Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][O:4][C:3]1=[O:27].[OH:28][C:29]1[C:30]([C:37](O)=[O:38])=[N:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][O:4][C:3](=[O:27])[C@@H:2]([NH:1][C:37](=[O:38])[C:30]2[C:29]([OH:28])=[C:34]([O:35][CH3:36])[CH:33]=[CH:32][N:31]=2)[CH2:10][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1COC[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)COC1=O
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)COC2=O)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a mixture of (3S,7S,8S)-3-amino-7,8-bis(benzyloxy)-1,5-dioxonan-2-one (47 mg, 0.127 mmol), 3-hydroxy-4-methoxypicolinic acid (32.1 mg, 0.190 mmol) and HATU (80 mg, 0.202 mmol) in a vial were added CH2Cl2 (1.5 mL), followed by 4-methylmorpholine (0.083 mL, 0.759 mmol), and the resulting suspension was stirred at room temperature for 12 h. The resulting orange solution was directly purified by flash chromatography (SiO2) to afford the title compound as a white foam (32 mg, 48%): 1H NMR (400 MHz, CDCl3) δ 11.90 (d, J=0.6 Hz, 1H), 8.61 (d, J=8.2 Hz, 1H), 8.49 (d, J=5.2 Hz, 1H), 7.43-7.24 (m, 11H), 6.86 (d, J=5.2 Hz, 1H), 5.03 (ddd, J=8.2, 6.8, 6.0 Hz, 1H), 4.80-4.62 (m, 5H), 4.21-4.07 (m, 2H), 3.93 (s, 3H), 3.85 (s, 1H), 3.79-3.65 (m, 2H), 3.55-3.47 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 170.83, 168.92, 155.37, 148.76, 140.66, 137.97, 137.94, 130.17, 128.48, 128.43, 127.91, 127.89, 127.87, 127.81, 109.61, 81.52, 79.29, 73.80, 73.44, 73.24, 72.97, 63.91, 56.10, 52.25; ESIMS m/z 524.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: OB(O)c1ccccc1
Product: CCCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (20% acetone in toluene to 60% acetone in toluene gradient) afforded 2-butyl-1-isobutyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. >250° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:24][C:25]([F:39])([F:38])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[O:27]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH:11]3[N:16]([CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:26](=[O:27])[C:25]([F:24])([F:38])[F:39])[CH:14]([CH2:13][CH2:12]3)[CH2:15]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OCCCCNC(=O)C(F)(F)F
Reactant: Clc1ccc(N2CC3CCC(C2)N3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCCN1C2CCC1CN(c1ccc(Cl)cc1)C2)C(F)(F)F
Yield: 39 %

Procedure:
3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1] octane hydrochloride salt (1.5 g, 5.79 mmol), triethylamine (1.77 mL, 12.73 mmol) and methanesulfonic acid 4-(2,2,2-trifluoro-acetylamino)-butyl ester (2.29 g, 8.68 mmol) were combined in tetrahydrofuran (25 mL). The resulting white heterogeneous reaction was heated at reflux for 24 hours. The mixture was cooled diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown oil. Silica gel flash chromatography using 5% methanol/ chloroform as eluent yielded N-{4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-2,2,2-trifluoro-acetamide (0.88 9, 39%) as an off-white solid which had the following properties: Mp. 83-85° C., 1H NMR CDCl3 δ: 7.77 (brd s, 1H), 7.16 (d, J=9.1 Hz, 2H), 6.68 (d, J=9.1 Hz, 2H), 3.44-3.35 (m, 4H), 3.29 (d, J=9.6 Hz, 2H), 3.02 (d, J=9.6 Hz, 2H), 2.51 (t, J=6.2 Hz, 2H), 2.10-1.90 (m, 2H), 1.83-1.76 (m, 2H), 1.73-1.57 (m, 6H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]([C:20]3[S:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)=[CH:18][C:17](=[O:29])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:43]1[C:51]2[C:46](=[CH:47][C:48](O)=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]([C:20]3[S:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)=[CH:18][C:17](=[O:29])[C:13]([C:14]([O:16][CH:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44]3)=[O:15])=[CH:12]2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CC(=O)Oc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2cc3ccccc3s2)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-n2cc(C(=O)OC3CCc4ccccc43)c(=O)cc2-c2cc3ccccc3s2)cc1
Temperature: -40 °C
Yield: 54 %

Procedure:
