Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:13]Br.OS([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:13][C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]=1
Reactant: BrBr
Reactant: Clc1ccc(-n2cccn2)cc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(-n2cc(Br)cn2)cc1
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A solution of 1-(4-chlorophenyl)pyrazole (834 mg, 4.67 mmol) in acetic acid (10 mL) is treated with bromine (0.26 mL, 5.08 mmol). After stirring for 18 h, the solution is diluted with 40 mL water, and satd. aq. NaHSO3 solution is added until the bromine color had dissipated. Then, solid sodium bicarbonate is added until a neutral pH is obtained. This mixture is extracted with ethyl acetate (2×50 mL), and the extracts are washed with brine, combined, dried over MgSO4, filtered and evaporated. The solid residue is recrystallized from cyclohexane to afford pure product, 4-bromo-1-(4-chlorophenyl)-pyrazole (797 mg, 3.10 mmol, 66%). m.p. 75-76° C. (cyclohexane), 1H NMR (300 MHz, CDCl3): δ 7.89 (1H, s), 7.66 (1H, s), 7.57 (2H, d, J=9.0 Hz), 7.41 (2H, d, J=9.0 Hz). MS (ES+): m/e 261 (26), 259 (100), 257 (77).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.[NH4+].[Cl-]>ClCCl>[Br:13][C:9]1[N:8]=[C:7]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Product: OC1(c2cccc(Br)n2)CCC1
Reaction time: 0.25 h

Procedure:
n-Butyllithium (6.85 mL, 11.0 mmol) was added to a suspension of 2,6-dibromopyridine (2.36 g, 9.96 mmol) in dichloromethane (60 mL) at −78° C. The reaction mixture was stirred for 15 minutes and cyclobutanone (0.838 g, 12.0 mmol) was added in one portion at −78° C. The reaction was stirred for an additional 30 minutes before pouring the reaction into a mixture of saturated aqueous NH4Cl and dichloromethane. The organic layer was concentrated to dryness and was purified by flash chromatography to yield 1-(6-bromopyridin-2-yl)cyclobutanol as a light yellow oil. MS ESI calc'd. for C9H11BrNO [M+H]+ 228 and 230. found 228 and 230.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10][O:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)Nc1ccc(CBr)cc1C(=O)OC
Reactant: Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)Nc1ccc(COc2ccc(Cl)cc2Cl)cc1C(=O)OC
Reaction time: 4 h
Yield: 71.8 %

Procedure:
A mixture of 5-bromomethyl-2-propionylamino-benzoic acid methyl ester (200 mg, 0.67 mmol), 2,4-dichloro-phenol (119 mg, 0.73 mmol) and potassium carbonate (278 mg, 2.01 mmol) in acetone (5 ml) was heated to reflux. After 4 hours, the reaction mixture was allowed to reach room temperature, was acidified with 1 M HCl and the resulting precipitate collected by filtration, washed with water and dried under vacuum to give pure 5-(2,4-dichloro-phenoxymethyl)-2-propionylamino-benzoic acid methyl ester (184 mg, 72%). This was hydrolyzed in ethanol (3 mL) and 1.0 M NaOH (3 mL) overnight and then acidified with 1.0 M HCl. The resulting precipitate was collected by filtration, washed with water and dried under vacuum (165 mg, 93%). 1H-NMR (DMSO-d6) δ 1.12 (t, 3H), 2.42 (q, 2H), 5.21 (s, 2H), 7.27 (d, 1H), 7.39 (dd, 1H), 7.60 (d, 1H), 7.66 (dd, 1H), 8.09 (d, 1H), 8.53 (d, 1H), 11.18 (s, 1H), 13.71 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C12BC(CCC1)CCC2.[OH-:34].[Na+].OO>O1CCCC1.O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:34])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: C=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 71.6 %

