Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]([F:32])([F:31])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](OC)=[O:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[F:10][C:11]([F:31])([F:32])[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][OH:28])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
DIBAL-H (20% w/w in toluene, 2 mL, 2.39 mmol) was added to a slurry of ester 100 (0.396 g, 1.23 mmol) in toluene (12 mL) at −78° C. The mixture was warmed to room temperature, stirred for 1 h, and then poured onto ice cold NH4Cl solution (50 mL). The mixture was diluted with CH2Cl2 (100 mL), filtered through Celite and the organic layer was dried and evaporated. Column chromatography of the residue on silica gel using gradient elution (CH2Cl2 to 95:5 CH2Cl2:EtOAc) gave (2E)-3-[4′-(trifluoromethoxy)[1,1′-biphenyl]-4-yl]-2-propen-1-ol (101) (0.195 g, 54%) as a white solid: mp 121-123° C.; NMR (CDCI3) δ 7.60 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 6.66 (d, J=15.9 Hz, 1H), 6.42 (dt, J=15.9, 5.7 Hz, 1H), 4.36 (dd, J=5.9, 5.7 Hz, 2H), 1.44 (t, J=5.9 Hz, 1H). APCI MS m/z 307 [M−H−H2O+MeOH]−.
Reaction SMILES: [CH:1]1([CH:6]([OH:8])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:7])[CH3:16]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(O)C1CCCC1
Agent: [Rh]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)COC(C)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of 1-cyclopentylethan-1-ol (1.14 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.03 mmol). The reaction mixture is stirred at rt for 0.5 h. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue is purified by chromatography on silica gel; elution with EtOAc:heptane (1:9) gives 0.81 g of the product 452. 1H NMR (CDCl3) δ 4.30-4.15 (m, 2 H), 4.09 (d, 2 H), 3.25-3.15 (m, 1 H), 2.00-1.78 (m, 2 H), 1.75-1.35 (m, 6 H), 1.29 (t, 3 H), 1.15 (d, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])=[C:10]([F:16])[CH:11]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Yield: 96.6 %

Procedure:
A solution of (2-fluoro-4-hydroxy-benzyl)-carbamic acid t-butyl ester (0.47 g, 1.95 mmol), methyl bromoacetate (0.203 mL, 2.15 mmol) and potassium carbonate (0.431 g, 3.12 mmol) in DMF (5 mL) was stirred at ambient temperature overnight. The reaction mixture was partitioned with water and ethyl acetate. The organic phase was washed with water and dried (Na2SO4). Removal of solvent in vacuo afforded 0.59 g of the title compound.
Reaction SMILES: [Zn:1].[Br:2]CCBr.Cl[Si](C)(C)C.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Br-:2].[CH2:12]([Zn+:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCBr
Reactant: BrCc1ccccc1
Reactant: [Zn]
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: [Br-]
Product: [Zn+]Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension mixture of zinc powder (active, 65 g, 1.0 mol) in dry THF (200 mL) was dropwise added 1,2-dibromoethane (3.5 mL, 40 mmol) at 65° C. under nitrogen atmosphere, followed by the addition of chlorotrimethylsilane (87 mg, 80 mmol). The mixture was then stirred at 60° C. for another 1 h. Subsequently, (bromomethyl)benzene (60 mL, 500 mmol) was dropwise added, and the suspension was stirred at 60° C. for another 1 h. The reaction mixture was directly used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[S:41]([NH2:44])(=[O:43])=[O:42]>>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[S:41]([NH:44][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:19][CH:18]=1)=[O:24])(=[O:42])=[O:43]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2s1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cc3ccccc3s2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 1-benzothiophene-2-sulfonamide (Chem, J.; Leu, Y.; et al. J. Med. Chem., 1997, 40, 2276.; Graham, S. L.; Shepard, K. L.; et al. J. Med. Chem., 1989, 32, 2548).
Reaction SMILES: [C@@H]1(C2C=CC=C(CC3SC(CC)=CC=3)C=2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[C:26]1([C:32]2[S:36][C:35]([C:37]([C:39]3[CH:44]=[C:43]([Br:45])[CH:42]=[CH:41][C:40]=3[C:46]([F:49])([F:48])[F:47])=O)=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O1CCCC1.[BH4-].[Na+]>CO>[Br:45][C:43]1[CH:42]=[CH:41][C:40]([C:46]([F:49])([F:47])[F:48])=[C:39]([CH2:37][C:35]2[S:36][C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:33][CH:34]=2)[CH:44]=1
Reactant: O=C(c1ccc(-c2ccccc2)s1)c1cc(Br)ccc1C(F)(F)F
Agent: CCc1ccc(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Br)cc1Cc1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of the above methyl 5-bromo-2-iodobenzoate (4.65 g) in N-methyl-2-pyrrolydinone (20 ml) were added copper (I) bromide (235 mg) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.6 ml), and the mixture was stirred under heating at 120° C. for 1.5 hours. The reaction mixture was cooled, and added thereto were 10% aqueous hydrochloric acid solution and ethyl acetate. Insoluble materials were filtered off, and an organic layer of the filtrate was washed with water for 4 times, and subsequently washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexan:ethyl acetate=80:1) to give methyl 5-bromo-2-trifluoromethylbenzoate (3.55 g) as colorless oil. (3) The above methyl 5-bromo-2-trifluoromethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2-trifluoromethylbenzoic acid as pale brown crystals. ESI-Mass m/Z 267/269 (M−H). (4) The above 5-bromo-2-trifluoromethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5-(1) to give 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone as pale yellow crystals. APCI-Mass m/Z 411/413 (M+H). (5) To a mixed solution of the above 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone (670 mg) in methanol (20 ml)-tetrahydrofuran (10 ml) was added sodium borohydride (62 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform (10 ml)acetonitrile (20 ml). Thereto was added triethylsilane (0.78 ml), and the mixture was cooled to 0° C. Thereto was added dropwise boron trifluoride•diethyl ether complex (0.52 ml). The mixture was stirred at room temperature for 45 minutes, and added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the desired 5-bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene (565 mg) as colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][SH:10].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].O>O1CCCC1.C(OCC)(=O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COCCOCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCCSc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
In a 100 mL round-bottomed flask was added sodium hydride (0.6 g) in tetrahydrofuran (10 ml) to give a suspension. 2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After the mixture stirred for 30 minutes, 4-fluoro-3-nitrobenzenesulfonamide (1.616 g) in 10 ml tetrahydrofuran was added slowly. After the mixture stirred overnight, water was added slowly, and ethyl acetate (20 ml×3) was used to extract the product. The combined organic layers were dried over Na2SO4. After the mixture was filtered and concentrated, the crude product was added to a silica gel column and purified eluting with 0-10% methanol in dichloromethane.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>CCOC(C)=O.CC(O)C>[CH:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[C:5]([O:4][CH2:3][C@@H:2]([OH:1])[CH2:18][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)c(OC)c1
Temperature: 85 °C
Yield: 47.6 %