In 18 ml of anhydrous methylene chloride was dissolved 0.36 g of 1-(4-acetoxyphenyl)-6-(2-benzo[b]thienyl)-4-oxo-1,4-dihydronicotinic acid, and to this solution was added 0.137 ml of triethylamine at room temperature. The reaction mixture thus obtained was cooled to -40° C., and 0.094 ml of ethyl chlorocarbonate was added thereto. The resulting mixture was subjected to reaction at the same temperature for 1 hour. This reaction mixture was then mixed with 0.14 g of 5-indanol. The mixture was subjected to reaction for 1 hour, and elevated to room temperature. After completion of the reaction, the reaction mixture was washed successively with 15 ml of water and a saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain 0.25 g of indanyl 1-(4-acetoxyphenyl)-6-(2-benzo[b]thienyl)-4 -oxo-1,4-dihydronicotinate having a melting point of 234°-236° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (14 g, 42.7 mmol) in dichloroethane (150 mL) was added acetaldehyde (3.75 g, 85.2 mmol) and acetic acid (15.3 g, 256 mmol). The resulting reaction mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0° C. and sodium triacetoxyborohydride (27 g, 128 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction as determined by TLC, aqueous sodium bicarbonate solution was added to the reaction mixture until a pH 7-8 was obtained, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate: hexane to afford the desired compound as a viscous liquid (14 g, 93%). 1H NMR (DMSO-d6, 400 MHz) δ 7.62 (s, 1H), 7.52 (s, 1H), 3.80 (bs, 5H), 3.31 (t, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1.37-1.50 (m, 2H), 0.87 (t, 3H, J=6.8 Hz).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)CC(C)C)=[O:7])(C)(C)C.[C:24]([NH:34][C@H:35](C(O)=O)[CH2:36][CH:37]([CH3:39])[CH3:38])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:27]([O:26][C:24]([NH:34][C@@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:6]([NH:8][CH2:9][C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)=[O:7])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1csc([C@H](CC(C)C)NC(=O)OC(C)(C)C)n1
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the procedure of Example 13, except substituting 1-(tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)methane for (1S)-1-(tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].Br[CH2:16][CH2:17][O:18][CH3:19]>>[CH3:19][O:18][CH2:17][CH2:16][O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Product: COCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 46.2 %

Procedure:
3-nitro-5-(trifluoromethyl)phenol (770 mg, 3.72 mmol) and 1-bromo-2-methoxyethane (1.75 mL, 19 mmol) were reacted using the procedure described in Example 40A Step 3 to give 1-(2-methoxyethoxy)-3-nitro-5-(trifluoromethyl)benzene (456 mg, 1.72 mmol, 46%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 4.36 (dd, 2H), 3.71 (dd, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 266 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:4]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:1][CH2:2][CH:3]2[CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5](=[O:15])[CH2:4]2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCC1CC(=O)N(Cc2ccccc2)C1
Solvent: C1COCCO1
Product: O=C(NCC1CC(=O)N(Cc2ccccc2)C1)Nc1ccc(Cl)cc1
Yield: 74.9 %

Procedure:
52 g (0.25 mol) of 4-aminomethyl-1-benzylpyrrolidin-2-one are stirred for 2 hours at ambient temperature in 70 ml of dioxane with 38 g (0.25 mol) of p-chlorophenylisocyanate and the solution is then evaporated in vacuo. The residue crystallizes out of ethyl acetate to yield 67 g of the title compound, m.p. 139°-140° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:14].P(=O)(O)(O)O.O>ClC1C=CC=CC=1Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[OH:14][C:8]1[CH:9]=[C:10]2[C:11](=[C:12]([CH3:13])[C:7]=1[CH3:6])[CH2:1][CH2:2][C:3]2([CH3:5])[CH3:4]
Reactant: C=CC(=C)C
Reactant: Cc1cccc(O)c1C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1c(O)cc2c(c1C)CCC2(C)C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
449 g of isoprene, stabilised with 1.3 g of phenothiazine, were added dropwise in the course of 7 hours to a solution of 732 g of 2,3-dimethyl-phenol, 76.5 g of 85% strength phosphoric acid and 6 ml of water in 1.44 liters of o-dichlorobenzene at 150° C. To complete the reaction, stirring of the mixture was continued overnight at 150° C. The acid phase was separated off and the organic phase was washed until neutral. Fractional distillation gave 526 g of 5-hydroxy-3,3,6,7-tetramethyl-indan; boiling point: 165°-167° C./15 mm Hg; melting point: 117°-118° C. ##STR7##
