Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:37]1[CH2:42][CH2:41][C:40]([C:48]([O:50][CH2:51][CH3:52])=[O:49])([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH:38]=1)(=O)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:37]3[CH2:42][CH2:41][C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:39][CH:38]=3)=[CH:14][CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC=C(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
A flask was charged with 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (3.9 g, 10.73 mmol) and potassium carbonate (6.77 g, 48.3 mmol) in dioxane (60 ml) and Water (25 ml), and stirred at room temperature for 10 minutes under nitrogen. Then Pd(PPh3)4 (1.240 g, 1.073 mmol) and diethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1,1-dicarboxylate (4.22 g, 11.27 mmol) were added to the reaction mixture. The flask was sealed, flushed with nitrogen for three times and heated at 100° C. for 1 hour. The organic solvent was evaporated under vacuum and EtOAc (3×100 ml) was used to extract and the combined organic solvent was washed by saturated aqueous sodium bicarbonate solution, brine, and dried over Na2SO4, then concentrated. The residue was purified by flash chromatography (heptanes/acetone 1/2) to afford diethyl 4′-(5-nitropyridin-2-yl)-5,6-dihydro-[1,1′-biphenyl]-4,4(3H)-dicarboxylate (2.8 g, 61%) as yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.25 (t, J=7.20 Hz, 6H) 2.30 (dt, J=6.28, 3.24 Hz, 2H) 2.53 (dd, J=4.67, 1.77 Hz, 2H) 2.76 (dd, J=3.98, 2.08 Hz, 2H) 4.20 (q, J=7.20 Hz, 4H) 6.19 (s, 1H) 7.06-8.88 (m, 7H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)O1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in analogy to example 166, from (+)-5-{3-(4-bromo-phenyl)-3-(4-fluoro-2-methyl-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 405) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (CAS RN 214360-51-7). The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown solid. MS (ESI+): m/z=520.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].[N:17]1([C:23]([O-:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:20]3[CH2:21][CH2:22][N:17]([C:23]([O:25][C:2]([CH3:14])([CH3:6])[CH3:1])=[O:24])[CH2:18][CH2:19]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C([O-])N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.12 g, 21.2 mmol, Aldrich, Cat. 525057) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.78 g, 44.5 mmol) at 0° C. The resulting solution was stirred at r.t. for one hour, and then tert-butyl 4-[methylsulfonyl)oxy]piperidine-1-carboxylate (6.3 g, 22 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 90° C. overnight. Then the reaction mixture was cooled to r.t., quenched with water, and extracted with AcOEt. The organic layer was washed with NaHCO3 aqueous solution and brine successively, dried with MgSO4, and concentrated. The residue was purified by flash column chromatography on a silica gel column using 30% ethyl acetate in hexane as eluent to afford the desired compound (2.30 g, 28.74%). LCMS (M+H)+: m/z=378.4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[CH:4]=1)#[N:2].CC(N=NC(C#N)(C)C)(C#N)C.[Br:23]N1C(=O)CCC1=O>ClCCCl>[Br:23][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1ccc(CBr)c(F)c1
Temperature: 72 °C

Procedure:
1,2-Dichloroethane (151 kg) was charged to a suitable vessel along with 4-cyano-2-fluorotoluene (24 kg) and AIBN (2 kg). The mixture was heated to 70˜74° C. Once the batch temperature reached 70° C., N-bromosuccinimide (47.4 kg) was added in portions at the rate of 12 kg/h, maintaining the temperature at 70˜74° C. (it is important to control addition rate to avoid exothermic reaction). The mixture was sampled via GC detection after 24 kg of N-bromosuccinimide was added, and the reaction was heated at 70-74° C. until complete reaction was observed. The mixture was cooled to 0-5° C. and allowed to stand for 2 additional hours. The mixture was filtered, and the cake was washed with MTBE (24 kg). The filtrate was washed with water (3×65 kg). The organic layer was dried with sodium sulfate (10.3 kg) for 6 hours, filtered and the cake was washed with MTBE (24 kg). The solution was evaporated under reduced pressure, ethanol (12 kg) was added and the mixture was heated to 40-45° C., then cooled slowly to 0-5° C. while stirring to crystallize. The mixture was filtered and the cake was washed with cold ethanol (5 kg). The crude solid was recrystallized from petroleum ether, filtered and washed with petroleum ether (10 kg), giving the title compound 4-(bromomethyl)-3-fluorobenzonitrile as an off white solid (21 kg, 55% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.46-4.50 (m, 2 H) 7.36 (dd, J=8.85, 1.32 Hz, 1H) 7.44 (dd, J=7.91, 1.32 Hz, 1 H) 7.52 (dd, J=7.91, 7.16 Hz, 1 H). 13C NMR (75 MHz, CDCl3) δ ppm 23.65 (d, J=4.60 Hz, 1 C) 113.76 (d, J=9.77 Hz, 1 C) 117.09 (d, J=2.87 Hz, 1 C) 119.44 (d, J=24.71 Hz, 1 C) 128.44 (d, J=4.02 Hz, 1 C) 130.66-130.81 (s, 1 C) 130.81-131.06 (s, 1 C) 132.18 (d, J=3.45 Hz, 1 C) 159.86 (d, J=254.03 Hz, 1C). IR: (KBr) 3088, 3077, 3040, 2982, 2250, 1571, 1508, 1439, 1248 cm−1.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>COCCO>[NH:36]1[C:37]2[C:33](=[CH:32][C:31]([NH:30][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[CH:39][CH:38]=2)[CH:34]=[CH:35]1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4[nH]ccc4c3)nn12
Yield: 23.1 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 5-Aminoindole (115 mg, 0.000870 mol) were dissolved in 2-Methoxyethanol (3.05 mL) and the The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 35.70 mg of (1H-Indol-5-yl)-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a lyophilized powder. (M+H)=356.18. 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.41 (s, 1H), 8.17 (m, 2H), 8.05 (d, 1H, J=6.13 Hz), 7.54 (m, 1H), 7.29 (m, 4H), 7.22 (m, 3H), 6.41 (m, 1H), 3.85 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH2:28][CH2:29][C:30]#[N:31])[CH:25]([CH3:27])[CH3:26])[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([Cl:33])[CH:20]=[C:21]([C:23](=[O:32])[N:24]([CH2:28][CH2:29][CH2:30][NH2:31])[CH:25]([CH3:26])[CH3:27])[CH:22]=1)[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)N(CCC#N)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N(CCCN)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A solution of (2-{3-chloro-5-[(-cyano-ethyl)-isopropyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4yl-carbamic acid tert-butyl ester (0.200 g) in methanol (2 ml) at 0° C. was treated with cobalt (II) chloride hexahydrate (0.195 g) and sodium borohydride (0.078 g) and stirred overnight at room temperature. Silica was added and the mixture was evaporated under reduced pressure, the residue was subjected to flash chromatography eluting with methanol:chloroform:ammonia(0.88) (10:89:1 v/v/v). The required fractions were evaporated under reduced pressure to give the title compound as a pale straw coloured oil (0.128 g).
