Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:16](Cl)=O)[CH:10]=[C:11]([CH:15]=2)[C:12](Cl)=O)=[CH:4][CH:3]=1.CC1C=C(C=C(C)C=1)[O-].[K+].BrC1C=CC(Br)=CC=1.[OH-].[K+]>[Cu]>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:15]=[C:11]([CH3:12])[CH:10]=[C:9]([CH3:16])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(Oc2ccc(Br)cc2)cc(C(=O)Cl)c1
Agent: [Cu]
Agent: Cc1cc(C)cc([O-])c1
Agent: [K+]
Solvent: Brc1ccc(Br)cc1
Product: Cc1cc(C)cc(Oc2ccc(Br)cc2)c1
Yield: 60 %

Procedure:
The synthetic route to 5-(4-bromophenoxy)isophthaloyl chloride is depicted in Equation II below. Potassium 3,5-dimethylphenoxide (1.0 mole) was reacted with 1,4-dibromobenzene (2.0 moles) in the presence of copper at 200° C. under nitrogen for two hours. The hot reaction mixture was poured into aqueous potassium hydroxide and subsequently filtered. The resulting oily filtrate was extracted with methylene chloride and the organic phase was washed with water. The methylene chloride was removed and the residue was distilled under vacuum to provide 1-(4-bromophenoxy)-3,5-dimethylbenzene as a colorless liquid in 60% yield. 1-(4-Bromophenoxy)-3,5-dimethylbenzene was oxidized with potassium permanganate (6:1 molar ratio) in a 1:1 mixture of pyridine and water at 90° C. for six hours. The brown reaction mixture was filtered and the filtrate was acidified to afford 5-(4-bromophenoxy)isophthalic acid (m.p. 310°-320° C.) in 80% crude yield. The dicarboxylic acid was refluxed in excess thionyl chloride containing a few drops of N,N-dimethylformamide for six hours. The excess thionyl chloride was removed under vacuum to yield an orange residue which was recrystallized twice from heptane to afford 5-(4-bromophenoxy)isophthaloyl chloride as pale yellow crystals, m.p. 80°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[Cl:32][C:33]1[S:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:36]2[S:37][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: OB(O)c1ccc(Cl)s1
Product: COC(=O)c1cc(-c2ccc(Cl)s2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 61.1 %

Procedure:
In the same manner as described in Example 241, 505 mg (1.0 mmol) of the product of Example 89 and 357 mg (2.2 mmol) of 5-chlorothiophene-2-boronic acid provided 332 mg (61%) of the desired product as an yellow solid. Electrospray Mass Spec 543 (M+H).
Reaction SMILES: FC1C=C([CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[O:9]2)C=CC=1.[N+](C1C=C(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=1)([O-])=O>>[O:9]1[C:10]2[C:15](=[CH:14][C:13]([OH:18])=[CH:12][CH:11]=2)[CH2:16][CH2:17][CH2:8]1
Reactant: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Agent: O=[N+]([O-])c1cccc(C2CC(O)c3cc(O)ccc3O2)c1
Product: Oc1ccc2c(c1)CCCO2

