sc(C)cc2-c2ccc(CC)cc2)c(F)c1
Product: CCc1ccc(-c2cc(C)sc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 207 by coupling of (3-(4-ethylphenyl)-5-methylthiophen-2-yl)methanol and ethyl 3-(4-hydroxy-2,3-dimethyl phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-methylthiophen-2-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=7.5 Hz, 2H), 7.26 (s, 1H), 7.18 (d, J=7.5 Hz, 2H), 6.95 (d, J=7.0 Hz, 1H), 6.64 (d, J=7.1 Hz, 1H), 5.05 (s, 2H), 2.95 (t, J=6.5 Hz, 2H), 2.68 (m, J=7.5 Hz, 2H), 2.58 (t, J=6.2 Hz, 2H), 2.51 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.26 (t, J=8.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.Cl.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[CH:14]1([N:13]([CH3:12])[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CNC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(c1ccnc2[nH]ccc12)C1CCCCC1
Temperature: 180 °C
Reaction time: 5 h
Yield: 14.8 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (224 mg) and N-methylcyclohexanamine hydrochloride (1.1g) was combined and stirred at 180° C. for 5 hours under nitrogen atmosphere. After cooled, the reaction mixture was dissolved in chloroform (20ml), washed with saturated aqueous sodium hydrogencarbonate (10ml) and brine, dried over MgSO4, and evaporated in vacuo to give crude red oil. The residue was purified by flash column chromatography over NH-silica gel with a EtOAc as eluant. The fractions containing the object compound were combined, and evaporated under reduced pressure. The residue was washed with ether to give N-cyclohexyl-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine (49.8 mg) as a pale yellow solid.
Reaction SMILES: C([NH:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[N:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([NH:19][C:20](=[O:23])[O:21][CH3:22])[NH:13]3)=[CH:7][CH:6]=1)(=O)C.Cl>O>[NH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[N:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([NH:19][C:20](=[O:23])[O:21][CH3:22])[NH:13]3)=[CH:7][CH:6]=1
Reactant: COC(=O)NC1Nc2ccc(Oc3ccc(NC(C)=O)cc3)nc2N1
Agent: Cl
Solvent: O
Product: COC(=O)NC1Nc2ccc(Oc3ccc(N)cc3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To the MeOH solution, 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.73 g, 8.4 mmol) was added and stirred at 75° C. After 8 days, AcOH (15 mL) was added and stirred at 80° C. overnight. Additional 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.73 g, 8.4 mmol) was added then stirred at 80° C. overnight. After cooling, the mixture was poured into NaHCO3 (aq). Formed precipitate was collected by filtration, washed with ethyl acetate then dried under reduced pressure to give methyl (5-(4-acetoamidophenoxy)-3,4-diazaindolin-2-yl)carbamate (983.0 mg, 41%). To a solution of methyl (5-(4-acetoamidophenoxy)-3,4-diazaindolin-2-yl)carbamate (102.4 mg, 0.3 mmol) in water (3 mL) was added 2N HCl (aq) (3.0 mL) then refluxed for 1 hr and stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate. The organic layer was washed with NH4OH (aq), dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (33.6 mg, 37%): MS m/e 342 (M+1).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[N+](=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[N-]>C(Cl)Cl>[C:20]1([C:18]2[O:19][C:12]([CH2:11][C:10]#[N:14])=[N:13][CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Reactant: N#CCC#N
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: N#CCc1ncc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
BF3.Et2O (1.1 mL, 8.5 mmol) was added dropwise to a solution of malononitrile (2.26 g, 34.2 mmol) in dry CH2Cl2 (20 mL) at 0° C., followed by addition of 2-diazo-1-phenylethanone (0.5 g, 3.4 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h and then quenched with aqueous 10% NaOH solution. The organic product was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleum ether) to get 2-(5-phenyloxazol-2-yl)acetonitrile (200 mg, yield 32%) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.66-7.63 (m, 2H), 7.47-7.38 (m, 3H), 7.32 (s, 1H), 4.02 (s, 2H). MS (ESI) m/z: Calculated for C11H8N2O: 184.06. found: 185.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1cc2nccc(O)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC

Procedure:
L1 was prepared from 6,7-dimethoxyquinolin-4-ol and 4-fluoro-nitrobenzene following the general procedure reported in Preparative Example 1 Step 1-2. 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.91 (s, 3H), 3.92 (s, 3H), 5.16 (br s, 2H), 6.36 (d, J=5.3 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 7.34 (s, 1H), 7.49 (s, 1H), 8.41 (d, J=5.3 Hz, 1H). MS (ES) C17H16N2O3 requires: 296. Found: 297 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([F:20])(=[O:19])=[O:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](O)(=[O:26])[CH2:22][C:23](O)=[O:24].C(Cl)(=O)C>O>[CH:1]1([N:7]2[C:21](=[O:26])[CH2:22][C:23](=[O:24])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([F:20])(=[O:19])=[O:18])[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccccc1S(=O)(=O)F)NC1CCCCC1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)Cl
Solvent: O
Product: O=C1CC(=O)N(C2CCCCC2)C(=O)N1c1ccccc1S(=O)(=O)F
Temperature: 25 °C

Procedure:
A mixture of N-cyclohexyl-N'-(2-fluorosulphonylphenyl) urea (300 g, 1 mole), malonic acid (156 g, 1 mole) and acetylchloride (427 ml, 6 moles) was refluxed for 4 hours with stirring, cooled to room temperature, poured into water (4.25 l) and stirred for 1 hour to decompose the excess of acetylchloride. Then the 1-cyclohexyl-3-(2-fluorosulphonylphenyl)barbituric acid formed was added with portions and with stirring to 1N ammoniumhydroxide (5 l, 5 moles). After the last addition, stirring was continued for still an hour. Some insoluble material was filtered off and the filtrate was carefully acidified with 6N sulphuric acid (835 ml) whilst cooling by the addition of crushed ice. After 1 hour the precipitate was collected, digested with water (2.5 l), filtered off and dried, yielding 180-270 g of a product containing 69-81% of the desired barbituric acid (by titration of the CH2), the remaining 19-31% consisting mainly of 1-cyclohexyl-2-acetyl-3-(2-sulphamoylphenyl)barbituric acid, as determined by TLC and NMR.