Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Br:12]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2
Reactant: Cc1ccc2ncccc2c1
Reactant: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2ncc(Br)cc2c1
Temperature: 80 °C

Procedure:
6-Methylquinoline (1.9906 g, 13.903 mmol) was dissolved in 20 mL of carbon tetrachloride. Bromine (0.72 mL, 14 mmol) was added dropwise to the reaction solution and the suspension was heated to reflux (80° C.). Pyridine (1.15 mL, 13.9 mmol) was added while reaction was heating to 80° C. and the reaction was allowed to stir at reflux for 1.5 hours. The reaction was cooled to room temperature and diluted with dichloromethane. The reaction was washed with water and the organic was dried over sodium sulfate, filtered and concentrated to give a thick brown oil that solidified upon standing. The crude solid was purified on an 80 g silica gel ISCO column eluting with a very slow gradient: 0% to 15% to 20% ethyl acetate in heptanes to give the desired 3-bromo-6-methylquinoline. 1H NMR (400 MHz, CDCl3) δ ppm 2.52 (s, 3 H) 7.47 (s, 1 H) 7.54 (dd, J=8.59, 1.95 Hz, 1 H) 7.95 (d, J=8.59 Hz, 1 H) 8.19 (d, J=2.15 Hz, 1 H) 8.81 (d, J=2.34 Hz, 1 H). GCMS=221 at 2.93 minutes.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1F
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
2-Fluoroaniline (1.45 mL, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH4Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 1.4 g 2-fluoro-N-(2-nitrophenyl)aniline that was carried on directly to the next step. MS (ES) m/z 232.9.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]=O)[CH2:19][CH2:18]2.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]=[C:31]1[S:27][C:28](=[O:33])[NH:29][C:30]1=[O:32])[CH2:19][CH2:18]2
Reactant: O=C1CSC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2c(c1)CCC(C=O)=C2
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(c1)CCC(C=C1SC(=O)NC1=O)=C2
Yield: 50 %

Procedure:
According to the same manner as that described in Example 1, 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3,4-dihydro-2-naphthoaldehyde was condensed with 2,4-thiazolidinedione to give 5-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3,4-dihydro-2-naphthylmethylidene]-2,4-thiazolidinedione (yield: 50%). This product was recrystallized from dichloromethane-methanol. Yellow needles, mp: 271-272° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C@@H:12]([OH:17])[CH2:13][C:14](O)=[O:15])#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.S(=O)(=O)(O)O>[CH2:1]([O:8][C:14](=[O:15])[CH2:13][C@H:12]([OH:17])[CH2:11][C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC[C@@H](O)CC(=O)O
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: N#CC[C@@H](O)CC(=O)OCc1ccccc1
Yield: 71.6 %

Procedure:
Benzylalcohol (216 g, 2 eq.) and conc. sulfuric acid (5 g) were added to (R)-4-cyano-3-hydroxybutyric acid (1.0 mol) dissolved in acetonitrile (500 ml) and refluxed for 5 hours. The reaction mixture was neutralized with sodium carbonate and filtered. The filtrate was concentrated in vacuo to afford (R)-4-cyano-3-hydroxybutyric acid benzyl ester (157 g, 92%) which was purified by column chromatography on a silica gel.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[C:3]1=[O:23].[CH3:24][C:25]([CH3:27])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][N:18]([CH:25]([CH3:27])[CH3:24])[CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[C:3]1=[O:23]
Reactant: CC(C)=O
Reactant: CN1CCN(c2ccc(-n3cc4c(n3)CCNCC4)cc2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCc2cn(-c3ccc(N4CCN(C)C4=O)cc3)nc2CC1
Temperature: 25 °C

Procedure:
A solution of 1-methyl-3-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-imidazolidinone (may be prepared as described in Description 29) (44.0 mg, 0.14 mmol) in dichloromethane (3 ml) was treated with acetone (41 μl, 0.56 mmol) and acetic acid (1 drop) and stirred at room temperature. Sodium triacetoxyborohydride (60.0 mg, 0.28 mmol) was added and the mixture stirred for 3 hours and then overnight with a further portion of acetone and sodium triacetoxyborohydride added. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (E10); MS (ES+) m/e 354 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:2]1[CH2:3][CH2:4]2)=O.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[N:26][CH:25]=[C:24]([Cl:28])[N:23]=2)[CH2:18][CH2:17]1>C(Cl)Cl>[Cl:28][C:24]1[N:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:6](=[O:8])[CH:5]4[O:1][CH:2]([CH2:3][CH2:4]4)[C:9]3=[O:10])[CH2:21][CH2:20]2)[CH:27]=[N:26][CH:25]=1
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Reactant: O=C1OC(=O)C2CCC1O2
Solvent: ClCCl
Product: O=C1C2CCC(O2)C(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran-2,5-dicarboxylic anhydride (1.26 g., 8.8 mmole) and 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine (2.37 g., 8.8 mmole) were combined and stirred for 30 minutes in 200 ml. of methylene chloride. The solvent was removed in vacuum and replaced with 300 ml. of xylene. The mixture as refluxed for 48 hours with water removal via a Dean-Stark trap. After cooling, the mixture was filtered through 75 g. of silica gel and the column rinsed with 5% ethanol/chloroform. The product was concentrated in vacuum and recrystallized from isopropanol with addition of 4N isopropanolic HCl. 0.60 Grams of the title compound was obtained as the monohydrochloride; m.p. 233°-235° C. (d).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.[Na+]>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3)c(C)o2)cc1
Yield: 87.7 %

Procedure:
A mixture of chloride 2 (1.54 g, 5.8 mmol) and sodium 4-methylbenzenesulfinate (1.08 g, 6.1 mmol) gave benzoate 3 (1.96 g, 88%) as a white powder: mp (EtOAc) 177-178° C.; 1H NMR (CDCl3) δ 8.08 (ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-2, H-6), 7.92 (ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-3, H-5), 7.69 (ddd, J=8.3, 1.9, 1.7 Hz, 2H, H-2′, H-6′), 7.30 (br d, J=8.3 Hz, 2H, H-3′, H-5′), 4.29 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.43 (s, 3H, CH3), 2.31 (s, 3H, CH3); MS m/z 386.5 (MH+, 100%). Anal. calcd for C20H19NO5S: C, 62.32; H, 4.97; N, 3.63. Found: C, 62.59; H, 4.96; N, 3.71%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.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]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:3]1=[O:14]
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)N(c2ccccn2)CC1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 2 mmol) (prepared as described in step (iii) of Example 13) and 2-bromopyridine (316 mg, 2 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (977 mg, 3 mmol), Xantphos™ (87 mg, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane (2 columns required) to give 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylate (198 mg, 36%). LC/MS [M+H]+=278. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylate (198 mg, 0.71 mmol) in TFA/DCM (1:2, 4.5 ml) was stirred at room temperature for 8 hours. The solution was evaporated and the residue was dried to give 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.71 mmol)) which was used in the next step. LC/MS [M+H]+=222.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:27][C:28]1([C:31]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[O:32])[CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.ClC1N(C)CC[NH+]1C.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:16])([F:15])[F:17])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1([C:31](=[O:32])[NH:33][CH2:34][C:35]([F:37])([F:38])[F:36])[CH2:30][CH2:29]1)=[O:6]
Reactant: NC1(C(=O)NCC(F)(F)F)CC1
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Agent: CN1CC[NH+](C)C1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)NCC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a stirred solution of (E)-2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (300 mg, 0.67 mmol) and 1-amino-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide (148 mg, 0.81 mmol) in DCM/DMF (5 mL, 1:1), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) (92 mg, 0.33 mmol), 1-hydroxy-7-azabenzotriazole (HOAt) (48 mg, 0.33 mmol) and DMAP (5 mol %) were added, and the resulting mixture was stirred at room temperature (RT) for 4 h. The reaction mixture was poured into ice-water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% EtOAc in petroleum ether to give the title compound as pale yellow gum (300 mg, 75%). Characterization data for this molecule is listed in Table 2.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[CH3:40][NH:41][C:42]([N:24]1[CH2:23][CH2:22][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:13]([Cl:28])=[CH:12][C:11]([C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:31][CH:30]=4)=[CH:10][C:9]=3[Cl:8])[C:17]2=[O:27])[CH2:26][CH2:25]1)=[O:43]
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(OC(F)(F)F)cc3)cc2Cl)CCN1C1CCNCC1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(OC(F)(F)F)cc4)cc3Cl)C2=O)CC1
Yield: 37.8 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-trifluoromethoxy-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 33) (85 mg, 0.17 mmol) in CH2Cl2 (4 mL) with methyl isocyanate (11 mg, 0.19 mmol). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute pure product. Remove the solvent to afford 0.035 g (37%) of product. MS (m/e): 544 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20].C([O:24]CC)C>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20])=[O:24]
Reactant: CC(=O)Nc1ccccc1CSc1nc2ccccc2[nH]1
Reactant: CCOCC
Product: CC(=O)Nc1ccccc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The title compound was prepared by the method of Example 3 using 1.80 g of the title product of Example 5 instead of the title product of Example 2. Trituration with diethylether gave 1.52 g of the title compound: m.p. 201-202.5° C. Anal. Calc'd. for C16H15N3O2S: C, 61.32; H, 4.82; N,13.41; S, 10.23. Found: C, 61.00; H, 4.90; N, 13.28; S, 10.50.
Reaction SMILES: ClC1C=CC(S([N:11]2[CH:16]([C:17]3[CH:22]=C(F)C=C(F)[CH:18]=3)[CH2:15][C:14]3[NH:25][N:26]=[CH:27][C:13]=3[CH2:12]2)(=O)=O)=CC=1.FC1C=C(C2CC(=O)CCN2[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])C=C(F)C=1.ClC1C=CC(C2CC(=O)CCN2C(OCC2C=CC=CC=2)=O)=CC=1.FC1C=C([Mg]Br)C=C(F)C=1.O.NN.N1CCC(=O)CC1>>[CH:17]([CH:16]1[N:11]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:12][C:13]2[CH:27]=[N:26][NH:25][C:14]=2[CH2:15]1)([CH3:18])[CH3:22]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2cc(F)cc(F)c2)C1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1Cc2cn[nH]c2CC1c1cc(F)cc(F)c1
Agent: Fc1cc(F)cc([Mg]Br)c1
Agent: NN
Agent: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Solvent: O
Product: CC(C)C1Cc2[nH]ncc2CN1C(=O)OCc1ccccc1

Procedure:
5-(4-Chlorophenylsulfonyl)-6-(3,5-difluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (Enantiomers A and B) Benzyl 2-(3,5-difluorophenyl)-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example 3 using 3,5-difluorophenylmagnesium bromide, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. The enantiomers were separated using HPLC Method [2].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 6 (0.250 g, 0.0073 mol) in dichloromethane (5 mL), pyridine (0.174 g, 0.00219 mol) was added and stirred for 5 min. To this reaction mixture, benzene sulfonyl chloride was added and stirred for about 16 h. After completion of the reaction, solvent was evaporated and the crude title compound obtained was directly used for the preparation of compound of example 78.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[C:16]([C@@H:23]([OH:26])[CH2:24][OH:25])[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>>[C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[C:16]([C@H:23]([OH:26])[CH2:24][OH:25])[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:29]([F:31])([F:30])[F:32])#[N:2]
Reactant: N#Cc1ccc(Oc2ccc(-c3nc(C(N)=O)cc([C@@H](O)CO)n3)cc2)cc1C(F)(F)F
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Product: N#Cc1ccc(Oc2ccc(-c3nc(C(N)=O)cc([C@H](O)CO)n3)cc2)cc1C(F)(F)F

Procedure:
(S)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl) pyrimidine-4-carboxamide (Compound Example No. 13) was prepared in a similar fashion to (R)-2-(4-(4-cyano-3-(trifluoromethyl) phenoxy)phenyl)-6-(1,2-dihydroxy-ethyl)pyrimidine-4-carboxamide (Compound Example No. 12) using AD-Mix alpha instead of AD-Mix beta. 1H NMR (400 MHz, DMSO-d6) δ 8.80-8.70 (2 H, m), 8.69-8.61 (1 H, m), 8.23-8.15 (1 H, m), 8.07-8.02 (1 H, m), 8.01-7.96 (1 H, m), 7.67-7.60 (1 H, m), 7.49-7.41 (1 H, m), 7.42-7.34 (2 H, m), 5.86-5.78 (1 H, m), 4.87-4.79 (1 H, m), 4.75-4.66 (1 H, m), 3.85-3.76 (1 H, m), 3.74-3.63 (1 H, m); LC/MS: m/z=445 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1
Reactant: O=C(Cn1cnnn1)c1ccc(Cl)cc1Cl
Reactant: ClCc1ccccc1
Product: Clc1ccc(C(=Cn2cnnn2)OCc2ccccc2)c(Cl)c1

