Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH2:6][CH2:5][N:4]([C:8]2[CH:34]=[CH:33][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=5)[N:17]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:3][N:4]([C:8]2[CH:34]=[CH:33][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:5][CH2:6][O:7]1
Reactant: [H][H]
Reactant: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc([N+](=O)[O-])cc45)nc3c2)CCO1
Agent: [Pd]
Solvent: CCO
Product: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CCO1
Yield: 71.1 %

Procedure:
2-Methyl-4-(2-(5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-benzo[d]imida-zol-5-yl)morpholine (60 mg, 0.130 mmol) was added to 10% Pd/C (10 mg) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for 8 h at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (40 mg). 1H NMR: (400 MHz, CD3OD): δ 7.66 (d, 1H, J=2.0 Hz), 7.52 (m, 2H), 7.13 (s, 1H), 7.04-7.00 (m, 2H), 5.79 (dd, 1H, J=2.4 and 9.2 Hz), 3.97 (m, 2H), 3.79 (m, 3H), 3.49 (m, 1H), 3.41 (m, 1H), 2.76 (m, 1H), 2.62 (m, 1H), 2.44 (m, 1H), 2.13 (m, 1H), 2.05 (m, 1H), 1.80 (m, 1H), 1.68 (m, 2H), 1.22 (d, 3H, J=6.4 Hz); ESI-MS [M+H]+: 433.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCCSc1cccc2nccn12
Yield: 50.7 %

Procedure:
To a solution of 5-[4-(amino)butylthio]imidazo[1,2-a]pyridine (440 mg, 1.99 mmoles) and triethylamine (0.42 ml, 3.01 mmoles) in methylene chloride (20 ml) was added methanesulfonyl chloride (0.19 ml, 2.45 mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 302 mg of the desired product (50.8%, light red brown solid).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26]>>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: NCc1ccccn1
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)NCc3ccccn3)s2)c(C)[nH]c1=O
Yield: 97 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and pyridin-2-ylmethylamine to afford the title compound (97% yield). LC/MS: RT 2.07 min; m/e 354 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].C[O-].[Na+]>CN(C=O)C>[NH2:11][C:10]1[C:3]2=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]2[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: COc1cnc(C#N)c(Cl)c1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cc(OC)cnc2c1N
Reaction time: 1 h
Yield: 71.3 %