Procedure:
2-3-Nitrophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 2-(3-nitrophenyl)chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 8.80 (s, 1H), 8.26 (s, 1H), 8.19 (dd, 1H, J 8.1, 2.3 Hz), 7.90 (d, 1H, J 7.9Hz), 7.70 (t, 1H, J 15.9, 7.9 Hz), 6.70 (d, 1H, J 8.4 Hz), 6.51-6.55 (m, 2H), 5.19 (dd, 1H, J 10.0, 2.0), 2.86-2.91 (m, 1H), 2.61-2.68 (m, 1H), 2.17-2.23 (m, 1H), 1.91-1.97 (m, 1H).
Reaction SMILES: [CH3:1][O-].[Na+].Cl.[CH3:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1.C=O.[BH4-].[Na+].[OH-].[Na+]>CO>[CH3:1][NH:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH3:5])=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: C[O-]
Reactant: Cc1n[nH]c2cc(N)ccc12
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CNc1ccc2c(C)n[nH]c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
To a 100-mL flask containing 1.88 g (34.8 mmol) sodium methoxide and 60 mL of dry methanol was added 1.27 g (6.96 mmol) of 3-methyl-1H-indazol-6-amine hydrochloride. After stirring the mixture at room temperature for 15 minutes, 0.38 g (12.6 mmol) of paraformaldehyde was added and the flask placed into a 60° C. oil bath for 10 minutes. The flask was then removed from the oil bath and allowed to stir at room temperature for 4.5 hours. To the reaction mixture was added 0.26 g (6.96 mmol) of sodium borohydride and the mixture heated to reflux for 2 hours then allowed to cool to room temperature and stir overnight. To the reaction mixture was added 1M sodium hydroxide (13 mL). After 10 minutes the reaction mixture was concentrated in vacuo to an aqueous suspension. The suspension was diluted with 40 mL of water and pH adjusted to pH 8 with aq. hydrochloric acid. The aqueous suspension was extracted three times with ethyl acetate, and the organic extracts combined and washed with brine, dried with sodium sulfate, and filtered. To the filtrate was added 5 g of silica gel and the resultant suspension concentrated to dryness in vacuo. The solid was loaded on top of a column of 90 g of silica gel and eluted with chloroform/ethyl acetate/methanol (9:0.5:0.5). The proper fractions were combined and concentrated to give 0.43 g (39%) of N, 3-dimethyl-1H-indazol-6-amine as a white solid. HNMR: δ 11.88 (s, 1H), 7.29 (d, 1H), 6.44 (d, 1H), 6.20 (s, 1H), 5.80 (brs, 1H), 2.67 (s, 3H) 2.32 (s, 3H); MS (ES+, m/z) 162 (M+H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]1[CH2:16][O:15][CH2:14][CH2:13]1>C[C@@H](N(C)C)[C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.[Fe].O>[OH:15][C@@H:16]1[C:12]2[C:2](=[CH:10][CH:9]=[CH:14][CH:13]=2)[CH:3]=[CH:7][C@H:8]1[N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C1CCOC1
Agent: [Fe]
Agent: C[C@H]([C]1[CH][CH][CH][C]1P(c1ccccc1)c1ccccc1)N(C)C
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=Cc2ccccc2[C@H]1O
Temperature: 80 °C
Yield: 52 %

Procedure:
To a flame dried round bottom flask, [Rh(COD)Cl]2 (5.4 mg, 0.011 mmol), (R)—(S)-BPPFA (12.2 mg, 0.022 mmol), phthalimide (510 mg, 3.47 mmol) and 1 (100 mg, 0.69 mmol) were added. THF (4 mL) was then added, followed by heating to 80° C. for 3 days. The reaction mixture was then poured in to water and extracted three times with ethyl acetate. The organic layers were combined, washed with brine dried over Na2SO4, and concentrated in vacuo. The resulting solid was purified by flash chromatography (30% ethyl acetate in hexanes) to give 2 as a white crystalline solid (103.5 mg, 52%). The ee was determined to be 74% using HPLC analysis on a CHIRALCEL OD column, λ=486 nm. Retention times in 10% isopropanol in hexanes were 21.1 min (major)and 29.1 min. Rf=0.36 on silica gel (30% ethyl acetate:hexanes); mp 175-176° (dec); [α]25D=6.1° (c=12.9, CHCl3); IR (KBr, cm−1) 3536 (br), 3067 (w), 2921 (w), 1772 (m), 1693 (s), 1388 (s), 1084 (m), 955 (m), 719 (s); 1H NMR (400 MHz, CDCl3) δ 7.78-7.75(2H, m), 7.68-7.64 (2H, m), 7.57-7.55 (1H, m), 7.26-7.22 (2H, m), 7.09-7.07 (1H, m), 6.51 (1H, dd, J=9.7, 2.7 Hz), 5.84 (1H, ddd, J=9.7, 2.7, 2.2 Hz), 5.48 (1H, d, J=12.8 Hz), 5.12 (1H, ddd, J=12.8, 2.5, 2.4 Hz), 2.82 (1H, s); 13C NMR (400 MHz, CDCl3) δ 168.6, 137.3, 134.2, 132.6, 132.1, 128.7, 128.2, 128.1, 126.9, 126.5, 124.4, 123.5, 70.9, 55.3. HRMS calcd for C18H11NO2 (M+-H2O): 273.2939. Found: 273.0793.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.Cl.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1)([O-:21])=[O:20]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:16]([O:15][C:13]([CH:4]1[CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][C:7]2[C:26]3[C:25](=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[NH:28][C:2]=2[CH2:3]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C1CCC(=O)CC1C(=O)OCC
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCOC(=O)C1Cc2[nH]c3ccc([N+](=O)[O-])cc3c2CC1C(=O)OCC
Yield: 21 %

Procedure:
To 50 ml of acetic acid were added 2.4 g of diethyl 4-oxocyclohexane-1,2-dicarboxylate, 3.0 g of zinc chloride and 1.9 g of 4-nitrophenylhydrazine hydrochloride. The mixture was refluxed for 4 hours. Then, acetic acid was removed by distillation under reduced pressure. To the residue were added 100 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with diluted hydrochloric acid, an aqueous saturated sodium chloride solution, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from iso-propyl alcohol to obtain 750 mg (yield: 21%) of diethyl-6-nitro-1,2,3,4-tetrahydrocarbazole-2,3-dicarboxylate as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O>C(O)C>[N:8]1([C:7]2[C:15]([CH3:14])=[C:16]([NH2:17])[C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1c(N2CCOCC2)ccc(N)c1N
Temperature: 20 °C
Yield: 98.6 %

Procedure:
4-(3,4-Dinitro-benzyl)-morpholine (0.800 Kg, 2.99 mol, 1.0 wt), and ethanol (11.20 L, 14.0 vol) were charged to a suitable flask and stirred at 15 to 25° C. and a vacuum/nitrogen purge cycle was performed three times. 10% Palladium on carbon (10% Pd/C, 50% wet paste, 0.040 Kg, 0.05 wt wet weight) was slurried in ethanol (0.80 L, 1.0 vol) and added to the reaction. The mixture was cooled to 10 to 20° C. and a vacuum/nitrogen purge cycle was performed three times. A vacuum/hydrogen purge cycle was performed three times and the reaction was stirred under a hydrogen atmosphere at 10 to 20° C. Reaction completion was determined by 1H NMR analysis (d6-DMSO), typically 14 to 20 hours. A vacuum/nitrogen purge cycle was performed three times and the reaction mixture was filtered through glass microfibre paper under nitrogen. The filter-cake was washed with ethanol (3×0.80 L, 3×1.0 vol) and the combined filtrate and washes were concentrated to dryness under vacuum at 35 to 45° C. to give 4-morpholin-4-yl-methyl-benzene-1,2-diamine (0.611 Kg 98.6%) as a brown solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1)(=O)C.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>CO>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]2[CH2:7][CH2:8][CH2:9][NH:4][CH2:5]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)N1CCCC(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C(c2ccccc2)C2CCCNC2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
1-acetyl-3-(diphenylmethyl)piperidine (250 mg) was added to methanol (12 ml) and 10N aqueous potassium hydroxide solution (4 ml), and the mixture was stirred at 80° C. for 3 hours. Aqueous saturated potassium carbonate solution was added to the reaction solution and the mixture was extracted once with ethyl acetate, followed by drying the organic layer over anhydrous sodium sulfate. The solvent was removed to obtain 220 mg of 3-(diphenylmethyl)piperidine. Yield: 100%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:29][CH2:28]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@H]1CC[C@H](C(=O)OCC)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with trans-4-amino-cyclohexanecarboxylic acid ethylester following general procedure B to afford 8-methoxy-4-(trans-4-ethoxycarbonyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (207 mg). Thus obtained amino-ester (200 mg, 0.50 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-cyclohexane-carboxylic acid ethyl ester (175 mg). LCMS: m/z 508 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC#N>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C1COCCN1
Reactant: COc1cccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)c1
Solvent: CC#N
Product: COc1cccc(Nc2nccc(-c3sc(NC(=O)CCN4CCOCC4)nc3C)n2)c1

Procedure:
By treatment of 3-bromo-N-{5-[2-(3-methoxyphenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with morpholine. Anal. RP-HPLC: tR=13.6 min (0-60% MeCN, purity>94%). 1H-NMR (DMSO-D6) δ: 1.20 (m, 2H, CH2), 2.48 (m, 4H, CH2), 2.58 (s, 3H, CH3), 3.41-3.57 (m, 6H, CH2), 3.79 (s, 3H, CH3), 6.52 (d, 1H, J=7.0 Hz, Ph-H), 7.07 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.15 (t, 1H, J=7.3 Hz, Ph-H), 7.22 (m, 1H, Ph-H), 7.62 (brs, 1H, Ph-H), 8.46 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.58 (brs, 1H, NH). MS (ESI+) m/z 456.01 [M+H]+ (C22H26N6SO3 requires 454.55).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:23]2[CH2:22][CH2:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)([OH:26])[CH2:25][CH2:24]2)=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)cc2)CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 59.1 %

Procedure:
A mixture of 3-(2-bromoethyl)indole (1.06 g; 4.73 mM), 4-(p-chlorophenyl)piperidin-4-ol (1.0 g; 4.72 mM), potassium carbonate (0.75 g; 5.42 mM) and dimethylformamide (12 ml) was stirred in an oil-bath maintained at 75° for 19.5 hours under a nitrogen blanket. The mixture was poured onto water (50 ml) and cooled in ice. The sticky, yellow solid which formed was filtered off and washed well with water. It was then promptly transferred to a new flask (the solid tended to gum) and dissolved in ethanol, acidified with ethanolic HCl and the solvents evaporated. The residue was crystallised from iso-propanol/ethyl acetate, then twice triturated well with ethanol/ethyl acetate. Filtration gave the title compound as the hydrochloride (0.99 g; 53.5%) as very pale pink plates, m.p. 248°-252° (dec; decomposition occurred above 235°).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([N+:9]([O-:11])=[O:10])[C:6](=[O:8])[N:7]=1.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:8][C:6]2[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:3]=[C:2]([NH2:1])[N:7]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Nc1nc(=O)c([N+](=O)[O-])c(-c2ccco2)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc(-c3ccco3)c2[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A suspension of 2-amino-6-(2-furyl)-5-nitropyrimidine-4(1H)-one (1.00 g, 4.50 mmol) in dichloromethane (50 mL) was treated with triethylamine (0.941 mL, 6.75 mmol) and p-toluenesulfonyl chloride (944 mg, 4.95 mmol), stirred for 1 h, diluted with dichloromethane (50 mL), washed with 2-M HCl (20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (2:1)] to give the title compound (410 mg, 24%) as a yellow solid; NMR δH (400 MHz, CDCl3) 7.95 (2H, d, J 8.5 Hz), 7.59–7.57 (1H, m), 7.39 (2H, d, J 8.5 Hz), 7.23–7.21 (1H, m), 6.59–6.51 (1H, m), 5.39 (2H, br s), 2.48 (3H, s); Retention time 5.68 min.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:38])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH:25]2[CH:29]([OH:30])[CH2:28][N:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26]2)[N:19]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16](=[O:38])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH:25]2[C:29](=[O:30])[CH2:28][N:27]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:26]2)[N:19]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CN(Cc3ccccc3)CC2O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(CC2CN(Cc3ccccc3)CC2=O)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of DMSO (0.02 mol) in 30 mL of anhydrous CH2Cl2 was added dropwise oxalyl chloride (0.015 mol). The mixture was stirred at −78° C. for 10 min. After this time a solution of [6-(1-benzyl-4-hydroxy-pyrrolidin-3-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester I-3 (0.01 mol) in 10 mL of anhydrous CH2Cl2 was added dropwise at a rate to keep the reaction temperature below −60° C. Upon complete addition, the mixture was allowed to stir at −78° C. for 2 h. Then anhydrous triethylamine (0.03 mol) was added dropwise to the mixture. After complete addition, the reaction mixture was allowed to warm to room temperature. The resulting solution was partitioned between 1 M NaOH (40 ml) and the product was extracted with CH2Cl2 (30 ml×2). All organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to yield crude product, which was purified using column chromatography (silica gel, CH2Cl2:EtOAc, 4:1) (87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:11])([CH3:10])[CH3:9].C([Li])CCC.C([O:20][B:21](OC(C)C)OC(C)C)(C)C.Cl>C1COCC1>[CH3:9][C:8]1([CH3:10])[O:11][B:21]([OH:20])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(O)c1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2ccccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
To a solution of 2-(2-bromo-phenyl)-propan-2-ol (4.0 g, 18.6 mmol, prepared as described in Egan, W. et al. J. Am. Chem. Soc., 1971, 93, 6205) in 60 mL of anhydrous THF under argon at −78° C. was slowly added n-butyl lithium (15 mL, 2.5 M). The mixture was stirred at −78° C. for 2 h, and then triisopropylborate (5.5 mL, 24.2 mmol) was added to the mixture. The mixture was allowed to warm to room temperature and stirred at room temperature for 12 h. The mixture was then cooled to 0° C. and hydrochloric acid (10 mL, 1N) was added to the mixture until pH was <5. The mixture was then stirred at room temperature for 1 h. The two layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford a yellow oil. The oil was purified by chromatography (silica, EtOAc: hexanes,1:3) to afford a white solid (1.16 g, 40%). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.53 (m, 1H), 7.36 (m, 2H), 7.28 (m, 1H), 1.62 (s, 3H), 1.61 (s, 3H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][C:8](=[O:38])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:37])[C@@H:19]([N:29]4[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]4)[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1.O>C(O)C>[C:1]([S:3][CH2:7][C:8](=[O:38])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:37])[C@@H:19]([N:29]4[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]4)[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)SCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 60.7 %