Procedure:
To a solution of (S)-(+)-4-(2,3-Epoxypropoxy)-carbazole (7.56 g, 0.031 mole) in EtOAc/IPA (40/80 mL) was added 2,4-dimethoxybenzylamine (9.48 mL, 0.063 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was cooled to room temperature and purified following the procedure similar to one described in step 11 for the synthesis of example 23, to afford the desired compound as colorless solid (6 g, 48%) with m.p: 152-154° C. 1H NMR (400 MHz, CDCl3): δ 2.17 (s 1H), 2.88-2.92 (m, 1H), 2.98-3.00 (m, 1H), 3.74-3.87 (m, 8H), 4.18-4.32 (m, 3H), 6.38-6.45 (m, 2H), 6.67 (d, 1H, J=8.0 Hz), 7.05 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.18-7.40 (m, 4H), 8.08 (s, 1H), 8.21 (d, 1H, J=8.0 Hz). MS m/z: 407.1 (M+1). Chiral purity: 99.96%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2.CC1C=C2[C:27](=C([N+]([O-])=O)C=1)[NH:26][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=CC=1)=C2>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:38]3[CH2:33][CH2:25][N:26]([CH3:27])[CH2:36][CH2:37]3)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Reactant: Cc1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Product: CN1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1
Yield: 69 %

