Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:37][C:38]1[C:42]([CH:43]=O)=[CH:41][NH:40][N:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH2:43][C:42]4[C:38]([CH3:37])=[N:39][NH:40][CH:41]=4)[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Cc1n[nH]cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(Cc4c[nH]nc4C)C3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.3 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.200 g, 0.415 mmol) in dichloroethane (5 mL) was treated with 3-methyl-1H-pyrazol-4-carboxaldehyde (0.091 g, 0.83 mmol) and sodium triacetoxy borohydride (0.176 g, 0.83 mmol). The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (100 mL) and ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (10 min), 20% methanol in dichloromethane (10 min) and 50% methanol in dichloromethane (8 min) as the eluent. The column afforded 0.106 g (44%) of pure N2-[4-(4-amino-1-{1-[(3-methyl-1H-4-pyrazolyl)methyl]tetrahydro-1H-3-pyrrolyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.446 (s, 1H), 8.247 (s, 1H), 8.1275-8.1071 (d, 1H, J=8.16 Hz), 7.72-7.7003 (d, 1H, J=7.96 Hz), 7.6004-7.5793 (d, 1H, J=8.44 Hz), 7.398-7.286 (m, 5H), 7.172-7.134 (m, 1H), 5.379 (m, 1H), 4.0443 (s, 3H), 3.962 (s, 3H), 3.492 (m, 2H), 3.1 (m, 1H), 2.75 (m, 3H), 2.352-2.335 (m, 2H), 1.909 (s, 31); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.17 min (100%), MH+ 577.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:14])[CH:13]=1)[C:8](O)=[O:9])=[O:4].[NH3:15]>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:14])[CH:13]=1)[C:8]([NH2:15])=[O:9])=[O:4]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: N
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc(C(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A solution of 3-methoxycarbonyl-5-iodobenzoic acid (3 g, 10 mmol) in thionyl chloride (2 mL) was heated for 2 hours at 60° C. The reaction mixture was cooled and concentrated in vacuo. The intermediate acid chloride was then diluted with tetrahydrofuran (10 mL) and cooled to 0° C. The mixture was then treated with a solution of 2M ammonia (20 mL, 40 mmol, methanol) and the reaction stirred for 1 hour at 0° C. The mixture was then filtered and the solvent removed in vacuo. Recrystallization from methanol afforded 2.5 g (82%) of 3-methoxycarbonyl-5-iodobenzamide, as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](Cl)=[O:10])[O:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][NH:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].C(N(CC)CC)C>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][NH:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])=[O:10])[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2C(=O)Cl)n1
Reactant: O=C(NCC1CCCCN1)N1CCc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccccc2C(=O)N2CCCCC2CNC(=O)N2CCc3ccccc32)n1
Yield: 50 %

Procedure:
2-(3-Methyl-1,2,4-oxadiazol-5-yl)-benzoyl chloride (0.045 g, 0.2 mmol) in MDC (2.7 ml) was added to a solution of 2,3-dihydroindole-1-carboxylic acid (piperidin-2-ylmethyl) amide (0.05 g, 0.193 mmol) and triethylamine (0.1 ml, 0.72 mmol) in MDC (3 ml). After 20 h the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate (8 ml). The organic layer was added directly onto a dry 10 g pre-packed silica gel cartridge and eluted with 10-100% ethyl acetate in hexane gradient to afford the title compound as a colourless solid (0.043 g, 50%). Mass Spectrum (API+): Found 446 (MH+). C25H27N5O3 requires 445.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([O:33][C:34]([CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH2:26]([O:33][C:34]([CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:5])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OCc1ccccc1)C1CCCN1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2C(=O)OCc2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(benzyloxycarbonyl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.82 minutes; C29H26Cl2N4O4 (565.45); mass spectrum: (M−H)=564/566/568 (chlorine isotope).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].CC(C)=O.Br[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>O>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:19]=1)[CH2:13][S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CSCc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.7 %

Procedure:
Mercapto-acetic acid (1.39 ml, 20 mmol) was dissolved in a 3.3 molar aqueous solution of sodium hydroxide (12 ml, 40 mmol) and cooled in an ice bath, before an acetone (50 ml) solution of 2-Bromomethyl-4-chloro-1-nitro-benzene (T. J. McCord et al, J. Het. Chem. 1972, 119–122)(5 g, 20 mmol) was added slowly. The resulting solution was stirred for 20 hours at room temperature before being diluted with water (50 ml) and extracted with dichloromethane (25 ml). The aqueous phase was made acidic with acetic acid and extracted with dichloromethane (2×25 ml). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to give the title product as an off-white foam (3.65 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]>C1COCC1.CO>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Under H2, 25 (2.7 mmol) was dissolved in a mixture of THF/MeOH (5/20 ml) and was then hydrogenated at room temperature for 1 h under 30 PSI. Pd (c) was filtered and the solvent removed via a rotary evaporator. The residue was purified by chromatography on silica gel using 7:3 hexane/ethyl acetate as the eluent to yield 560 mg (71%) of 26 as a white solid.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:11]=[C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2][N:3]1[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: O=c1[nH]nnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCn1nnc2ccccc2c1=O
Temperature: 25 °C
Yield: 76.6 %