Procedure:
To 1-(4-(trifluoromethoxy)phenyl)-3-(4-vinylphenyl)-1H-1,2,4-triazole (C43) (2.0 g, 6.0 mmol) in tetrahydrofuran (50 mL) was added 9-borabicyclo(3.3.1)nonane (24 mL, 12.1 mmol), and the reaction was stirred at room temperature for 4.5 hours. Sodium hydroxide (3 N, 4.0 mL, 12.0 mmol) was added, followed by hydrogen peroxide (30% wt, 1.5 mL, 15.1 mmol). The light green solution was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a light green oil. The crude compound was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (1.5 g, 69%): mp 85-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.06 (d, J=9.0 Hz, 2H), 8.01 (d, J=8.1 Hz, 2H), 7.61 (dd, J=9.2, 1.0 Hz, 2H), 7.41-7.30 (m, 2H), 4.69 (t, J=5.2 Hz, 1H), 3.65 (td, J=7.0, 5.1 Hz, 2H), 2.79 (t, J=6.9 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 162.18, 147.08, 143.70, 141.45, 135.72, 129.39, 128.23, 127.93, 125.96, 122.57, 121.10, 61.90, 61.90; 19F NMR (376 MHz, DMSO-d6) δ −56.98; ESIMS m/z 349 ([M+H]+).
Reaction SMILES: C[O-].[Na+].[O:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O>CN(C=O)C>[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=[C:5]1[C:6](=[O:14])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:4]1
Reactant: O=C1COc2ccccc2N1
Reactant: O=Cc1ccc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2OC1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0,01 mol) and pyrrole-2-carboxaldehyde (1.58 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed for 48 h, then cooled at room temperature and poured into crushed ice and left overnight at 4° C. The precipitated solid was collected by filtration, washed with water and dried. The precipitate was boiled with ethanol (150 ml) and filtered while hot to remove impurities. The filtrate was evaporated to dryness under reduced pressure, and the residue was chromatographed on a silica gel column using (95:5) toluene:ethyl acetate as the mobile phase.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[H][H].C(N(CC)CC)C>O1CCCC1.[Pd]>[O:12]=[S:9]1(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]2[CH:14]=[CH:2][CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[C:5]=2[O:10]1
Reactant: [H][H]
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 0 °C
Yield: 75.1 %

Procedure:
120 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide are dissolved in 2.4 liters of tetrahydrofuran and the solution is hydrogenated with hydrogen for 40 minutes, in the presence of 41.3 g of triethylamine and 12.0 g of 5% palladium on carbon catalyst, under normal pressure and in the temperature range from 20° to 25° C. The mixture is filtered, the filtrate is concentrated, and the residue is taken up in 1300 ml of hot 90% aqueous ethanol. The insoluble constituents are separated and the solution is cooled to 0° C. The precipitate is separated and dried, affording 70 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 204°-205° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]2([C:31]([F:34])([F:33])[F:32])[CH2:17][CH2:16][N:15]([C:18]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:13]2([C:31]([F:32])([F:33])[F:34])[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[CH:20][C:21]([CH2:22][OH:23])=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)c1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reaction time: 5 h
Yield: 90.6 %

Procedure:
6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoromethyl)nicotinic acid (1.11 g) was dissolved in methylene chloride (30 ml), and to the solution was added oxalyl chloride (0.54 ml, 6.16 mmol) and one drop of dimethylformamide at room temperature. After stirring for 5 hours, the solvent and excess oxalyl chloride were distilled off under reduced pressure. The residue was dissolved in dioxane, added with water, and then added with sodium borohydride (0.23 g) at 0° C. The mixture was stirred for 2 hours at room temperature and added with diluted hydrochloric acid. The mixture was extracted with ethyl acetate, dried over magnesium sulfate and filtered. After concentration under reduced pressure, the target compound (0.98 g) was obtained by purification with silica gel column chromatography.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21](=O)[CH3:22].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:28][O:27][C:25]([CH2:24][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:22])=[C:13]([Cl:12])[CH:14]=1)=[O:26]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(Cl)c1
Yield: 9.7 %