Procedure:
5-Chloro-7-nitro-2-phenyl-1H-indole (337 mg, 1.23 mmol) was reacted instead of 5-methyl-7-nitro-2-phenyl-1H-indole in Preparation 50 to give the title compound 288 mg (Yield 69%).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH3:13][CH:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19].C(Br)=C>O1CCCC1>[CH3:13][C:14]1([CH:1]=[CH2:2])[CH2:18][CH2:17][O:16][C:15]1=[O:19]
Reactant: CC1CCOC1=O
Reactant: CC(C)NC(C)C
Agent: C=CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC1(C)CCOC1=O
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 47.7 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (4.7 mL, 33.815 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (20 mL) was treated with a solution of n-butyllithium in hexanes (12.7 mL, 31.702 mmol, 2.5 M). After stirring at −78° C. for 25 minutes, the mixture was treated with 3-methyl-dihydro-furan-2-one (2 mL, 21.135 mmol). After stirring at 0° C. for 1 h, the reaction was subsequently treated with a solution of di-μ-bromobis(tri-tert-butylphosphino)dipalladium(I) (164.2 mg, 0.211 mmol) in anhydrous tetrahydrofuran (5 mL) and a solution of vinyl bromide in tetrahydrofuran (31.7 mL, 81.702 mmol, 1 M). The reaction was slowly warmed to room temperature. After stirring for 16 h, the reaction was quenched with hydrochloric acid (2 M) and water. The aqueous layer was extracted with diethyl ether (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 3:2 to afford the title compound (1.272 g, 48%) as an orange oil. 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 3H), 2.11-2.22 (m, 1H), 2.31-2.41 (m, 1H), 4.20-4.36 (m, 2H), 5.16-5.26 (m, 2H), 5.84-5.96 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[C:2]=1[C:10]([OH:12])=O.S(=O)(=O)(O)O.[C:18](=O)([O-])[O-].[Na+].[Na+].[CH3:24][OH:25]>>[CH3:24][O:25][C:10]([C:2]1[C:3]([C:7]([O:9][CH3:18])=[O:8])=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccnc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cccnc1C(=O)OC

Procedure:
To a solution of pyridine-2,3-dicarboxylic acid (50.0 g, 0.299 mol) in methanol (500 ml) was added con. sulfuric acid (20 ml). After heated to reflux for 24 hours, the mixture was basified with saturate sodium carbonate solution until pH=8 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated to give D78 (45.7 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19].N12CCCN=C1CCCCC2.Cl[Si:32]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[O:33][Si:34](Cl)([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36]>C(C#N)(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:12]([OH:19])[C@@H:13]2[O:18][Si:32]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[O:33][Si:34]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:36])[CH3:37])[O:17][CH2:16][C@H:14]2[CH2:15]1
Reactant: OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Agent: CC(=O)C#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
To a solution of (1R,2S,3R,5R)-3-(6-chloro-purin-9-yl)-5-hydroxymethylcyclopentane-1,2-diol (Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1969, 91, 3075-308) (0.44 g, 1.55 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.461 mL, 3.1 mmol) in AcCN (15 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (0.581 mL, 1.8 mmol). The reaction mixture was stirred at room temperature for 14 h then concentrated. The residue was purified by flash chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.545 g, 67%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([Li])CCC.[CH2:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=[O:22])C>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:14]2([OH:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:7]=1
Reactant: C1CCCCC1
Reactant: CC(=O)O
Reactant: Cc1ccc(O)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Oc1ccc(CC2(O)CCCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-2-methylpyridine (10.66 g) in tetrahydrofuran (426 ml) was added a solution of n-butyllithium (1.5M in hexane, 143 ml) at -30°~-10° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature. After cooling to -78° C., cyclohexane (11.14 ml) was added dropwise and allowed to warm to 0° C. and stirred for 30 minutes at 0° C. After addition of acetic acid (24.6 ml), the solvent was distilled off and the residue was diluted with ethyl acetate, and washed successively with water, 10% aqueous sodium hydrogen carbonate and aqueous saturated sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated. The residue was washed with ethyl acetate to give 5-hydroxy-2-[(1-hydroxycyclohexyl)methyl]pyridine (11.96 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:12]3[O:17][CH2:16][C@@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.[CH3:30][C@@H:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C@@H:41]3[O:46][CH2:45][C@@H:44]4[CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50][N:43]4[CH2:42]3)[CH:38]=2)[C:33](=[O:58])[O:32]1.BrC1C=C2C(=CC=1)C(=O)O[C@@H](C)C2>>[CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:12]3[O:17][CH2:16][C@@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.[CH3:30][C@H:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C@@H:41]3[O:46][CH2:45][C@@H:44]4[CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50][N:43]4[CH2:42]3)[CH:38]=2)[C:33](=[O:58])[O:32]1
Reactant: C[C@@H]1Cc2cc([C@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1
Reactant: C[C@@H]1Cc2cc([C@@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1
Agent: C[C@H]1Cc2cc(Br)ccc2C(=O)O1
Product: C[C@H]1Cc2cc([C@@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1
Product: C[C@H]1Cc2cc([C@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1