Procedure:
Analogously to Example 7a,b, after reacting 1-(2,4-dichlorophenyl)-2-tetrazol-1-yl-ethanone with benzyl chloride there was obtained 1-[2-(2,4-dichloro-phenyl)-2-benzyloxy-vinyl]-1H-tetrazole as colourless crystals with m.p. 92° C.
Reaction SMILES: CN.[Br:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1.[C:18]([BH3-])#[N:19].[Na+].C(O)(=O)C>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([NH:19][CH3:18])[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CN1CCCC1)c1cccc(Br)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(CN1CCCC1)c1cccc(Br)c1
Reaction time: 1 h
Yield: 47.9 %

Procedure:
2.0 M methylamine solution in THF (55 mL, 110.0 mmol) was added to a solution of 1-(3-bromophenyl)-2-(1-pyrrolidinyl)ethanone (7.40 g, 27.62 mmol) in anhydrous THF (30 mL) at room temperature. The reaction mixture was stirred for 1 h and then sodium cyanoborohydride (5.21 g, 82.86 mmol) and acetic acid (3 mL) were added. The resulting reaction mixture was continually stirred at room temperature for 96 h until the starting material was consumed completely. Saturated K2CO3 solution (100 mL) was added and after stirring for 15 min, the solution was extracted with ethyl acetate (2×80 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting residue was isolated by column chromatography on silica gel (MeOH/EtOAc, 1:10) to yield the title compound as a yellow oil (3.75 g, 48%), MS (ES) m/e 283[M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH:15]([C:23]([O:25]C(C)(C)C)=[O:24])[C:16]([O:18]C(C)(C)C)=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH:15]([C:23]([OH:25])=[O:24])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2ccc(C(C(=O)O)C(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Di-tert-butyl [2-(ethoxycarbonyl)-1-benzothien-6-yl]malonate (0.873 g, 2.08 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue partitioned between saturated NaHCO3-EtOAc. The aqueous phase was acidified with 2N HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 0.60 g of product (white solid, 94%). 1H NMR (DMSO-d6) δ 13.10 (br s, 2H), 8.17 (s, 1H), 8.03 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 1.8 Hz, 1H), 4.83 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)=[C:8]([O:29][CH3:30])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:32]1[C:33]2[N:40]=[CH:39][N:38]([CH2:41][CH3:42])[C:34]=2[N:35]=[N:36][CH:37]=1>>[CH2:41]([N:38]1[C:34]2[N:35]=[N:36][CH:37]=[C:32]([C:14]3[CH:13]=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=4[O:29][CH3:30])[C:17]([O:18][CH3:19])=[CH:16][CH:15]=3)[C:33]=2[N:40]=[CH:39]1)[CH3:42]
Reactant: CCn1cnc2c(Cl)cnnc21
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2OC)c(OC)c1
Product: CCn1cnc2c(-c3ccc(OC)c(-c4ccc(S(=O)(=O)CC)cc4OC)c3)cnnc21
Yield: 13 %

Procedure:
Prepared according to the method described for Example 45 using 2-(4′-(Ethylsulfonyl)-2′,6-dimethoxy-[1,1′-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 59) and 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8) to afford the title compound as an off white solid in 13% yield, 14.7 mg.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].O>CS(C)=O>[CH2:24]([N:7]1[C:8](=[O:9])[C:10]([CH3:11])=[CH:12][N:4]([CH3:3])[C:5]1=[O:6])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Reactant: C=CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
This example illustrates a synthesis of 3-(11,10-Oxidoundecyl)-1-methylthymine (inventive compound no. 1932). Sodium hydride (95%) (168 mg, 7 mmol) was added to a solution of 1-methylthymine (700.5 mg, 5 mmol) in dimethylsulfoxide (15 mL). After 20 minutes of stirring, 1-bromundec-10-ene (1.165 g, 5 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing 100 mL of water and extracted with dichloromethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and saturated aqueous salt solution (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using a 20% ethyl acetate/hexane eluant to yield 1.22 g (83.7% yield) 3-(10-undecenyl)-1-methylthymine (inventive compound no. 1931).