Procedure:
The product from Example 27B (0.168 g, 1.0 mmol) and methyl thioglycolate (0.09 mL, 1.0 mmol) were combined in DMF (2 mL). To the solution was added 0.054 g NaOMe. After 1 hr, and additional 0.07 g NaOMe was added. After an additional 1 hr, the reaction was quenched in sat aq. NH4Cl and extracted with ethyl acetate. The organic phase was dried (MgSO4), and evaporated to yield 0.17 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.90 (s, 3H), 3.93 (s, 3H), 6.15 (br s, 2H), 7.44 (d, 1H), 8.36 (d, 1H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH:4]([CH2:8][CH3:9])[C:5](Cl)=[O:6].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])#[N:11].C(N(CC)CC)C>C(Cl)Cl>[C:10]([C:12](=[C:5]([OH:6])[CH:4]([CH2:3][S:2][CH3:1])[CH2:8][CH3:9])[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])#[N:11]
Reactant: CCCOC(=O)CC#N
Reactant: CCC(CSC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)C(C#N)=C(O)C(CC)CSC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At 25° C., 16.7 g (0.1 mol) of 2-[(methylsulfanyl)methyl]butyryl chloride were added to a solution of 12.7 g (0.1 mol) of n-propyl cyanoacetate in CH2Cl2, and the mixture was cooled to 0° C. At 0° C., 20.2 g (0.2 mol) of triethylamine were then added dropwise. After 16 h of stirring at 25° C., the reaction mixture was hydrolyzed and the organic phase was separated off, dried and concentrated. Customary purification gave 15 g (58% of theory) of the title compound as a yellow liquid (b.p. 118 to 120° C./2 mbar).
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:42][CH2:43][O:44][CH3:45])(=O)=O)=CC=1>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:42][CH2:43][O:44][CH3:45])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCn1c(C(=O)N2CCC(C(=O)N(C)Cc3ccccc3)CC2)cc2ccccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (50 mg, 0.133 mmol) dissolved in 0.5 mL of DMF was added to a suspension of sodium hydride (7.99 mg, 0.200 mmol) in 1.0 mL of DMF. The reaction was heated at 70° C. for ten minutes before adding 2-methoxyethyl 4-methylbenzenesulfonate (0.144 mL, 0.266 mmol). The reaction was allowed to stir overnight. After 18 hours, the reaction was cooled to room temperature before diluting with water and ethyl acetate. The organic phase was washed with water followed by saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via column chromatography using 50-80% ethyl acetate/hexanes. The purification provided product as a white solid 1H-NMR (400 MHz, DMSO-d6) 7.63-7.49, 7.43-7.14, 7.12-7.03, 6.67-6.58, 4.68, 4.63-4.06, 3.53, 3.20-3.13, 3.10-2.92, 2.79, 1.92-1.50
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:46]=[C:45]3[C:41]([C:42](=[O:52])[C:43](=[O:51])[N:44]3[CH2:47][C:48](O)=[O:49])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:48](=[O:49])[CH2:47][N:44]1[C:45]2[C:41](=[CH:40][CH:39]=[C:38]([N:35]3[CH2:34][CH2:33][O:32][CH2:37][CH2:36]3)[CH:46]=2)[C:42](=[O:52])[C:43]1=[O:51].[CH2:13]([O:21][CH2:22][CH3:23])[CH3:12]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOCC
Product: O=C(CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol) in DCM (15 ml), DMAP (0.070 g, 0.571 mmol), EDC (0.274 g, 1.428 mmol) and 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetic acid (0.166 g, 0.571 mmol) were added in one portion at room temperature, and the resulting solution was stirred overnight. The solvent was removed under vacuum and the crude was purified by silica gel flash chromatography (DCM:MeOH=98:2) to afford a red solid. After trituration with diethyl ether (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(6-morpholino-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide was obtained (0.145 mg, 0.209 mmol, 44% yield). MS/ESI+ 692.31 [MH]+; [αD]=+227.4, c=0.25, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.33 (s, 2H), 7.44 (d, 1H), 7.17 (d, 1H), 7.04 (d, 1H), 6.94 (dd, 1H), 7.08 (t, 1H), 6.59 (dd, 1H), 6.48 (d, 1H), 6.01 (dd, 1H), 4.56 (s, 2H), 3.90 (d, 2H), 3.63-3.80 (m, 4H), 3.43-3.55 (m, 4H), 3.37 (dd, 1H), 3.18 (dd, 1H), 1.13-1.35 (m, 1H), 0.50-0.66 (m, 2H), 0.23-0.48 (m, 2H)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14](O)=[O:15])[CH2:6][CH2:5]2.C1N=C[N:21](C(N2C=NC=C2)=O)C=1.N.CO>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:21])=[O:15])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Yield: 37.7 %

Procedure:
Following the amide coupling procedure described in protocol A, 498 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.99 mmol), 367 mg CDI (2.26 mmol) and 1.4 mL of 7.0M NH3 in MeOH (9.8 mmol) produced 187 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:13][C:12](=[O:14])[NH:11][N:10]=1.Br[CH2:16][CH2:17][CH3:18].C(OCC)C>CN(C)C=O.O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:13][C:12](=[O:14])[N:11]([CH2:16][CH2:17][CH3:18])[N:10]=1
Reactant: CCCBr
Reactant: O=C1CC(c2ccccn2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCCN1N=C(c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.1 %

Procedure:
To a suspension of 0.29 g (7.3 mmol) of 60% oily sodium hydride in 10 ml of anhydrous dimethylformamide was added dropwise a solution of 1.2 g (6.2 mmol) of 3-(2-pyridyl)-4, 5-dihydropyrazol-5-one in dimethylformamide (10 ml) at 0° C. After one hour of stirring at room temperature, 0.92 g (7.5 mmol) of 1-bromopropane was added dropwise and stirring was continued for another 18 hours. To the reaction solution was added 50 ml of diethyl ether and 50 ml of water, and vigorously agitated. The resultant solution was separated, and the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layer was combined and washed successively with water and saturated brine solution, and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1 (v/v)) to give 1.4 g of the object compound as a colorless oil (yield 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1OS(C(F)(F)F)(=O)=O.[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:36]
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C
Temperature: 80 °C
Yield: 97.1 %

Procedure:
To a solution of 4-(3-pyridyloxymethyl)-2-(trifluoromethanesulfonyloxy)benzoic acid methyl ester (216 mg, 0.55 mmol), prepared as in Example 203C, in 4 mL of DMF at 25° C. was added PdCl2(PPh3)2 (38 mg, 0.055 mmol, 10 mol %) followed by 2-tolyl boronic acid (113 mg, 0.83 mmol) and Cs2CO3 (270 mg, 0.83 mmol) and the reaction was heated to 80° C. for 12 hours. The reaction was then cooled to ambient temperature, taken up in 50 mL ethyl acetate, and washed with H2O (5×10 mL). The organic phase was dried over Na2SO4, filtered and evaporated to an oil. Purification by radial chromatography using a gradient of 25% ethyl acetate-hexanes to 75% ethyl acetate-hexanes gave 4-(3-pyridyloxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester (178 mg, 97%) as an oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH3:23]>C(#N)C>[Br-:1].[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][N+:16]=1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCCCCCCc1ccccc1
Reactant: Cc1ccnc(C)c1
Solvent: CC#N
Product: Cc1cc[n+](CCCCCCCCc2ccccc2)c(C)c1
Product: [Br-]
Yield: 70 %

Procedure:
(8-Bromo-octyl)-benzene (1 mmol) was added to a solution of 2,4-lutidine (3 mmol) in acetonitrile, and the solution refluxed for 24 hours. The acetonitrile was removed in a vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no 2,4-lutidine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (70%). 1HNMR (300 MHz, CDCl3, ppm), 9.50 (d, 1H), 7.70 (d, 1H), 7.60 (s, 1H), 7.10-7.30 (dd, 1H), 4.78 (t, 2H), 2.84 (s, 3H), 2.54-2.60 (m, 5H), 1.80-1.92 (m, 2H), 1.50-1.60 (br, 2H), 1.20-1.45 (br, 6H).
Reaction SMILES: [C:1]12([C:11]([S:13]C)=S)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[NH2:16][NH2:17]>CO>[C:1]12([C:11]([NH:16][NH2:17])=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NN
Reactant: CSC(=S)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: CO
Product: NNC(=S)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of the product of step (a) (1 g) in methanol (50 ml) was treated with hydrazine hydrate (0.3 g) and the mixture stirred at room temperature for 1 hour. The solvent was evaporated, the residue triturated with water, and the pH adjusted to 7 to give the sub-title product (0.8 g) as a white solid.
Reaction SMILES: CSC.ClN1C(=O)CCC1=O.[CH:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])([CH3:14])[CH3:13]
Reactant: CC(C)OCCCCCCO
Agent: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)OCCCCCC=O
Reaction time: 1.5 h

Procedure:
7.5 cc (0.132 mol) of dimethyl sulphide are added dropwise at 0°, whilst stirring and under nitrogen, to a solution of 13.4 g (0.10 mol) of N-chlorosuccinimide in 250 cc of absolute toluene. A white precipitate is formed. The reaction mixture is subsequently cooled to -25° and a solution of 8.0 g (0.05 mol) of 6-isopropoxyhexanol in 25 cc of absolute toluene is added over the course of 15 minutes. After stirring at -25° for 90 minutes, a solution of 7.5 g (0.074 mol) of triethylamine in 25 cc of toluene is added over the course of 15 minutes to the white suspension. The cooling bath is then separated and after 10 minutes 500 cc of ether are added. The organic phase is washed with 1% aqueous hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated at 30° /20 mm Hg. After fractional distillation almost pure 6-isopropoxyhexanol is obtained (B.P. 90-93° /15 mm Hg). Said compound may be used for the production of 1-(7-isopropoxy-1-heptenyl)-4 -nitrobenzene without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH2:15])=O.COC(OC)[N:24]([CH3:26])C.O.[NH2:30]N>C(O)(=O)C>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:13]2[N:24]=[CH:26][NH:30][N:15]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: NC(=O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccccc1-c1cccc(-c2nc[nH]n2)c1
Temperature: 90 °C