Procedure:
8C and 8D were prepared in a similar manner as Intermediates 8A and 8B except (3S)-6-Bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one was used as the starting material. The cis/trans mixture was purified via chiral HPLC (30% 2:1 MeOH:MeCN/CO2) on an AD column. The faster eluting diastereomer was the trans isomer. 8C: 1H NMR (500 MHz; CDCl3): 8.07 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 4.72 (dd, J=1.8, 10.5 Hz, 1H), 4.68 (m, 1H), 4.1-3.8 (bs, 2H), 3.96 (dd, J=3.0, 11.3 Hz, 2H), 3.48 (t, J=10.7 Hz, 1H), 2.95 (m, 4H), 2.74 (d, J=10.5 Hz, 1H), 2.2 (m, 3H), 1.54 (d, J=6.2 Hz, 3H), 1.49 (s, 9H); LC-MS: (M+1)+403; 8D: 1H NMR (500 MHz; CDCl3): 8.10 (d, J=8.2 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 4.81 (bt, 1H), 4.71 (m, 1H), 3.62 (dd, J=2.8, 11.5 Hz, 1H), 3.41 (m, 1H), 3.25 (dd, J=3.7, 12.1 Hz, 1H), 2.95 (m, 4H), 2.76 (m, 3H), 2.50 (m, 2H), 2.28 (m, 1H), 1.54 (d, J=6.2 Hz, 3H), 1.48 (s, 9H); LC-MS: (M+1)+403.
Reaction SMILES: C(OC(C1NN=C(CCC)C=1)=O)C.FC1C=CC(CBr)=CC=1.[F:23][C:24]1[CH:41]=[CH:40][C:27]([CH2:28][N:29]2[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]([CH2:37][CH2:38][CH3:39])=[N:30]2)=[CH:26][CH:25]=1.[NH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]([CH2:37][CH2:38][CH3:39])=[N:30]2)=[CH:40][CH:41]=1.[S:44]1[CH:45]=[CH:46][N:47]=[C:43]1[NH:42][C:34]([C:33]1[N:29]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:41][CH:40]=2)[N:30]=[C:31]([CH2:37][CH2:38][CH3:39])[CH:32]=1)=[O:36]
Reactant: Nc1nccs1
Agent: CCCc1cc(C(=O)O)n(Cc2ccc(F)cc2)n1
Agent: CCCc1cc(C(=O)OCC)[nH]n1
Agent: Fc1ccc(CBr)cc1
Product: CCCc1cc(C(=O)Nc2nccs2)n(Cc2ccc(F)cc2)n1

Procedure:
2-(4-Fluorobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid (0.78 g) was prepared from 5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.91 g, 5.0 mmol) and 4-fluorobenzyl bromide (1.05 g, 5.5 mmol) following the general procedures D and E. 2-(4-Fluorobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid thiazol-2-ylamide (50 mg) was prepared from 2-(4-fluoro-benzyl)-5-propyl-2H-pyrazole-3-carboxylic acid (65 mg, 0.25 mmol) and 2-aminothiazole (25 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (2.5 g, 7.56 mol) in acetonitrile (25 mL) was Cs2CO3 (3.93 g, 12.06 mol) with stirring at RT. After 15 min, MeI (2.34 g, 16.48 mol) was added. The reaction mixture was stirred at rt for 14 h. The reaction was monitored by TLC. When SM was finished, reaction mixture was filtered through celite pad and filtrate was concentrated. Column chromatography of crude material afforded product 1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (29) as white solid (2.35 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:24])OC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:6]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16]([N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:11][CH:12]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)cs1
Reactant: CCCCNCCCC
Solvent: CS(C)=O
Product: CCCCN(CCCC)C(=O)NCCc1ccc(-c2csc(N)n2)cc1

Procedure:
The title compound: A solution of phenyl N-{2-{4-(amino-4-thiazolyl)phenyl}ethyl}carbamate (200 mg, 0.59 mmol), prepared in the preceding section (a), and dibutylamine (76.0 mg, 0.59 mmol) in DMSO (1 mL) was stirred at room temperature for 3 d. The reaction mixture was diluted with EtOAc (30 mL) and washed with aqueous saturated NaHCO3 (2×30 mL). The aqueous layers were back extracted with EtOAc (30 mL). The combined organic extracts were dried (MgSO4) then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, EtOAc:Hexane, 4:1) to give N-{2-{4-(2-amino-4-thiazolyl)phenyl}ethyl}-N',N'-dibutylurea (167 mg, 76% yield): M.p. 42-43°; 1H NMR (DMSO-d6) δ 7.70 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 6.99 (broad s, 2H), 6.92 (s, 1H), 6.11 (broad t, J=5.4 Hz, 1H), 3.23 (broad q, J=6.6 Hz, 2H), 3.09 (t, J=7.5 Hz, 4H), 2.70 (t, J=7.3 Hz, 2H), 1.37 (m, 4H), 1.21 (m, 4H), 0.86 (t, J=7.3 Hz, 6H); MS (FAB) m/z 375 (MH)+.