Procedure:
In a dry round bottom flask, 1,2,3-benzotriazin-4(3H)-one (50 g), ethyl 4-bromobutanoate (86.2 g) and potassium carbonate (141 g) were taken and dissolved in dimethylformamide (350 mL) and heated to 60° C. to 70° C. for 3 to 4 hours. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layer was washed with water and brine and dried over anhydrous sodium sulfate. Solvents were evaporated under reduced pressure and the crude product was purified by silica gel flash column chromatography over silica gel using 20% ethylacetate in hexane as eluant to afford the title compound (68 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc2nc(-c3ccc(F)cc3)cc(Cl)c2c1
Solvent: O
Solvent: Oc1ccccc1
Product: Cc1ccc2nc(-c3ccc(F)cc3)cc(N3CCC(C(N)=O)CC3)c2c1

Procedure:
A mixture of 2.0 g of 4-chloro-2-(4-fluorophenyl)-6-methylquinoline, 1.88 g (10 mmol) of isonipecotamide, and 4 g of phenol was stirred and heated in an oil bath at 165°-170° for 2 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 1.9 g of crude product, mp 264°-271° dec. Recrystallization from pyridine gave the titled product as off-white prisms, mp 275°-277° dec.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:27][C:2]1([CH3:1])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:21]([CH:26]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CC1(C)CC(C(Nc2cnc3ccccc3c2)c2ccc(C(=O)O)cc2)C1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3ccccc3c2)C2CC(C)(C)C2)cc1
Reaction time: 18 h
Yield: 66.4 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoic acid (14.0 mg, 0.0390 mmol) was added 3-aminopropionic acid ethyl ester hydrochloric (6.60 mg, 0.0430 mmol), 1-Hydroxy-7-azabenzotriazole (6.40 mg, 0.0470 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (9.00 mg, 0.0470 mmol). Anhydrous methylene chloride (0.390 mL) was added followed by triethylamine (0.007 mL, 0.0510 mmol). After 18 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 26.0 mg of crude material. Purification by column chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzamido)propanoate (11.9 mg, 66% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ: 8.48 (d, J=2.7 Hz, 1H), 7.88 (dd, J=8.3, 1.3 Hz, 1H), 7.74-7.67 (m, 2H), 7.46-7.41 (m, 2H), 7.41-7.29 (m, 3H), 6.81 (t, J=6.1 Hz, 1H), 6.69 (d, J=2.7 Hz, 1H), 4.42 (br. s., 1H), 4.25 (dd, J=9.3, 4.4 Hz, 1H), 4.19-4.08 (m, 2H), 3.70 (q, J=6.0 Hz, 2H), 2.61 (t, J=5.7 Hz, 2H), 2.59-2.45 (m, 1H), 2.07-1.97 (m, 1H), 1.76-1.67 (m, 2H), 1.66-1.55 (m, 1H), 1.28-1.21 (m, 3H), 1.13 (s, 3H), 1.09 (m, 3H). MS (M+1): 460.4.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1>>[CH3:21][C:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:23]4[C:32]5[C:27](=[CH:28][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CCN(Cc3ccc(N)cc3)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: Cc1ccc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(p-tolyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(p-methylphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:33])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([OH:31])=[C:17]([Br:32])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1.[OH-].[Na+].Cl[S:42]([C:45]1[CH:53]=[CH:52][C:48]([C:49]([OH:51])=[O:50])=[C:47]([OH:54])[CH:46]=1)(=[O:44])=[O:43]>C(O)C(N)(CO)CO>[Br:32][C:17]1[C:18]([O:31][S:42]([C:45]2[CH:53]=[CH:52][C:48]([C:49]([OH:51])=[O:50])=[C:47]([OH:54])[CH:46]=2)(=[O:44])=[O:43])=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH:20]=[C:15]([C:14](=[O:33])[NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:16]=1
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a suspension of N-dodecyl-3-bromo-4-hydroxy-5-(m-trifluoromethylphenyl)-benzamide (1.799 g, 1.51 mmol, 1 eq) in 0.05 N tris(hydroxymethyl)aminomethane pH 9 buffer/THF (10:3) (7.5 mL) was added 2.5 N NaOH (0.665 mL, 1.66 mmol, 1.1 eq) and THF (10 mL). The reaction was stirred at rt for 30 minutes and then cooled to 5° C. 4-Chlorosulfonyl-2-hydroxy-benzoic acid (0.715 g, 3.02 mmol, 2 eq) was added portionwise while keeping the pH at 9 by the addition of 2.5 N NaOH. This mixture was allowed to warm to rt and to stir for 2 days. The reaction was quenched by the addition of 2 M HCl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane+1% Formic Acid) to afford the title compound (0.895 g, 79%) as a yellow foam. 1H NMR (DMSO-d6) δ 11.40 (bs, 1H); 10.35 (bs, 1H); 8.70 (t, 1H); 8.22 (d, 1H); 7.85 (d, 1H); 7.72–7.45 (m, 5H); 6.98 (dd, 1H); 6.86 (d, 1H); 3.25 (dd, 2H); 1.50 (dd, 2H); 1.25 (m, 18H); 0.85 (t, 3H); IR (KBr) 3410, 2800, 2700, 1690, 1640, 1605, 1390, 1330, 1180, 1120, 620, 600 cm1; mass spectrum [(+)APCI], m/z 728/730 (M+H)+; Anal. Calcd. for C33H37BrF3NO7S+0.25 C4H8O2: C, 54.40; H, 5.24; N, 1.87. Found: C, 53.23; H, 4.77; N, 1.79.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]([OH:21])[CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc(C)on1
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CC(O)c2cccc(Cl)c2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dimethylisoxazole (104 g, 1.07 mol, 1 eq) in THF (1 L) cooled to −78° C. under nitrogen, a solution of lithiumdiisopropylamide (1.8M ethylbenzene in THF) (630 mL, 1.134 mol, 1.06 eq) was added dropwise. After 1 hr, a solution of 3-chlorobenzaldehyde 100 g, 0.711 mole, 0.66 eq) in THF (300 mL) was added drop wise at −78° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was cooled to 0° C., and quenched by saturated ammonium chloride solution (130 mL). The organic layer was concentrated to dryness. Water (1 L) was added to the residue was extracted with ethyl acetate (2×1 L). Combined organic extracts were washed with brine (700 mL) dried over anhydrous sodium sulfate. Concentrated and purified by column chromatography (50% ethyl acetate in hexane) over silica gel using a mixture of ethyl acetate and hexanes as eluant. The title compound was obtained as viscous brown oil (120 g, 0.507 mol, 48%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[C:14]1([C@@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc([C@H]2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
1.280 g (S)-2-Phenyl-morpholine-4-carboxylic acid tert-butyl ester was dissolved in 31 mL 4N HCl in dioxane and stirred at room temperature overnight. Concentrated in vacuo and diluted with 1N HCl. The aqueous was extracted with ether and then basicified to pH12-14 with 2N NaOH followed by extraction with DCM. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford 617 mg of product by H NMR. 78% yield.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Br:1][C:2]1[C:7]([C:8](=[S:26])[NH2:10])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:4][CH:3]=1
Reactant: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Temperature: 70 °C
Yield: 75.8 %