Procedure:
Following a procedure similar to that described in Example 6, but using 5.15 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 10.3 g of methyl 3-chloro-4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 19), 200 ml of benzene, 100 ml of absolute methanol and 6 g of sodium cyanoborohydride, 1.2 g of the title compound were obtained as crystals, melting at 83°-103° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1cccc(Br)c1
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
3-Bromoaniline is coupled with 4-chloro-6-nitroquinazoline, to produce 4-[(3-bromophenyl)amino]-6-nitroquinazoline, which is reduced thereafter to the corresponding 6-aminoquinazoline. The 4-[(3-bromophenyl)amino]-6-aminoquinazoline is then reacted with bistributyltin, using tetrakis(triphenylphosphine)palladium in THF solution as the reaction catalyst, as is described hereinbelow (see, iodine-124 labeled Compound 5). The stanylated quinazoline is then reacted with bromine-76 or bromine-77, in the presence of an oxidizing agent, to produce bromine-76 labeled or bromine-77 labeled 4-[(3-bromophenyl)amino]-6-aminoquinazoline, which is farther reacted with acryloyl chloride as described, to yield the final bromine-76 labeled or bromine-77 labeled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[N:61]=[C:60]([NH2:62])[CH:59]=[CH:58][N:57]=2)=[CH:51][CH:50]=1>ClCCCl>[NH2:62][C:60]1[CH:59]=[CH:58][N:57]=[C:56]([NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][NH:46][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:50][CH:51]=2)[N:61]=1
Reactant: NCCc1ccc(Nc2nccc(N)n2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4nccc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), DIPEA (0.134 mL, 0.76 mmol) and N2-[4-(2-aminoethyl)phenyl]pyrimidine-2,4-diamine (49 mg, 0.15 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[S:7][CH:8]=[C:9]([CH3:10])[C:5]=2[CH:4]=1.C([Li])CCC.[C:18](=[O:20])=[O:19]>CCOCC>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[S:7][C:8]([C:18]([OH:20])=[O:19])=[C:9]([CH3:10])[C:5]=2[CH:4]=1
Reactant: Cc1csc2ccc(CO)cc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(C(=O)O)sc2ccc(CO)cc12
Reaction time: 2 h

Procedure:
A solution of 5-hydroxymethyl-3-methylbenzo[b]thiophene (8.50 g.) in dry ether (120 ml.) was added dropwise to a stirred solution of n-butyl lithium (72 ml. of 1.6 M solution in hexane) in dry ether (120 ml.) at 0° under an atmosphere of dry nitrogen. The resulting mixture was stirred at 0° for 2 hours and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The solid was filtered off, washed well with water and crystallized from ethanol to give 5-hydroxymethyl-3-methylbenzo[b]thiophene-2-carboxylic acid (4.80 g.), m.p. 260°-262°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([CH3:23])[CH:19]=[CH:18]2)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Se](=O)=[O:25]>O1CCOCC1.O>[Si:1]([O:8][CH2:9][C@H:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([CH:23]=[O:25])[CH:19]=[CH:18]2)[CH3:11])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: Cc1ccc2cccc(O[C@H](C)CO[Si](C)(C)C(C)(C)C)c2n1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc2ccc(C=O)nc12
Yield: 83.9 %

