Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCC(CC)Nc1nc(SC)nc(Cl)c1C=O
Product: CCC(CC)Nc1nc(SC)nc(-c2ccccc2Cl)c1C=O

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-chlorophenylboronic acid to give the title compound 4-(2-chloro-phenyl)-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.91 (m, 6H), 1.42-1.60 (m, 4H), 2.45 (s, 3H), 4.21 (m, 1H), 7.32 (m, 4H), 8.96 (br s, 1H), 9.44 (s, 1H). LC MS (m/e)=350 (MH+).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]=[CH2:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl:12][C:13]([Cl:18])(Cl)[C:14](Cl)=[O:15]>C(OCC)C>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]2[CH2:11][C:14](=[O:15])[C:13]2([Cl:18])[Cl:12])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: C=C[C@H]1CC[C@H](CCC)CC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](C2CC(=O)C2(Cl)Cl)CC1

Procedure:
A mixture of 0.25 mol of trans-4-propyl-1-vinylcyclohexane (prepared according to WO 88/02357) and 800 ml of diethyl ether is reacted with trichloroacetyl chloride in accordance with Example 1B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([C:27]([F:30])([F:29])[F:28])([C:23]([F:26])([F:25])[F:24])[OH:22])[CH2:9]2)=[CH:4][CH:3]=1.[C:31]([N:38]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([N:41]3[CH2:42][CH2:43][CH2:44][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39][CH2:40]3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:21]([C:27]([F:30])([F:29])[F:28])([C:23]([F:24])([F:26])[F:25])[OH:22])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 40.6 %

Procedure:
5-(4-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (500.0 mg, 0.99 mmol) prepared in Step 2 of Preparation 22, 1-BOC-homopiperazine (235.0 uL, 1.19 mmol), Pd2(dba)3 (45.0 mg, cat.), BINAP (62.0 mg, cat.) and sodium t-butoxide (143.0 mg, 1.49 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 250.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>[OH-].[Na+]>[C:1]1([NH:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[C:13]([OH:15])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nnsc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of ethyl 5-(N-phenylamino)-1,2,3-thiadiazole-4-carboxylate (0.1 g, 0.4 mmol, prepared as in Example 6) in 10 ml of 10% NaOH solution was stirred at room temperature for 1.5 h. The pH of the solution was adjusted with 5% HCl solution to about 2. The solution was extracted with CHCl3 (2×20 mL). The organic layer was dried with anhydrous Na2SO4. The product was obtained as an off-white solid after the removal of the solvent (0.06 g, 67%). m.p.: 165° C. (decomp.). 1H NMR (ppm, in DMSO-d6): 10.22 (s, br., 1H), 7.3-7.7 (m, 5H). FTIR (cm−1, KBr pellet): 3407, 3024, 1673, 1524, 1501, 1464, 1340, 1266, 1090, 784, 754.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CS(C)=O>[N+:8]([C:4]1[CH:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 33.1 %

Procedure:
To a solution of 3-fluoronitrobenzene (2 mL, 18.8 mmol) in DMSO (20 mL) was added Boc-piperazine (10 g, 56.4 mmol), after stirring at 100° C. for 3 days, the mixture was poured to ice water, the resulting precipitate was collected by filtration to give tert-butyl 4-(3-nitrophenyl)piperazine-1-carboxylate (1.91 g).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:15]([O:17]C)=[O:16])[C:11]([O:13]C)=[O:12].Cl>[Cl-].C[N+](C)(C)C.O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:11]([OH:13])=[O:12])[C:15]([OH:17])=[O:16]
Reactant: COC(=O)C(C(=O)OC)c1ccccc1F
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: O=C(O)C(C(=O)O)c1ccccc1F
Temperature: 12.5 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Sodium hydroxide (117.11 g of a 50% aqueous solution) was added to water (160.5 g), and the solution was cooled to 10-15° C. Tetramethylammonium chloride (4.88 g) was added, followed by the dropwise addition of 1,3-dimethyl 2-(2-fluorophenyl)propanedioate (150 g) over a period of 30 minutes at 10-15° C. The temperature of the reaction was slowly raised to 30° C. after the addition and maintained at 27-32° C. The reaction mass became a thick slurry, and water (25 g) was added to improve stirring. The progress of the reaction was monitored by HPLC. After stiffing for 2 hours, the reaction mixture was added to a solution of HCl (231 g) and water (150 mL) over a period of 30 minutes at 5-10° C. The pH of the mixture was adjusted to <2, and the reaction mixture was stirred at 5-10° C. for half an hour. The reaction mixture was then filtered to isolate a solid product that was air dried, and then further dried under reduced pressure at 35° C. for 3 hours. The dried solid was slurried with petroleum ether, and the slurry was filtered to reisolated the solid. The solid was then dried under reduced pressure at 35° C. for 3 hours to give the title product (115.5 g, 93.97%).
Reaction SMILES: Cl[C:2]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[C:5]1([CH3:16])[CH3:15])=[O:3].CC1(C)NC2C(=CC=CC=2)NC1=O.FC1C=C2C(=CC=1)NC(=O)C(C)(C)N2.[CH3:44][CH:45]([CH3:47])[O-:46].[Li+]>CC(O)C>[CH3:15][C:5]1([CH3:16])[N:4]([C:2]([O:46][CH:45]([CH3:47])[CH3:44])=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14]
Reactant: CC1(C)C(=O)Nc2ccccc2N1C(=O)Cl
Reactant: CC(C)[O-]
Agent: CC1(C)Nc2cc(F)ccc2NC1=O
Agent: CC1(C)Nc2ccccc2NC1=O
Agent: [Li+]
Solvent: CC(C)O
Product: CC(C)OC(=O)N1c2ccccc2NC(=O)C1(C)C
Reaction time: 1.5 h

Procedure:
To 2.28 g of 4-chlorocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one (prepared by the method of Example 32 but using 3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one rather than 6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one) in 25 ml of 2-propanol (the starting material is not all in solution) are added 0.694 g of lithium isopropoxide. After about 1.5 hr the reaction mixture became homogeneous and then again heterogeneous as the product precipitated out. After a total of 2 hr the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane aid saline. The organic layers are dried over sodium sulfate and the filtrate is concentrated. Ether is added and the resulting solid is collected to give the title compound. NMR (CDCl3) 1.28, 1.63, 5.01, 6.80, 6.98-7.11, 7.27, 7.96 δ.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)[CH2:10][CH2:11]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Clc1cccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
11 mg of the target compound (0.03 mmol, 3.7%) was obtained using 1-(3-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[CH:24]([C:28]1[N:33]=[C:32]([N:34]=[CH:35]N(C)C)[C:31]([C:39]#[N:40])=[CH:30][CH:29]=1)([CH2:26][CH3:27])[CH3:25].NC1C=C(OCC2C=CC(OC)=CC=2)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([S:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:2]([NH:1][C:39]2[C:31]3[CH:30]=[CH:29][C:28]([CH:24]([CH2:26][CH3:27])[CH3:25])=[N:33][C:32]=3[N:34]=[CH:35][N:40]=2)[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CCC(C)c1ccc(C#N)c(N=CN(C)C)n1
Agent: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: CCC(C)c1ccc2c(Nc3cc(OCc4ccccc4)ccc3Sc3ccc(O)cc3)ncnc2n1

Procedure:
The product from Example 27A was reacted with the product from Example 140A using the procedure from Example 10F substituting the product from Example 27A for the product from Example 10E and substituting the product from Example 140A for the product from Example 10B to provide the title product. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.82 (t, J=7.35 Hz, 3H), 1.30 (d, J=6.62 Hz, 3H), 1.58-1.73 (m, 1H), 1.75-1.87 (m, 1H), 2.89-3.08 (m, 1H), 5.11 (s, 2H), 6.67 (d, J=8.82 Hz, 2H), 6.85-7.03 (m, 1H), 7.11 (d, J=8.46 Hz, 2H), 7.30-7.50 (m, 6H), 7.56 (d, J=8.82 Hz, 1H), 8.56 (s, 1H), 8.75 (d, J=8.46 Hz, 1H), 9.64 (s, 1H), 9.95 (s, 1H); MS (APCI) m/z
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][OH:11])[C:5]([F:16])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:11][CH2:10][C@@H:9]([NH:8][C:6]1[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:12]([CH3:13])([CH3:15])[CH3:14])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[C@@H](CO)Nc1nc(Cl)ncc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol, 14a, (1.95 g, 7.87 mmol) and triethylamine (1.37 mL, 9.84 mmol) in dichloromethane (25 mL) was added methanesulfonyl chloride (0.76 mL, 9.84 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (50 mL) were added. The organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to afford 2.55 g of the desired product as a pale yellow foamy solid: LC/MS (10-90% ACN/water 5 min with 0.9% FA, C4) m/z 326.99 (M+H) RT=2.96 minutes.
Reaction SMILES: [NH:1]([CH2:8][C:9]1([CH3:35])[CH:13]([C:14]([O:16]CC(Cl)(Cl)Cl)=[O:15])[N:12]2[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:11]2[S:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CN(C)C=O.[Zn]>[NH:1]([CH2:8][C:9]1([CH3:35])[CH:13]([C:14]([OH:16])=[O:15])[N:12]2[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:11]2[S:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reaction time: 6 h
Yield: 65.4 %