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][C:13]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:14]=1[NH:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClC(Cl)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:13]([O:12][CH3:11])=[C:14]2[C:24]=1[CH:1]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([CH3:23])=[N:15]2
Reactant: CCOC(=O)/C=C(/C)Nc1cc(OC)ccc1OC
Reactant: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(OC)ccc(OC)c2nc1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 127.3 %

Procedure:
To a 0° C. solution of dimethylformamide (7.5 mL, 0.097 mol) in dichloroethane (20 mL) is added dropwise phosphorous oxychloride (9.0 mL, 0.097 mol). After stirring for 3.5 hours at room temperature, a solution of ethyl 3-(2,5-dimethoxyanilino)crotonate (25.8 g, 0.097 mol) in dichloroethane (130 mL) is added dropwise at 25° C. The resulting solution is heated at reflux temperature for 3 hours. After cooling to room temperature, the reaction is quenched by the addition of an aqueous ammonium chloride solution. Methylene chloride (200 mL) is added and the layers are separated. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is purified by chromatography using silica gel and ethyl acetate in hexanes as eluant to yield the title compound (34 g, 100%) as a yellow solid identified by IR and NMR spectral analyses.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(#N)C>O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Br:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Solvent: CC#N
Solvent: O
Product: CC(C)N(C)c1nc2c(nc1Br)CN(Cc1ccccc1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 19.5 %

Procedure:
A mixture of 8-benzyl-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (500 mg), N-bromosuccinimide (342 mg) and acetonitrile (10 mL) was stirred at room temperature for 16 hr and at 50° C. for 24 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 0-40% ethyl acetate/hexane) to give the title compound (122 mg, 20%) as a colorless oil.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[CH:9]=[CH:8][CH:7]=2.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[C:3]([OH:2])[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc2cccc(O)c2cc1O
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2cc1O
Yield: 7 %

Procedure:
To a stirred solution of 7.8 g (0.34 g atom) of sodium in 1,000 cc of ethanol, was added 85 g (0.37 mole) of ethyl 3,5-dihydroxy-2-naphthoate. After one-half hour 47 g (0.37 mole) of benzyl chloride was added. The reaction mixture was warmed under reflux for 24 hours. The hot reaction mixture was filtered and cooled in an ice bath. A tan solid precipitated out, which was filtered off yielding 15.0 g (m.p. 98°-115° C.) of the crude product. Recrystallization first from ethanol and then from acetonitrile furnished ethyl 5-benzyloxy-3-hydroxy-2-naphthoate, m.p. 112° C.-114° C. in 7 percent yield (7.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:30])/[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.NN>CO>[F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:30])/[CH2:18][NH2:19])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CN
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of (E)-2-(3-(3,5-difluoro-4-phenoxyphenyl)-2-methylallyl)isoindoline-1,3-dione (Intermediate 93.2, 100 mg, 0.25 mmol) in methanol (1 mL) was added hydrazine hydrate (25 mg, 0.5 mmol) and the reaction stirred at 50° C. overnight. The white solid was filtered with DCM, and the solvent removed from the filtrate. The residue was brought up in DCM and filtered. This was repeated until no further precipitate formed to give 49.5 mg of the title compound (71%) as a yellow oil, a 10 mg portion of which was diluted with 1N HCl and freeze dried to give 7.8 mg of the title compound as an HCl salt. 1H-NMR (400 MHz, d6-DMSO): δ 8.25 (s, 2H), 7.37 (t, 2H), 7.20 (d, 2H), 7.12 (t, 1H), 6.97 (s, 1H), 3.57 (s, 2H), 1.96 (s, 3H). MS (m/z): 258.96 (M-NH2).