Procedure:
To a solution of (R)-8-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-methylquinoline (0.33 g, 1.0 mmol) in dioxane (40 mL) and water (0.4 mL) was added selenium dioxide (0.13 g, 1.2 mmol) and the resultant mixture heated at reflux for 1 hour. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10% ethyl acetate/hexanes) providing the title compound (0.29 g, 84%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([SiH](CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]cc(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution of 5-cyanoindole (10.00 g, 70.34 mmol) in acetonitrile (120 ml) was added to a solution of 1-benzyloxycarbonyl-4-piperidone (8.20 g, 35.17 mmol) and trimethylsilyl trifluoromethanesulfonate (6.80 ml, 35.17 mmol) in acetonitrile (230 ml) via addition funnel at 0° C. over 1.5 h. Triethylsilane (4.2 ml, 26.28 mmol) was added at 0° C. and reaction mixture was allowed to gradually warm to RT over 2 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over MgSO4, and concentrated in vacuo. The residue was diluted with acetonitrile (300 ml) and hexanes (200 ml) and stirred for 20 min. The organics were removed in vacuo and the residue was chromatographed (SiO2, 20-40% ethyl acetate/hexanes) to give 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine as a white crystalline solid (59%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:2]=[O:3].[CH:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=2[CH:15]=[CH:14][N:13]=1.BrC1C=CC(CN=C=O)=CC=1>>[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:3])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1cccc2cnccc12
Reactant: CCCCCCCCN=C=O
Agent: O=C=NCc1ccc(Br)cc1
Product: CCCCCCCCNC(=O)Nc1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 60F using 1-isocyanatooctane and 5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) δ 9.53 (s, 1H), 9.23 (s, 1H), 8.65 (d, 1H), 8.99 (d, 1H), 8.05 (d, 1H), 7.86 (t, 1H), 7.01 (m, 1H), 3.15 (m, 2H), 1.51 (m, 2H), 1.28 (m, 5H), 0.83 (m, 3H); MS (ESI) (M+H)+ 300.
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].Cl.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([SH:20])[N:15]=1.C(N(CC)CC)C>CCO>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[CH2:3][S:20][C:16]1[N:15]=[C:14]([CH3:13])[CH:19]=[CH:18][N:17]=1
Reactant: Cc1ccnc(S)n1
Reactant: Clc1cncc(Cl)c1CBr
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccnc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (1.3 g, 5.0 mmol), 4-methylpyrimidine-2-thiol hydrochloride (543 mg, 3.3 mmol), and triethylamine (1.8 mL, 12.9 mmol) in absolute EtOH (35 mL) was stirred at room temperature overnight. The mixture was evaporated, co-evaporated with EtOAc (10 mL), and dried in vacuo. The solid residue was treated with water (75 mL). The mixture was extracted with 50% ethyl acetate/Et2O (75 mL). The organic extract was extracted with brine (2×75 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-4% MeOH/CH2Cl2), affording the title compound (800 mg, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H), 4.70 (s, 2H), 7.17 (d, 1H, J=5.1 Hz), 8.54 (d, 1H, J=5.1 Hz), 8.67 (s, 2H); M+ 287.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl (±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (124 mg, 0.27 mmol) and corresponding 2,3-dichlorophenylboronic acid (104 mg, 0.54 mmol), to afford after chromatographic purification the title compound (157 mg, 99%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.30-7.40 (m, 1H), 7.20 (s, 1H), 7.18 (d, 1H, J=3.6 Hz), 6.99 (s, 1H), 6.94 (s, 1H), 3.80-3.90 (m, 1H), 3.60-3.80 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS (CI, NH3): 445 (base, M+H).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][C:14]([CH:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)=[CH:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([CH:5]1[CH2:6][CH2:7][CH:8]([CH:11]2[CH2:16][CH2:15][C:14]([CH:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[CH:13][CH2:12]2)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCC(C2CC=C(C3CCC(=O)CC3)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC1CCC(C2CC=C(C3CCC(O)CC3)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
In 50 ml of ethanol was dissolved 4.0 g (13 mmol) of the 4-(4-(4-n-butylcyclohexyl)-1-cyclohexenyl)cyclohexanone described above, and the solution was cooled down to 0° C. Sodium borohydride in an amount of 0.25 g (6.6 mmol) was gradually added thereto such that the liquid temperature did not exceed 15° C., and the mixture was stirred for 1 hour. Water in an amount of 50 ml was added to the reaction solution, the product thus formed was extracted with ether, the extract was washed with 1N hydrochloric acid and water in this turn, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=3/1), the solvent was distilled off. The residue was recrystallized from ethanol to give 1.6 g (5.0 mmol) of 4-(4-(4-n-butylcyclohexyl)-1-cyclohexenyl)cyclohexanol. Yield of this compound based on 4-(4-(4-n-butylcyclohexyl)-1-cyclohexenyl)-cyclohexanone was 38%.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:8][CH:7]=1.Br[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][C:30](=[O:38])[CH:29]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30](=[O:38])[CH:29]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:11])=[CH:24][CH:25]=1
Reactant: O=c1cc(CBr)c2ccccc2[nH]1
Reactant: CCOC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(=O)[nH]c2ccccc12)(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Reaction time: 1 h

Procedure:
100 ml of anhydrous ethyl alcohol and 2.23 g of sodium ethoxide (96%) were added to a 500 ml flask, and the mixture was cooled down to below 5° C. After adding 7.91 g of diethyl 4-chlorobenzamidomalonate, the resulting solution was stirred at below 5° C. for one hour. 5.00 g of 4-bromomethylquinolinon was added to the mixture and the resulting solution was stirred at the room temperature for 16 hours to produce an intermediate, ethyl 2-(4-chlorobenzoylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate. After the completion of the reaction, 2.71 g of sodium hydroxide (93%) was added to the above solution, which was then stirred at the room temperature for about 2 hours. Subsequently, the resulting solution was warmed to about 60° C. and stirred for 4 hours to complete the reaction. The concentrated hydrochloric acid were added to the residue for crystallization. The crystal thus obtained was filtered and then subjected to recrystallization with DMF and water to yield 7.15 g (91.78%) of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid.