Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(I)cc1
Temperature: 100 °C

Procedure:
Under an argon atmosphere, to 4-iodophenylacetic acid (11) (prepared by the process described in Chen, Q.-H. et al., Bioorg. Med. Chem. 14, 7898-7909 (2006)) (1.06 g, 4.05 mmol) was added thionyl chloride (5.00 mL, 68.6 mmol) and heated to reflux (100° C.) for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-iodophenylacetyl chloride (12) as a brown oily crude product, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13](C(Cl)(Cl)Cl)[N:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=3)[C:11]=2[CH:26]=1>>[NH2:25][C:21]1[N:20]=[C:19]([N:12]2[C:11]3[CH:26]=[C:7]([Br:6])[CH:8]=[CH:9][C:10]=3[N:14]=[C:13]2[NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:24]=[CH:23][N:22]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: COCCN
Product: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
A mixture of 2-methoxyethanamine (5 mL) and 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol) were stirred at RT for 3 days. The reaction mixture was then concentrated in vacuo and EtOAc/heptane (2:1) added. The solvent was removed in vacuo and this was repeated (×2). The resulting solid was then triturated from EtOAc:heptane (1:2). The solid was then dissolved in DCM (5 ml) and washed with water (2×2 ml). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (145 mg, 45% yield): 1H NMR (500 MHz, DMSO) delta 3.28 (3H, s), 3.71-3.53 (4H, m), 6.93 (1H, d, J=5.5), 7.14 (2H, s), 7.31-7.20 (2H, m), 7.67 (1H, d, J=1.6), 8.13 (1H, t, J=5.3), 8.41 (1H, d, J=5.5); LC-MS: m/z+363/365 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:8]=[CH:7][C:6]=1[CH2:9][C:10]([OH:12])=[O:11])([O-:17])=[O:16]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0°) solution of 4-trifluoromethylphenylacetic acid (550 g; 1.45 mol) in sulfuric acid (2.0 L) was added, over 1.5 hours, nitric acid (90%; 300 mL) at such a rate as to maintain the temperature between 0° and 5° C. The solution was stirred for 15 minutes, then poured into ice water (17 L). The solid that separated was collected on a filter, washed with water (2 times with 2.5 L, by resuspension), then dissolved in ether (3.0 L). The ethereal solution was washed with water (2 times with 1.0 L), dried, then concentrated in vacuo. The last traces of water were removed by co-distillation with ethanol (500 mL). Yield: 588.2 g (96.4%). The material was suitable for further transformation. Additional product (116.6 g) was obtained from a scouting run.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(C(C2C=CC=CC=2)(P)CC)C=CC=CC=1.CC(C)([O-])C.[K+]>C(Cl)(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CO.C1(C)C=CC=CC=1>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:10]1[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:7]=2)[C:9]1=[O:20]
Reactant: C1CCNC1
Reactant: Cc1ccncc1N1CCN(c2ccnc(Cl)c2)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccncc1N1CCN(c2ccnc(N3CCCC3)c2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.2 %

Procedure:
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (58A: 100 mg, 0.3463 mmol) and pyrrolidine (0.145 mL, 1.7317 mmol) were added to toluene previously degassed for 10 minutes. The resulting mixture was stirred for 5 minutes. This was followed by the addition of Pd(OAc)2 (4 mg, 0.01732 mmol), diphenyl-phosphino-propane (14.3 mg, 0.03463 mmol) and potassium tertiary butoxide (66 mg, 0.6926 mmol) and stirring was continued for a further 10 minutes. The reaction mixture was heated to reflux for 16 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (8% MeOH in chloroform) afforded 45 mg of the product (40% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][C:11]([CH3:13])([CH3:10])[O:5][CH2:4]1
Reactant: CC(C)=O
Reactant: OCC(CO)(CBr)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OCC(CBr)(CBr)CO1

Procedure:
A mixture of 10 g of 2,2-bis(bromomethyl)-1,3-propanediol, 5 ml of acetone and a catalytic quantity (0.1 g) of p-toluenesulfonic acid was heated under reflux in 150 ml of benzene until the theoretical amount of water (0.8 ml) had been collected in a Dean-Stark trap (2 hours). Evaporation of the solvent gave 5,5-bis(bromomethyl)-2,2-dimethyl-1,3-dioxane (1A), as a solid, m.p.: 56°-58° C. The purity according to gas-liquid chromatography and proton NMR was 99%.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Li]CCCC.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)=O.CC(C)=O.[Cl-].[NH4+]>C1COCC1.CCOCC>[CH3:24][O:23][C:17]1[CH:22]=[CH:21][C:20]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[C:6]([CH:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:19][CH:18]=1
Reactant: COc1ccccc1
Reactant: CNC(=O)c1ccccc1C
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a solution of N-methyl-o-toluamide (4.47 g) in THF (100 ml) was added dropwise 1.6 M n-BuLi (40 ml, 2.2 equivalents) in nitrogen atmosphere at 0° C. After stirring for 2 hr, the resulting solution was cooled in a dry ice/acetone bath to −70° C., followed by the addition of anisole (4.0 g) at once. The reaction mixture was drawn out of the dry ice/acetone bath, and then returned to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, which was stirred for further 1 hr. The resulting white precipitates were collected by filtration, and then washed with water, ether and n-hexane, in this order. The resulting precipitates were dried, to give the title compound (1.72 g, yield; 24%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH3:8])SC)#[N:2].[CH3:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH2:15][S:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>N1C=CC=CC=1.[N+]([O-])([O-])=O.[Ag+]>[C:1]([NH:3][C:4]([NH:7][CH3:8])=[N:19][CH2:18][CH2:17][S:16][CH2:15][C:11]1[N:12]=[CH:13][NH:14][C:10]=1[CH3:9])#[N:2]
Reactant: CN=C(NC#N)SC
Reactant: Cc1[nH]cnc1CSCCN
Agent: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of N-cyano-N', S-dimethylisothiourea (0.81 g) and silver nitrate (1.06 g) in pyridine (100 ml) was added to a stirred mixture of 2-((5-methyl-4-imidazolyl)methylthio)-ethylamine (1.07 g), anhydrous potassium carbonate (0.44 g) and anhydrous dimethylformamide (4ml). The mixture was stirred at room temperature for 18 hours and filtered. The filtrate was evaporated to dryness and the residue was eluted from a column of silica gel using isopropyl alcoholethylacetate (1:4) followed by isopropyl alcohol-ethyl acetate (1:3) to give N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine (0.71 g) m.p. 139°-141° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2CC[CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CC1CCN(C(OCC2C=CC=CC=2)=O)CC1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]methyl}-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:15]Br>CO>[Br:15][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: BrBr
Reactant: Nc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(Cl)cc1Br
Reaction time: 8 h

Procedure:
To a stirred mixture of 6-chloropyridazin-3-amine (D-1) (52.0 g, 0.4 mol, 1.0 eq) and sodium carbonate (84.8 g, 0.8 mol, 2.0 eq) in MeOH (500 mL) at RT, bromine (70.6 g, 0.44 mol, 1.1 eq) is added dropwise and the resulting mixture is stirred overnight. The reaction mixture is filtered and the filter cake is washed with ethyl acetate. The filtrate is concentrated in vacuo and the residue is poured into water (300 mL). The resulting mixture is extracted with ethyl acetate (2×300 mL). The combined organic layers are dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (0-50% ethyl acetate-petroleum ether) to afford the product, 4-bromo-6-chloropyridazin-3-amine (D-2).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:14][CH2:13]2)=[N:7][CH:6]=1)C.O.[Li+].[OH-].Cl>C1COCC1.CCO>[Cl:11][C:9]1[C:8]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:16][CH2:17]2)=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)CC2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(C(=O)O)cc3Cl)CC2)n1
Temperature: 55 °C

Procedure:
To a solution of 5-chloro-6-{4-[6-(4-fluoro-phenyl)2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (427 mg, 0.813 mmol) in THF, add water dropwise until the cloudiness almost persists. To this mixture add LiOH.H20 (350 mg, 8.13 mmol) followed by a small amount of EtOH. Heat the mixture at 55° C. for 2 h, and then concentrate under reduced pressure. Add a small amount of water to the residue, followed by 8.13 mmol of HCl (3M solution). Adjust the final pH to 4 and collect the off-white solid via filtration. Wash the solid with water and dry to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-5-methylphenol (10) (250 g, 1.75 mol) in CH3N (2.5 L) was added Me2SO4 (184 mL, 1.93 mol) and K2CO3 (314 g, 2.28 mol). The reaction mixture was heated to reflux for 6 h with mechanical stirring. The reaction mixture was cooled to ambient temperature and filtered through Celite. The filtrate was evaporated. The residue was diluted with EtOAc (1.5 L), washed with water (1.5 L*2) and brine (1.5 L) successively, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-chloro-5-methylanisole (11) as a light yellow oil (274 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 7.20-7.25 (d, 1H), 6.73 (s, 1H), 6.68-6.71 (d, 1H), 3.86 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.O=S(Cl)[Cl:12]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccn1
Temperature: 60 °C
Reaction time: 0.03 h

Procedure:
To a solution of pyrazine-2-carboxylic acid (1.36 g, 10.9 mmol, 1 eq.) in SOCl2 (20 mL) was added DMF (2 drops). The mixture was stirred at 60° C. for 2.0 min. The volatiles were removed in vacuo to give crude pyrazine-2-carbonyl chloride, which was used in the next step directly. TO a suspension of 2-amino-5-nitrobenzoic acid (2.00 g, 10.9 mmol, 1.0 eq.) in THF (50 mL) was added Et3N (1.09 g) and pyrazine-2-carbonyl chloride in anhydrous THF (50 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed. The residue was suspended in H2O (10 mL) and the pH was adjusted to 5 by slow addition of 2N HCl in water. The resulting solid was collected and dried in vacuo to give 3.12 g of 5-nitro-2-(pyrazine-2-carboxamido)benzoic acid as a brown solid (99%). LCMS m/z=289.0 (M+1) (Method B) (retention time=1.24 min),
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.CC(C)([O-])C.[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCC23CCNC3)cc1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCCC23CCN(c2cccnc2)C3)cc1
Temperature: 90 °C

Procedure:
A mixture of 1-benzyl-1,7-diazaspiro[4.4]nonane (2.00 g, 9.26 mmol), 3-bromopyridine (1.38 g, 8.73 mmol), potassium tert-butoxide (2.50 g, 22.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.318 g, 0.347 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.324 g, 0.520 mmol) and dry toluene (50 mL) was placed in a pressure tube under argon. The mixture was stirred and heated at 90° C. (bath temperature) for 24 h and cooled. Water (20 mL) was added and the mixture was extracted with ethyl acetate (6×25 mL). The extracts were dried (K2CO3) and concentrated. Column chromatography of the residue on Merck silica gel 60 (70-230 mesh), with 6:4 (v/v) chloroform/acetone, gave 1.80 g (66.2%) of light brown oil, after concentration of selected fractions.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:9]2[C@H:10]3[C@H:11]([CH2:20][CH2:21][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH2:19]3
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 74.5 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (100.03 g, 0.28001 mol) and potassium t-butoxide (31.42 g, 0.2800 mol) in anh. dimethylsulfoxide (DMSO, 320 mL) under argon was stirred in an oil bath (68-81° C.) 1 h, after which estrone (15.14 g, 55.99 mmol) in anh. DMSO (320 mL) was added via syringe. See FIG. 17. Stirring was continued 1 h and the reaction allowed to cool. The mixture was poured into 800 mL of ice-1N hydrochloric acid and then extracted three times with 400 mL aliquots of ether. The combined organic extracts were washed with 350 mL of saturated sodium bicarbonate+400 mL of brine, dried over sodium sulfate, and flash filtered through a 58mm high×84 mm dia. column of silica gel (200-40 mesh). Product continued eluting with additional ether. Concentration of appropriate fractions under reduced pressure and three-fold recrystallization from aqueous ethanol gave very fine white needles (11.47 g, 42.73 mmol, 76%), m.p. 134-136° C., homogeneous to TLC (20% ethyl acetate/hexanes on silica gel, Rf 0.45). (NA-1994A-242B)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Br.[NH2:15][C:16]1[S:17][C:18]([Br:21])=[CH:19][N:20]=1>N1C=CC=CC=1>[Br:21][C:18]1[S:17][C:16]([NH:15][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:20][CH:19]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Br
Solvent: c1ccncc1
Product: O=C(Nc1ncc(Br)s1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
A solution of 4-chloro-3-nitrobenzoyl chloride (1.539 g, 7.694 mmol) in anhydrous pyridine (40 mL) was treated with 2-amino-5-bromothiazole monohydrobromide (2.00 g, 7.694 mmol), and the reaction stirred under a nitrogen atmosphere at room temperature for 18 hours. The solvent was removed by rotary evaporation in vacuo and the oil dried on hi-vacuum. The residue was taken up in ethyl acetate (150 mL) and washed with water (4×50 mL) and brine (50 mL), then dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 6% ethyl acetate/methylene chloride afforded the title compound as a pinkish-tan solid (1.92 g, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>C1C(Cl)=CC=C(Cl)C=1.S(=O)(=O)(O)N>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Agent: NS(=O)(=O)O
Solvent: Clc1ccc(Cl)cc1
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
83.5 g (0.50 mol) of 4-nitrobenzoic acid, 30.0 g (0.50 mol) of urea and 0.5 g of sulfamic acid are heated in 200 ml of dichlorobenzene with stirring at from 180° to 181° C. for 16 h. After cooling to 25° C. the solid is filtered off with suction and is washed with 50 ml of dichlorobenzene. The filter cake is introduced into 250 ml of water and the mixture is adjusted to a pH of 12 with aqueous sodium hydroxide solution and subjected to steam distillation. Subsequently the solid is filtered off with suction and is dried at 100° C. 40.6 g of 4-nitrobenzamide are obtained having a melting point of from 192° to 195° C. This corresponds to a yield of 48.9% of theory.
Reaction SMILES: [C:1]([O-:10])(=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Na+].Cl[CH2:13][CH2:14][CH2:15][Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.CCCCCCCCCCCCCC>[C:1]([S:9][CH2:13][CH2:14][CH2:15][Si:16]([O:17][CH2:18][CH3:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: CCCCCCCC([O-])=S
Agent: CCCCCCCCCCCCCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Temperature: 55 °C

Procedure:
The aqueous solution of sodium thiooctanoate was heated to 50° C. and stirred with a mechanical stirrer throughout this procedure. To this solution was added, all at once, 0.21 grams of a concentrated aqueous solution of methyltrioctylammonium chloride. Immediately thereafter was added a solution of 3-chloro-1-propyltriethoxysilane (310 grams, 1.29 moles) in 23.6 grams of n-tetradecane. Over the next 15-20 minutes, the temperature of the contents of the 5-liter flask was increased to 55° C., with continued stirring. This temperature was then maintained for 5-6 hours, with continued stirring. The temperature was then ramped up to 70° C. over the next 7 minutes, and maintained for about another 2 hours, with continued stirring, whereupon the temperature was raised to and subsequently maintained at 78° C. for an additional 24 hours or so, with continuous stirring. After cooling to ambient temperature, the organic phase was separated from the aqueous phase. Gas chromatography and mass spectrometry (GC and GCMS) revealed a product containing 85% 3-octanoylthio-1-propyltriethoxysilane and 5.5% residual 3-chloro-1-propyltriethoxysilane (reported purities are based on area percent GC responses). Vacuum stripping at 110° C. at 0.1 torr to remove volatiles, primarily 3-chloro-1-propyltriethoxysilane, yielded a product of 90+% purity. Product identity using this process confirmed by nuclear magnetic resonance spectroscopy (NMR).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O>[CH3:1][O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
To a solution of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (21.7 g, 92.7 mmol) in dry DMF (250 mL) was added K2CO3 (17.9 g, 130 mmol), benzyl bromide (13 mL, 111 mmol) and Bu4NI (0.250 g) at room temperature under nitrogen. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified using silica gel column chromatography (2-5% ethyl acetate-hexane) to yield 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (25.4 g, 84%) as an off-white solid. MS cald. for C20H18FO3 [(M+H)+]: 325, obsd. 325.1.
Reaction SMILES: [CH:1]([CH:14]1[NH:23][CH:22]2[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[N:16](C(OC(C)(C)C)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[CH:1]([CH:14]1[CH2:15][NH:16][CH:17]2[CH:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:23]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(c2ccccc2)c2ccccc2)NC2CCCCC21
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)C2CNC3CCCCC3N2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-Butyl (3RS,4aSR,8aSR)-3-benzhydryloctahydroquinoxaline-1-carboxylate (42 mg) was dissolved in 4N ethyl acetate solution of hydrogen chloride (4 ml) and the mixture was stirred at ambient temperature for 3 hours. The volatile materials were removed under reduced pressure to give (2RS,4aSR,8aSR)-2-benzhydryldecahydroquinoxaline dihydrochloride (28 mg).