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.C([Li])CCC.C=O.[OH:15][CH2:16]C1N2CCCCC2=CN=1>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:16][OH:15]
Reactant: Cc1cn(C)cn1
Reactant: OCc1ncc2n1CCCC2
Agent: C=O
Agent: [Li]CCCC
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde according to the method described for the preparation of 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (used for Example 224) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p. 125°-126° (ethyl acetate-petroleum ether).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1ccccn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccccn1
Temperature: 150 °C

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 5.10 mmol, Aldrich) in 1,4-dioxane (10 mL) in a sealed tube was treated with 2-bromopyridine (0.40 g, 2.50 mmol, Aldrich) and heated at 150° C. for 12 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.48 (m, 9H), 1.86-1.94 (m, 2H), 3.30-3.58 (m, 4H), 4.52 (brs, 0.5H), 4.67 (brs, 0.5H), 4.80 (brs, 0.5H), 4.92 (brs, 0.5H), 6.32 (d, J=9.0 Hz, 1H), 6.57 (t, J=6.0 Hz, 1H), 7.38-7.55 (m, 1H), 8.12 (d, J=6.0 Hz, 1H). MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=1)[C:5]2=O.O.[NH2:28][NH2:29]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:7][NH:29][N:28]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: O=c1c(-c2cccc(-c3ccc(F)cc3)c2)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(-c3ccc(F)cc3)c2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(4′-fluoro-biphenyl-3-yl)-7-hydroxy-chromen-4-one (0.2 g, 0.54 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-[4-(4′-fluoro-biphenyl-3-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as an off white solid (0.13 g, 63.3%); Rf 0.2 cf SM 0.7 ethyl acetate/hexane (80/20).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].Cl.[CH3:9][O:10][C:11](=[O:17])[C@H:12]([CH:14]([CH3:16])[CH3:15])[NH2:13].C(N(CC)CC)C>C1COCC1>[CH3:9][O:10][C:11](=[O:17])[C@H:12]([CH:14]([CH3:16])[CH3:15])[NH:13][C:6]([NH:5][CH2:4][CH2:3][CH2:2][Cl:1])=[O:7]
Reactant: O=C=NCCCCl
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)NCCCCl)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloropropylisocyanate (0.31 mL, 3.0 mmol) was added to a slurry of L-valine methyl ester hydrochloride (0.5 g, 3.0 mmol) and triethylamine (0.42 mL, 3.0 mmol) in THF (10 mL). The reaction mixture was stirred for 4 hours at room temperature and was then quenched with the addition of aqueous sodium bicarbonate. The quenched reaction mixture was extracted with ethyl acetate. The organic layer was separated, dried and evaporated to give the desired product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])cc1C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
2-Isopropyl-4-nitrophenol (4.7 g, 26 mmol) was dissolved in 100 mL of acetone, and 5.4 g (39 mmol) of K2CO3 was added, followed by 14.8 g (6.5 mL, 104 mmol) of iodomethane. The reaction flask was capped and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford 4.53 g of 3-isopropyl-4-methoxynitrobenzene.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:33]2([CH3:34])[C@H:18]([C@H:19]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:22]([CH2:23][C@H:24]([CH2:26][CH2:27]2)[OH:25])=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)[CH3:14])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([C@:24]1([OH:25])[CH2:26][CH2:27][C@@:28]2([CH3:29])[C:22](=[CH:21][CH2:20][C@@H:19]3[C@@H:30]2[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:8]([CH3:9])[CH3:7])[CH2:23]1)=[O:3]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@](O)(C(=O)OCCl)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
Chloromethyl chloroformate (1.96 g, 15.2 mmol) and cholesterol (5.0 g, 12.9 mmol) was dissolved in CH2Cl2 (10 ml). The solution was cooled. Pyridine (1.21 g, 15.3 mmol) was dripped into the stirred solution over 5 minutes. Heat was produced and the reaction gave a clear solution from a somewhat unclear starting solution. After 24 hours at room temperature, the mixture was diluted with CH2Cl2 (50 ml), washed with 0.5M HCl (50 ml) and water (3×25 ml). After treatment with MgSO4, the solution was evaporated to dryness.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 68.7 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-isopentyl-3-D-galactopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-isopentyl-3-D-galactopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]([N:8]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([C:16]2[C:17]([Cl:34])=[CH:18][C:19]([F:33])=[C:20]([N:22]3[C:31](=[O:32])[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[C:23]3=[O:24])[CH:21]=2)[C:9]1=[O:35])[CH:6]=[CH2:7].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:12]1[C:13](=[O:14])[N:8]([CH2:5][C:6]#[CH:7])[C:9](=[O:35])[N:10]([C:16]2[C:17]([Cl:34])=[CH:18][C:19]([F:33])=[C:20]([N:22]3[C:31](=[O:32])[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[C:23]3=[O:24])[CH:21]=2)[C:11]1=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)[nH]c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)n(CC=C)c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Reaction time: 7 h
Yield: 55.2 %

Procedure:
Propargyl bromide (0.37 mL, 3.36 mmol) is added to a mixture of N-[5-(3-allylhexahydro-2,4,6-trioxo-s-triazin-1-yl)-4-chloro-2-fluorophenyl]-1-cyclohexene-1,2-dicarboximide (1.00 g, 2.24 mmol), and potassium carbonate (0.62 g, 4.48 mmol) in N,N-dimethylformamide. The reaction mixture is stirred for 7 hours, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow oil. Flash column chromatography of the oil using silica gel and an ethyl acetate/hexanes (1:4) solution gives the title product as a white solid (0.60 g, mp 107°-114° C.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Mg].Br[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CCOCC>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21][CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)[N:14]=1)[OH:16]
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CC(C)CCBr
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (350 mg, 1.39 mmol) in Et2O (14 mL) was cooled to 0° C. To this was slowly added the freshly prepared Grignard reagent (1.26 mL, 1.53 mmol), prepared from magnesium turnings (500 mg, 0.02 mol) and 1-bromo-3-methyl butane (2.34 mL, 0.02 mol) in dry Et2O (16.5 mL). The resulting mixture was stirred under nitrogen at 0° C. After 1.5 hours, more Grignard reagent (0.3 mL, 0.36 mmol) was added and the resulting mixture stirred at 0° C. for a further 1.5 hours. The reaction mixture was then quenched by cautious addition of aqueous HCl (2M, 3 mL) and the solvent removed under vacuum. The residue was partitioned between EtOAc (30 mL) and water (20 mL), the layers separated and the aqueous re-extracted with EtOAc (30 mL). The combined organic layer was washed with brine (50 mL), dried (MgSO4) and reduced under vacuum. Purification by SPE (silica, 20 g cartridge), eluting with cyclohexane:EtOAc (gradient 99:1 to 1:1) followed by EtOAc then MeOH afforded the title compound as a colourless oil (179 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([Li])(CC)C.[B:15](OCCCC)(OCCCC)[O:16]CCCC.Cl>C1COCC1>[F:1][C:2]1[C:3]2[B:15]([OH:16])[O:6][CH2:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: OCc1cccc(F)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: OB1OCc2cccc(F)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-fluorobenzyl alcohol (3.5 parts; 0.028M) was stirred in THF (100 ml) containing tetramethylene ethylenediamine (10.2 ml; 0.067M). After cooling to -78° C., sec-butyl-lithium (77 ml of 0.8M solution in cyclohexane ex Aldrich; 0.061M) was slowly added over 45 min at between -78° and -65° C. with stirring under a nitrogen blanket. After 1 hour at -78° C., tributyl borate (16.78 ml; 0.061M) was added dropwise and the reactants stirred under nitrogen for 16 hrs allowing the temperature to slowly raise to 20° C. Dilute hydrochloric acid was added to bring the pH to about 12 and the aqueous phase separated and washed with diethylether. The pH of the aqueous phase was then acidified to about pH 2 with hydrochloric acid and extracted with ether (3×100 ml). These ether extracts were washed with saturated brine, dried over magnesium sulphate and the ether evaporated whereupon the product separated as a pale solid (2.6 parts; 62% theory) mp=132°-134° C. after recrystallisation from aqueous methanol.