Procedure:
2,2,2-Trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.00 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.5 ml) and then zinc powder under cooling at -15° C and the mixture was stirred for 6 hours. After the reaction, zinc powder was filtered off and the filtrate was poured into ethyl acetate. The solution was washed 4 times with water and dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was dissolved in a small amount of methanol and then pulverized by adding water to the solution. The powder was collected by filtration, washed with water and dried to give 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylic acid (0.50 g), mp. 120° C.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][C:12]=1[OH:13].C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[O:4]=[C:3]1[CH2:2][O:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:8][C:7]=2[NH:6]1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2c(c1)NC(=O)CO2
Reaction time: 1 h
Yield: 90 %

Procedure:
Chloroacetyl chloride (1 equiv.) was added at room temperature to a mixture of methyl (3-amino-4-hydroxyphenyl)acetate (5.5 mmol) and sodium hydrogen carbonate (1.1 equiv.) in ethyl acetate (5 ml)/water (5 ml). The reaction mixture was stirred for 1 h, then the phases were separated and the organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in DMF (11 ml); activated potassium carbonate was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was again washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexane). Yield: 90%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])(=[O:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[C:22]([Cl:31])[CH:23]=1)(=[O:28])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1Cl

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 133 mg of 4-acetylamino-3-chloro-benzenesulfonyl chloride 1H-NMR (400 MHz, CDCl3): δ 2.24 (s, 3H), 7.36 (d, 1H, J=2.4), 7.40-7.60 (m, 8H), 7.66 (d, 1H, J=2.0 Hz), 7.71 (d, 1H, J=8.8 Hz), 8.36 (d, 1H, J=8.8 Hz), 9.63 (s, 1H). MS: m/z 463.0 (M++1).
Reaction SMILES: [Li]CCCC.[CH2:6]([O:12][C:13]1[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:14]=1Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1>[CH2:21]([O:20][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:18][C:17]=1[Br:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOc1cc(Br)c(OCCCCCC)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(OCCCCCC)c(Br)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under N2 and at -78° C., n-BuLi (23.8 mL, 2.5M in hexanes) was added, over 30 min, to a solution of 1,4-dihexyloxy-2,5-dibromobenzene (25.92 g., 59.45 mmol) in THF (150 mL). After the addition, the reaction mixture was stirred at -78° C. for 1 h and was then quenched with aq. NH4Cl at -78° C. After the usual workup, 1,4-dihexyloxy-2-bromobenzene was obtained as a pale yellow liquid (97% yield).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH:4]=[N:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:49]=[N+:50]=[N-:51])(=O)=O)(C)C.C(O)(=O)C>O1CCCC1.CCOC(C)=O>[N:49]([CH:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH:4]=[N:3][N:2]([CH3:1])[C:8]1=[O:9])=[N+:50]=[N-:51]
Reactant: CN1N=Cc2ccccc2CC1=O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1N=Cc2ccccc2C(N=[N+]=[N-])C1=O
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a well stirred solution of 4,5-dihydro-3-methyl-3H-2,3-benzodiazepin-4-one (3.0 g, 17.2 mmol) in anhydrous tetrahydrofuran (100 mL) at −78° C. was added a solution of 0.5 M potassium bis(trimethylsilyl)amide in toluene (45 mL, 22.4 mmol). The reaction mixture was stirred for another 15 min followed by addition of a pre-cooled solution of 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) (5.8 g, 19 mmol) in THF (0.4M) via a cannula over a period of 2 min (Evans, et al., J. Amer. Chem. Soc., 1990, 112, 4011-4030; Butcher, et al., Tetrahedron Lett., 1996, 37 (37), 6685-6688). After 5 min, acetic acid (4.9 mL, 86 mmol) was added and stirring continued for another 6 h. The reaction mixture was diluted with EtOAc (300 mL), washed with water (300 mL), aqueous NaHCO3 (2×150 mL), 0.5 N HCl (200 mL) and brine (150 mL). The solvent was removed and the 5(R,S)-azido-4,5-dihydro-3-methyl-3H-2,3-benzodiazepin-4-one was purified by flash chromatography (silica) using 10% EtOAc in hexane. The azide was obtained in 75% yield.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH2:28][OH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:29][CH2:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:49])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C[C@]12CCCCC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
The title compound II-ad was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6α-hydroxymethylandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.50 (3H, m), 2.52-0.74 (21H, m), 1.11 (3H, s), 0.88 (3H, s).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[H-].[Na+].Cl.[NH2:11][C:12]([NH2:14])=[NH:13].C(=[C:17]1[CH:21]([C:22](OCC)=[O:23])[CH:20]([CH2:27][CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)[CH2:19][NH:18]1)=S>>[NH2:13][C:12]1[NH:14][C:22](=[O:23])[C:21]2[CH:20]([CH2:27][CH2:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[CH2:19][NH:18][C:17]=2[N:11]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1C(=C=S)NCC1CCc1ccc(C(=O)O)cc1
Agent: CC[O-]
Agent: Cl
Agent: [H-]
Solvent: CCO
Product: Nc1nc2c(c(=O)[nH]1)C(CCc1ccc(C(=O)O)cc1)CN2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 80.5 %