Procedure:
Potassium thioacetate (1.32 g) was added to a solution of the 21-chloro-compound of Example 2 (2.22 g) in ethanol (11.1 ml). The mixture was heated under reflux in an atmosphere of nitrogen for 40 min and then poured into water (100 ml). The precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate the solvent was removed under reduced pressure and the residue was chromatographed on silica gel. The purified product was crystallised from methanol to give (2β,3α,5α)-21-(acetylthio)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (1.46 g). m.p. 181°-182° C.; [α]D +131.9° (c 0.88).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][C:12]([O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[CH:17]([C:18](=O)[CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C:24]2=[O:34])[CH2:16]1)=[O:13].[ClH:36].[NH2:37][OH:38]>>[ClH:36].[NH2:9][CH2:10][CH2:11][C:12]([O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[CH:17](/[C:18](=[N:37]/[OH:38])/[CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C:24]2=[O:34])[CH2:16]1)=[O:13]
Reactant: C[C@]12CC[C@H](OC(=O)CCN)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: C[C@]12CC[C@H](OC(=O)CCN)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Following the procedure described in Example 1 and starting from 3β-(3-aminopropionyloxy)androstane-6,17-dione fumarate (Prepn. 69, 260 mg) and hydroxylamine hydrochloride (41 mg), the title compound I-dm was obtained (168 mg, 75%), after purification by flash chromatography (SiO2; CH2Cl2:MeOH 9:1). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.42 (1H, s), 8.13 (3H, bb), 4.63 (1H, m), 3.27 (1H, m), 2.98 (2H, t), 2.64 (2H, t), 2.45-0.95 (19H, m), 0.77 (3H, s), 0.69 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([CH3:28])=[CH:26][S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.