Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[N:7]([C@@H:10]1[C@@H:14]([CH2:15][OH:16])[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11]1)=[N+:8]=[N-:9].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([O:16][CH2:15][C@H:14]1[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11][C@@H:10]1[N:7]=[N+:8]=[N-:9])(=[O:28])[CH3:27]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 8 h

Procedure:
To a pyridine (50 ml) solution of 3'-azido-3'-deoxythymidine (5.0 g, 18.7 mmole) 1 was added acetic anhydride dropwise in an ice-water bath. The mixture was allowed to stand overnight in the refrigerator. The solution was then poured into CHCl3 (20 ml), washed with H2O (200 ml×2), with a saturated solution of sodium bicarbonate and then H2O (200 ml×2). The organic layer was then dried (MgSO4). After removing the solvent, a syrup (6.5 g) was obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])(=O)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:22][C:21]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:22][C:21]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:42][CH:43]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCC(F)F)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.3 %

Procedure:
2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (53 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a reaction flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (98 mg, 0.30 mmol) was added to the flask, and the resulting mixture was stirred for 48 hr at room temperature. The reaction was diluted with diethyl ether (50 mL) and the organic layer was washed with an aqueous solution of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 ml), after which it was dried over sodium sulfate, filtered and concentrated en vacuo. The residue was purified by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.6 mg, 5.0%). 1H NMR (CDCl3, 300 MHz); δ 7.33 (d, 1H, J=11.2 Hz), 7.15 (d, 1H, J=11.2 Hz), 7.14 (s, 1H), 7.06 (d, 2H, J=11.6 Hz), 6.79 (d, 2H, J=11.6 Hz), 5.86 (tt, 1H, J1=5.2 Hz, J2=66.4 Hz), 4.07-3.98 (m, 3H), 3.87-3.84 (m, 3 H), 3.84-3.71 (m, 2H), 3.74 (td, 2H, J1=5.6 Hz, J2=18.4 Hz), 3.66-3.54 (m, 3 H), 3.30-3.36 (m, 2H), 2.78 (br s, 1H), 2.42 (br s, 1H), 1.65 (s, 2H); LC/MS: theoretical mass=488.14; observed M+1=489.2, M+Na=511.4).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([SH:11])[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[OH-].[Na+].Cl.[CH3:18][C:19]1[C:20]([CH2:26]Cl)=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25]>CO.O>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:26][C:20]3[C:19]([CH3:18])=[C:24]([CH3:25])[CH:23]=[CH:22][N:21]=3)[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14]
Reactant: Cc1ccnc(CCl)c1C
Reactant: COc1c(C)cc2[nH]c(S)nc2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)cc2[nH]c(SCc3nccc(C)c3C)nc2c1C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To 4,6-dimethyl-5-methoxy-2-mercapto-1H-benzimidazole (1.04 g, 0.0050 mol) in methanol (50 ml) were added (in the following order) NaOH (0.2 g, 0.0050 mol) dissolved in water (2 ml) and 3,4-dimethyl-2-chloromethylpyridine hydrochloride (0.96 g, 0.0050 mol). The mixture was heated until reflux. NaOH (0.2 g, 0.0050 mol) dissolved in water (2 ml) was added dropwise and then the reflux was continued for 3 hours. The mixture was poured on ice-water (200 ml). Filtration and recrystallization from CH3CN gave the desired product (1.1 g, 67%). NMR data for the final product is given below.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17](Br)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH:23]1([SH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[H-].[Na+].N#N>CN(C=O)C>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([S:29][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccc(Br)nc2)cc1
Reactant: SC1CCCCC1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(SC3CCCCC3)nc2)cc1
Temperature: 110 °C

Procedure:
The compound from Example 1, Step 3 (0.16 g 0.45 mmol), cyclohexyl mercaptan (0.16 g, 1.35. mmol) and sodium hydride (60% dispersion in oil, 4.0 equiv, 0.032 g) were suspended in DMF (0.5 mL) in an N2 purged sealed tube and heated at 110° C. for 4hr. The residue was dissolved in methanol and purified on a C18 preperative hplc column. Lyophilized from dioxane/HCl to provide the title compound. FAB-MS: calc: 389 found: 389. 1H-NMR (CD3OD): 1.4-2.1 ppm (10H); 3.8 ppm (1H); 4.2 ppm (2H); 5.45 ppm (2H); 7.2-7.6 ppm (7H); 8.2 ppm (1H); 9.1 ppm (1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:27])[C:12]2[CH:13]=[CH:14][C:15]([CH3:26])=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:27])[C:12]2[CH:13]=[CH:14][C:15]([CH3:26])=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccnc3Cl)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N(C)S(=O)(=O)c2cccnc2Cl)c2[nH]c(C(=O)O)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 7-[[(2-chloropyridin-3-yl)sulfonyl](methyl)amino]-4-methyl-1H-indole-2-carboxylate (0.86 g), 1N aqueous sodium hydroxide solution (4.2 mL), methanol (6 mL) and tetrahydrofuran (6 mL) was stirred at 50° C. for 1 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was concentrated. The resulting crystals were collected by filtration, washed with water, dried, and concentrated to give 7-[[(2-chloropyridin-3-yl)sulfonyl](methyl)amino]-4-methyl-1H-indole-2-carboxylic acid as crude crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])=[C:7]([CH3:18])[C:6]=2[CH:19]=1.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:12]1([C:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([N:20]4[CH2:25][CH2:24][S:23][CH2:22][CH2:21]4)=[CH:19][C:6]=3[C:7]=2[CH3:18])=[O:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CSCCN1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(Br)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(N3CCSCC3)cc12
Temperature: 25 °C
Yield: 103.5 %

Procedure:
To a solution (15 mL) of (5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanone (0.75 g) synthesized in Example A174(1) in toluene were added thiomorpholine (0.72 g), cesium carbonate (2.3 g), tris(dibenzylideneacetone)dipalladium (0) (0.16 g) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.2 g), and the mixture was heated under reflux under argon atmosphere for 18 hr. The reaction mixture was cooled to room temperature and filtered through celite, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was concentrated to give a crude product (0.83 g, quantitative) of the title object compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][O:53][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:50])[F:51])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][OH:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CO
Solvent: CC(=O)Cl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 34.5 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 12g (4.10 g, 4.78 mmol) was dissolved in 30 mL methanol, followed by addition of acetyl chloride (51 μL, 0.72 mmol). The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoro-ethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 12h (1.23 g, white grease), yield: 34.6%.
Reaction SMILES: [CH:1]1[C:10]2C(=CC=CC=2)C=C[CH:2]=1.C(C1C2C(=CC=CC=2)C=CC=1)(C)C.[CH:24]([C:27]1[C:28](C(C)C)=[C:29](C(C)C)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:26])[CH3:25]>>[CH:24]([C:27]1[CH:28]=[CH:29][C:30]2[C:35](=[CH:34][CH:33]=[C:32]([CH:1]([CH3:10])[CH3:2])[CH:31]=2)[CH:36]=1)([CH3:25])[CH3:26]
Reactant: c1ccc2ccccc2c1
Reactant: CC(C)c1cc2ccccc2c(C(C)C)c1C(C)C
Agent: CC(C)c1cccc2ccccc12
Product: CC(C)c1ccc2cc(C(C)C)ccc2c1

Procedure:
Substantially pure 2,6-diisopropylnaphthalene can be recovered from the diisopropylnaphthalene products in a multi-stage separation scheme. In one embodiment, the diisopropylnaphthalene product is first fractionally distilled to obtain a low boiling fraction which contains unreacted naphthalene and monoisopropylnaphthalene, a middle fraction containing the diisopropylnaphthalenes, and a high boiling fraction containing triisopropylnaphthalene and tetraisopropylnaphthalenes. 2,6-diisopropylnaphthalene is obtained from the middle fraction by cooling the liquid to a temperature between 0° C. and -20° C. to fractionally crystallize the 2,6-isomer from the other diisopropylnaphthalenes. The mother liquor from the crystallization can be subjected to a second crystallization step, or it can then be combined with the low boiling and high boiling fractions, and subjected to transalkylation before recycle to the alkylation reactor, along with fresh naphthalene.
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:25][CH3:26])[C:5]1=[O:33])C=C.C(#N)C.I([O-])(=O)(=O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC[O:59][C:60]([CH3:62])=[O:61]>O.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@H:24]([C:27](=[O:32])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:25][CH3:26])[C:5](=[O:33])[C@:4]([CH2:62][C:60]([OH:59])=[O:61])([CH3:1])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CC(C)C)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC[C@@H](C(=O)CC(C)C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a rapidly stirring solution of 120 mg (0.239 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydroxy-6-methylheptan-3-yl)-3-methylpiperidin-2-one (Example 204, Step A) in a mixture of 1.5 mL of water, 1.0 mL of acetonitrile and 1.0 mL of CCl4 was added sodium periodate (204 mg, 0.995 mmol), followed by ruthenium(III) chloride hydrate (5.38 mg, 0.024 mmol). After being stirred vigorously for 2 h, the reaction was acidified (10% citric acid) and diluted with EtOAc. The reaction mixture was filtered through Celite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth) and the filtrate was extracted with EtOAc. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by the flash chromatography on silica gel (eluent: 10 to 20% iPrOH/hexane, gradient elution) to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[C:6]([CH2:13][CH3:14])[N:5]=1)C.[CH2:15](OC(C1C=C(CCC)N=C(S(C)(=O)=O)N=1)=O)C.CC([O-])(C)C.[K+]>CO>[CH3:1][O:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[C:6]([CH2:13][CH2:14][CH3:15])[N:5]=1
Reactant: CCOc1nc(CC)cc(C(=O)O)n1
Reactant: CCCc1cc(C(=O)OCC)nc(S(C)(=O)=O)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CCCc1cc(C(=O)O)nc(OC)n1

Procedure:
The title compound is obtained as a beige solid (84 mg) in analogy to 2-ethoxy-6-ethyl-pyrimidine-4-carboxylic acid starting from 2-methanesulfonyl-6-propyl-pyrimidine-4-carboxylic acid ethyl ester, KOtBu and methanol; LC-MS: tR=0.71 min, [M+H]+=196.96.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:11]=2[C:10]=1[OH:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:24].C(OC(C)C)(C)C.C(OCC)(=O)C>>[NH2:24]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:19])[C:11]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: [NH4+]
Reactant: Cc1cccc2sc(C(=O)c3ccccc3)c(O)c12
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1cccc2c1C(=O)/C(=C(\N)c1ccccc1)S2
Yield: 50 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-4-methyl-benzo[b]thiophen-3-ol and ammonium acetate with a yield of 50% of theory. M.p. 198°-200° C. (diisopropyl ether/ethyl acetate 2:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[Br:12][C:13]1[CH:18]=[C:17](/[C:19](/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[C:34]#[N:35])=[N:20]\S(C(C)(C)C)=O)[CH:16]=[CH:15][N:14]=1>>[Br:12][C:13]1[CH:18]=[C:17]([C:19]2([C:2]3[CH:3]=[C:4]([CH3:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=3)[C:27]3[C:28](=[C:29]([F:33])[CH:30]=[CH:31][CH:32]=3)[C:34]([NH2:35])=[N:20]2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1c(C)cc(Br)cc1F
Reactant: CC(C)(C)S(=O)/N=C(\c1ccnc(Br)c1)c1cccc(F)c1C#N
Product: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)cc1F

Procedure:
The title compound was synthesized as described in Example 24i starting from 5-bromo-1-fluoro-2-methoxy-3-methylbenzene (177 mg, 0.81 mmol) and (E)-N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) to give the title compound which was used without further purification (330 mg, 99%). MS (ES+) m/z 444, 446 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]([CH2:19][C:20]2[NH:21][CH:22]=[N:23][CH:24]=2)[CH:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[N:23]1[CH:24]=[C:20]([CH2:19][N:15]([CH:16]([CH3:18])[CH3:17])[C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[NH:21][CH:22]=1
Reactant: CC(C)N(Cc1cnc[nH]1)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(Cc1cnc[nH]1)c1cccc(O)c1
Reaction time: 8 h

Procedure:
(3-Benzyloxy-phenyl)-(3H-imidazol-4-ylmethyl)-isopropyl-amine (0.109 g, 0.34 mmol) was dissolved in ethanol (10 ml), palladium on charcoal (10 mg, 10% Pd) was added and the mixture was hydrogenated overnight at room temperature. The catalyst was filtered off and the solvent was evaporated. The residue was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/methanol=95:5) to yield a white foam, (0.042 g, 53%); MS (ISP): 232.1 ((M+H)+.).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[CH3:10][C:11]1([CH3:18])[CH2:16][NH:15]C(=O)[CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:10][C:11]1([CH3:18])[CH2:12][CH2:13][C:6]([O:7][CH3:9])=[N:15][CH2:16]1
Reactant: C[O+](C)C
Reactant: CC1(C)CCC(=O)NC1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCC(C)(C)CC1
Reaction time: 14 h