Procedure:
A solution of sodium ethoxide in ethanol [prepared by reaction of 1.06 grams (44.1 mmol) of sodium hydride and 50 ml of ethanol] was combined with 4.22 grams (44.1 mmol) of guanidine HCl and then stirred at 50° C. for 20 minutes. The cooled suspension was filtered (celite) to remove NaCl and the filtrate was mixed with 2.83 grams (8.81 mmol) of 4-(2-(2-thiocarbonyl-3-carboethoxypyrrolidin-4-yl)ethyl)benzoic acid. The resulting solution was concentrated in vacuo to remove most of the alcohol and the residue was slowly heated to 90° C. while maintaining a vacuum of 10 torr. After heating 1 additional hour, the mixture was cooled and the reaction product taken up in 75 ml of water. The pH of the mixture was adjusted to 6 by addition of 6M HCl and the mixture was then filtered. The precipitate was consecutively washed with 20 ml water, 20 ml methanol, and 40 ml ether. After drying, 2.13 grams (64%) of 4-(2-[2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-])=O)[CH:12]=3)=[CH:10][N:4]2[N:3]=1>[Fe].CCO.CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH:12]=3)[NH2:18])=[CH:10][N:4]2[N:3]=1
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Iron (1.34 g) is added to a mixture of 6-chloro-2-(4-methyl-3-nitro-phenyl)imidazo[2,1-f]pyridazine (1.15 g, 0.004 mol) and EtOH—AcOH (120 mL, 2:1). The mixture is stirred at 80° C. for 2 hours, cooled to room temperature, filtered through celite which is washed with EtOAc, and concentrated. The oily residue is dissolved in EtOAc (500 mL) and washed once with sat. NaHCO3 (200 mL). Organic layer is dried and concentrated to give the title compound (0.85 g, 82%), which is used without further purification. LCMS m/z=259.4 [M+H]+, tR=1.64 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH2:11]([NH2:14])[C:12]#[CH:13]>>[N:14]1[CH:11]=[CH:12][CH:13]=[C:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:3][C:2]=12
Reactant: O=C1Cc2ccccc2C1
Reactant: C#CCN
Product: c1ccc2c(c1)Cc1ncccc1-2
Yield: 56 %

Procedure:
The title compound is prepared from 2-indanone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 56% of theory; Mass spectrum (ESI+): m/z=168 [M+H]+.