Procedure:
To a mixture of 5-bromo-2-(3-ethylureido)isonicotinamide (Intermediate 43, 1.25 g, 4.35 mmol) in THF (20 mL), was added Lawessons reagent (1.761 g, 4.35 mmol). The reaction mixture was then heated to 70° C. overnight. The solid that formed was collected by filtration and washed with THF to provide 1 g of desired product. MS (ESP): 304 (M+1) for C19H11BrN4OS
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:21][CH:22]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH3:23]>O1CCCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:23])[CH3:21])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) in tetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide in tetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with ether, and the resulting solution was washed twice with water. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 10% ethyl acetate/hexanes.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11](=[C:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[BH4-].[Na+].C1C=CC=CC=1>CO>[OH:22][C@H:6]1[CH2:5][CH2:4][C@@:3]2([CH2:2][OH:1])[C:8]([CH:9]=[CH:10][C:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C:12]=3[CH2:13][CH2:14][C@@H:15]2[OH:21])=[CH:7]1
Reactant: C[C@]12CC[C@H]3C(=C1CCC2=O)C=CC1=CC(=O)CC[C@@]13CO
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: C[C@]12CC[C@H]3C(=C1CC[C@@H]2O)C=CC1=C[C@@H](O)CC[C@@]13CO
Reaction time: 1 h

Procedure:
To a mixture of 4.5 g of 19-hydroxyandrost-4,6,8(14)-trien-3,17-dione in 40 ml of methanol, which was cooled externally by an ice-bath, was added 1.8 g of sodium borohydride with stirring. Stirring was continued for 1 hour, 450 ml of benzene was added and the mixture was concentrated at reduced pressure to a small volume. Benzene and a small volume of water was added and the mixture was concentrated again. Subsequent filtration and recrystallization of the precipitate from methanol gave 3β,17β,19-trihydroxyandrosta-4,6,8(14)-triene as a white solid, uv max 275 (sh), 285 and 298 (sh) mμ.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:28][CH:29]=1)(=[O:40])=[O:39]
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Yield: 97.1 %

Procedure:
Methyl 2-({4-[3-(4-hydroxyphenoxy)propyl]phenoxy}methyl)benzoate (0.32 g, 0.81 mmol) was dissolved in dichloromethane (10 ml) and cooled to −20° C. Triethylamine (0.123 g, 1.22 mmol) was added drop wise and methanesulfonyl chloride (0.10 g, 0.89 mmol) was added drop wise. The ice bath was removed and the mixture was wormed to room temperature. Diethyl ether (5 ml) was added and the precipitate was filtered off. The organic phase was washed with two portions of brine (5 ml) and dried (MgSO4). Removing the solvent by evaporation gave 0.37 gram of methyl 2-{[4-(3-{4-[(methylsulfonyl)oxy]phenoxy}propyl)phenoxy]methyl}benzoate (yield 97.3%).