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH:20](=[O:24])[CH2:21][CH2:22][CH3:23]>O1CCCC1>[OH:24][CH:20]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC=O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)OCC)cc1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
At −40° C., isopropylmagnesium chloride lithium chloride (15.3 mL, 1.3 M in THF, 19.9 mmol) was added dropwise to a solution of ethyl 4-iodobenzoate (5000 mg, 18.11 mmol) in tetrahydrofuran (30 mL). The solution was stirred at −40° C. for 40 minutes. Butyraldehyde (1830 mg, 25.4 mmol) was added. The mixture was allowed to warm to room temperature over 3 hours. The reaction was quenched with 1N HCl and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1-hydroxybutyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 4.83-4.66 (m, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.86 (d, J=3.7 Hz, 1H), 1.83-1.61 (m, 2H), 1.51-1.42 (m, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.36-1.23 (m, 1H), 0.94 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]1[C:8](=[O:10])[C:7]2[C:2](=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=2)[NH:1][C:26]1=[O:27]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
To a solution of 1.0 g of ethyl 4-amino-2-(methylsulfanyl)pyrimidine-5-carboxylate in 15 mL of N,N-dimethylformamide, 315 mg of sodium hydride was added, and the resulting mixture was stirred at room temperature for 5 minutes. To the reaction mixture, 970 mg of 2,6-dichlorophenyl isocyanate was added, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture, ethyl acetate and a 1 N aqueous hydrochloric acid solution were added and the organic layer was separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The precipitated solid was solidified with methanol and collected by filtration, whereby 1.43 g of the title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2(C=O)[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2CC[C@@]2(C)[C@H]1CCC2=O.O[C@@]1(C)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C=O)C(=CC(=O)CC1)C=C3.O[C@@]1(C#CC)CC[C@H]2[C@H]3[C@H:65](CC[C@]12C)[C@:62]1([CH:63]=[O:64])[C:57](=[CH:58][C:59](=[O:68])[CH2:60][CH2:61]1)[CH:56]=[CH:55]3.C[C@]12CC[C@H]3[C@@H](C=CC4[C@]3(C=O)CCC(=O)C=4)[C@@H]1CCC2=O>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][CH2:17][C@@:16]2([CH3:15])[C:3]=1[CH2:4][C@@H:5]([CH3:6])[C@@H:58]1[C@:59]2([OH:68])[CH2:60][CH2:61][C@@:62]2([CH3:65])[C@H:57]1[CH2:56][CH2:55][C@@H:63]2[OH:64]
Reactant: CC#C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@@]21C
Reactant: CC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C=O)CCC1=O
Agent: C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@@]21C
Agent: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O
Product: CC1=C2C[C@@H](C)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@]3(O)[C@@]2(C)CC[C@@H]1O

Procedure:
Substituting 4-methyl-4,6-androstadiene-3,17,19-trione, 17β-hydroxy-17α-methyl-4,6-androstadiene-3,19-dione and 17β-hydroxy-17α-propinyl-4,6-androstadiene-3,19-dione for the 4,6-androstadiene-3,17,19-trione above results in the formation of 4,7α-dimethyl-4-androstene-3β,17β,9-triol, 7α,17α-dimethyl-4-androstene-3β,17β,19-triol and 7α-methyl-17α-propinyl-4-androstene-3β,17β,19-triol, respectively.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cc1ccc(C(=O)CCCCCBr)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)c(C)c2)CC1
Yield: 42.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound, potassium carbonate (3.0 g) and 6-bromo-1-(3,4-dimethylphenyl)-1-hexanone (1.1 g) were reacted and treated in the same manner as in Example 172 to give 0.82 g of 4-amino-5-chloro-N-((1-(6-(3,4-dimethylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH:12]=[CH:11]2.[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][C:34]=2[O:40][CH3:41])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:12]=[CH:11][C:10]4[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@@H:2]5[CH2:3][CH2:4][CH2:5][O:1]5)[CH:9]=4)[C:14]3=[O:18])=[CH:35][C:34]=2[O:40][CH3:41])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=c1occc2cc(OC[C@@H]3CCCO3)ccc12
Reactant: COc1cc(N)ccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(C(=O)OC(C)(C)C)CC1

Procedure:
Reaction of 6-[(S)-1-(Tetrahydro-furan-2-yl)methoxy]-isochromen-1-one with 4-(4-Amino-2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester by method AJ resulted in the desired product with the molecular weight of 549.67 (C31H39N3O6); MS (ESI): 550 (M+H+).
Reaction SMILES: [CH2:1]([C:8]([NH2:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C1O[N:17]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C(Cl)Cl>[CH2:1]([C:8]([NH:13][NH:17][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:11][CH3:12])[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(N)(CC)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC(CC)(Cc1ccccc1)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.68 g of 3-benzylpentan-3-amine was dissolved in 20 mL of methylene chloride, mixed with 4.8 g (18 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice, and stirred at room temperature for 30 minutes, and the reaction solution was washed with 10% aqueous citric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate, and methylene chloride was removed under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=0:100 to 20:80) to give 1.62 g of the desired product as a light brown solid.