Procedure:
A solution of 0.137 g (0.48 mmol) of 3-(2-trifluoromethoxyphenyl)-benzamide in 1 Ml of N,N-dimethylformamide dimethyl acetal was heated at 120° C. for 2 h at which time the reaction was concentrated in vacuo. To this material in 2.3 Ml of acetic acid was added 0.028 g (0.55 mmol) of hydrazine hydrate and the reaction mixture was heated at 90° C. for 2 h. The reaction mixture was then concentrated and partitioned between EtOAc and saturated NaHCO3 solution. The organic fraction was washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30:1, 9:1, 3:1 successively CH2Cl2:acetone) to give the title compound. 1H NMR (CD3OD) (δ, ppm): 8.32 (s, 1H), 8.06 (s, 1H), 7.98 (m, 1H), 7.50 (m, 3H), 7.39(m, 3H) Mass Spectrum (ESI) m/e (M+1): 306.1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@:19]3([OH:23])[C@H:10]([C@H:11]4[C@@:15]([CH2:17][C@@H:18]3[OH:24])([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[Cr](O)(O)(=O)=O.CO.O>CC(C)=O>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@:19]3([OH:23])[C@H:10]([C@H:11]4[C@@:15]([CH2:17][C:18]3=[O:24])([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@]21O
Agent: O=[Cr](=O)(O)O
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC(=O)[C@]21O
Reaction time: 0.08 h
Yield: 36 %

Procedure:
3-Acetoxy-9α,11β -dihydroxy-oestra-1,3,5(10)-trien-17-one (690 mg.) in acetone (30 ml) at 5° was treated dropwise with stirring with 8N chromic acid (1.0 ml). The solution was stirred for 5 mins. then methanol (1 ml), and water (30 ml) were added. The organic solvents were distilled off in vacuo and the steroid extracted into ethyl acetate. The organic solution was washed with dilute hydrochloric acid, then water, dried and the solvent was evaporated. The resulting gum was crystallised from methanol to give the title compound (247 mg, 36%), m.p. 247°-8°, [α]D + 297° (c. 1.0 in dioxan).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][CH:16]=[CH:15]2.Br[C:24]1C=C2C(=CC=1)C(=O)NC=C2C>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][CH:16]=[C:15]2[CH3:24]
Reactant: Cc1c[nH]c(=O)c2ccc(Br)cc12
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]ccc3c2)c1
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]cc(C)c3c2)c1

Procedure:
The sub-title compound was prepared by the method of intermediate 3 using the product of step i).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:9].[CH3:10][C:11]([CH3:14])([O-])C.[K+].BrC1CC1.COC(C)(C)C>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:14]2[CH2:11][CH2:10]2)=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(S)ccc1Br
Reactant: CC(C)(C)[O-]
Agent: BrC1CC1
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: Fc1cc(SC2CC2)ccc1Br
Temperature: 90 °C
Reaction time: 30 h
Yield: 27.3 %

Procedure:
A stirred mixture of 4-bromo-3-fluorobenzenethiol (Preparation 26, 400 mg, 1.93 mmol), potassium tert-butoxide (238 mg, 2.12 mmol) and bromocyclopropane (701 mg, 5.80 mmol) in DMSO (10 mL) was heated at 90° C. for 16 hours. Additional potassium tert-butoxide (43 mg, 0.386 mmol) and bromocyclopropane (467 mg, 3.86 mmol) were added and heating continued at 90° C. for 30 hours. The mixture was cooled to room temperature and poured into 2-methoxy-2-methylpropane (30 mL). The mixture was washed with water (2×30 mL), dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography eluting with heptanes to give the title compound as a colourless oil 27% yield, 130 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[F-:12].[K+].[F-].[Cs+].C1S(=O)(=O)CCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [F-]
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 93 %

Procedure:
1,500 parts of 3,4-dichloronitrobenzene, 680 parts of potassium fluoride and 5 parts of cesium fluoride are stirred in 1,500 parts of tetramethylenesulfone under nitrogen for 3 hours at 220° C. Working up takes place as described in Example 1(a). 1,275 parts (93% of theory) of 3-chloro-4-fluoronitrobenzene of melting point 41°-42° C. are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(OCCCN2CCCCC2)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Yield: 27 %

Procedure:
A suspension of potassium carbonate (290 mg) and palladium tetrakistriphenylphosphine (49 mg) in a solution of 1-[3-(4-bromophenoxy)-propyl]piperidine (250 mg) and 4-methylbenzeneboronic acid (228 mg) in toluene (5 mL) is heated overnight at a temperature close to 100° C. The mixture is diluted with ethyl acetate (200 mL) washed with a saturated aqueous sodium bicarbonate solution (3 mL), dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with dichloromethane then dichloromethane/methanol/ammonia 99/1/0.5. Fractions containing the expected product are pooled, concentrated under reduced pressure and salted with oxalic acid to give 70 mg of 1-{3-[(4′-methylbiphenyl-4-yl)oxy]propyl}piperidine, oxalate as a white solid melting at 195° C.