Procedure:
Trimethyloxonium tetrafluoroborate (97%, 11.9 g, 78 mmol) was added to the dry dichloromethane (156 mL) solution of 5,5-dimethyl-2-piperidone (9.93 g, 78 mmol) at room temperature and stirred for 14 h. The reaction mixture was neutralized with 10% sodium hydrogen carbonate aqueous solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×120 mL), then the combined organic layer was washed with 10% sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the titled compound was obtained as pale yellow oil (9.0 g, 82.0%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][N:8]1[C:12](=[O:13])[C:11](=[O:14])[NH:10][C:9]1=[S:15]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:10]1[C:11](=[O:14])[C:12](=[O:13])[N:8]([CH3:7])[C:9]1=[S:15]
Reactant: BrCCCCBr
Reactant: CN1C(=O)C(=O)NC1=S
Product: CN1C(=O)C(=O)N(CCCCBr)C1=S

Procedure:
By the procedure of Example 1(i), 1,4-dibromobutane is reacted with 1-methyl-2-thioxo-4,5-imidazolidinedione to yield 1-(4-bromobutyl)-3-methyl-2-thioxo-4,5-imidazolidinedione which, on reaction with thiourea by the procedure of Example 1(ii) gives S-[4-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))butyl]isothiourea hydrobromide, m.p. 113°-114°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:4][CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])([OH:9])[CH3:17])=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1F
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Cl)cc1)c1ccccc1F
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-chlorophenyl)-(2-fluorophenyl)-methanone (200 mg, 0.717 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:31][CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:30])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:21])[F:23])[O:18][N:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NC1CCOCC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 86 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (100 mg, 0.24 mmol), was converted, using 4-aminotetrahydropyran instead of cyclopropanemethylamine, to the title compound (110 mg, 86%) which was obtained as a white solid. MS: m/e=484.2 [M+H]+.
Reaction SMILES: [Na+].CS([CH2-])=O.[Br-].[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:9])=[O:8].[CH:33](=O)[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1>CS(C)=O>[O:38]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:33]=[CH:13][CH2:12][CH2:11][CH2:10][C:7]([OH:9])=[O:8]
Reactant: O=Cc1ccco1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [CH2-]S(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=Cc1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of dimsyl sodium (prepared by heating 4.35 g. of 50% oil dispersion of sodium hydride in 50 ml. dimethylsulfoxide at 60° for 2 hours under argon) is added dropwise 20.0 g. of (4-carboxybutyl)triphenylphosphonium bromide in 90 ml. dimethylsulfoxide. After the solution has stirred at room temperature for one hour, a solution of 4.34 g. furfural in 20 ml. dimethylsulfoxide is added dropwise to the cool (15°) solution over 20 minutes. After 2 hours the dimethylsulfoxide is evaporated, the residue is dissolved in 100 ml. water, filtered and extracted four times with 150 ml. portions of ethyl acetate. The aqueous solution is acidified to pH 1 with 1 N hydrochloric acid, saturated with sodium chloride and extracted twice with 150 ml. portions of ethyl ether. The ether is dried and evaporated to yield the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(Cl)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-chloro-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2B) (0.10 g, 0.35 mmol), 2-chloro-5-fluoro-pyrimidine (0.047 g, 0.35 mmol) and triethylamine (0.099 mL, 0.71 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-chloro-benzyl ester. M.S.(M+1):379.26
Reaction SMILES: [CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:28][NH:29]C(OC(C)(C)C)=O)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[NH2:25])=[C:20]([F:27])[CH:19]=2)=[O:16])=[CH:10][CH:9]=1)=[O:5].Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:28][NH2:29])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[NH2:25])=[C:20]([F:27])[CH:19]=2)=[O:16])=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc(C(N)=O)c(F)c3)cc2)c(C)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)OCc2ccc(C(CN)C(=O)Nc3ccc(C(N)=O)c(F)c3)cc2)c(C)c1
Reaction time: 8 h

Procedure:
To 4-(3-(tert-butoxycarbonylamino)-1-(4-carbamoyl-3-fluorophenylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E337-2) in CH2Cl2 was added HCl (4 N in dioxane) and the solution was stirred overnight. The solvents were evaporated to give pure 4-(3-amino-1-(4-carbamoyl-3-fluorophenylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E338).