Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.C1COCC1.[H-].[Na+].[C:50]1([S:56](Cl)(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C.CCCCCC>[C:50]1([S:56]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:40])[CH:9]=3)([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:39])[CH:25]=3)[C:15]2=[O:23])(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(S(=O)(=O)c3ccccc3)c3ccccc32)cc(C)c1O
Reaction time: 0.5 h
Yield: 47 %

Procedure:
In a 40-mL vial, combine 0.15 g (1.0 mmol) of 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one with 15 mL of dry THF under nitrogen. Add 1.0 equivalent of sodium hydride and stir the resulting mixture 30 minutes under nitrogen. Add 2.0 equivalence of benzenesulfonyl chloride and stir an additional 30 minutes. Remove solvent in vacuuo and chromatograph the crude intermediate (1-Benzenesulfonyl-3,3-bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one) using 1:4 ethyl acetate/hexane to elute. Dissolve the intermediate in refluxing 1:1 THF/methanol and add excess cesium fluoride. Stir for 10 minutes, remove solvent in vacuuo, and add 10 mL of water. Extract with ethyl acetate to obtain 0.06 g (47%) of the titled compound as an off-white solid: LCMS (system 2) tR=4.05 min (100%), ESMS (M+1) m/z=514.2; 1H NMR (DMSO-d6); 8.28 (s, 1H), 7.98 (d, 2H), 7.90 (d, 1H), 7.81 (t, 1H), 7.65 (t, 2H), 7.39 (m, 1H), 7.20 (m, 2H), 6.30 (s, 4H), 1.93 (s, 12H).
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[NH:3]1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1>>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:18][CH2:19]1)[C:7]([C:4]1[NH:3][C:2](=[O:1])[O:6][N:5]=1)=[O:9]
Reactant: O=C(O)c1noc(=O)[nH]1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1noc(=O)[nH]1

Procedure:
The title compound was prepared from commercially available 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) analogously to Example 15 step 3;
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13].C(O)(=[O:33])C.OO>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)(=[O:33])=[O:13]
Reactant: O=C(O)c1ccc(COc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: ClCCl
Product: O=C(O)c1ccc(COc2ccc(S(=O)(=O)Cc3ccc4ccccc4n3)cc2)cc1
Temperature: 25 °C

Procedure:
To 3 mmol of the sulfinyl compound from Step A in acetic acid (40 mmol) is added 30% hydrogen peroxide (2 ml). The mixture is stirred at ambient temperature and assayed by TLC. Upon disappearance of the sulfinyl starting compound, the reaction mixture is diluted with dichloromethane, washed with dilute aqueous sodium bisulfite and water, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfonyl)phenoxymethyl)benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].P(Cl)(Cl)(Cl)=O.CN([CH:19]=[O:20])C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:19]=[O:20])=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(C)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOc1ccc(C=O)c(C)c1
Yield: 9.2 %

Procedure:
Using an analogous formylation procedure to that employed by Campaigne et al 3-ethoxytoluene (10.18 g, 75 mmol) was added dropwise to a mixture of phosphorous oxychloride (6.88 mL, 75 mmol) and DMF (21 mL, 0.272 mol) at 0° C. and the resultant mixture was heated to 80-90° C. for 4 hrs before being poured onto crushed ice. The solution was taken to pH 7 with saturated sodium acetate, extracted with dichloromethane and upon drying and solvent removal a clear colourless oil was obtained. Column chromatography (silica, ethyl acetate/hexane, 1:9, Rf 0.33) gave the title compound as a clear colourless oil (1.13 g, 20.40% based on reacted material). 1H n.m.r. [400 MHZ, CDCl3] δ 6 10.09, s, 1H, CHO; 7.73, d, J 8.6 Hz, 1H, H6; 6.81, dd, J 8.5, 1, 1H, H5, 6.72, d, J 1 Hz, 1H, H3; 4.09, q, J 7 Hz, 2H, OCH2CH3; 2.63, s, 3H, ArCH3; 1.43, t, J 6.95 Hz, 3H, CH2CH3. 13C n.m.r. [100 MHZ, CDCl3] d 190.95, CHO; 162.88, C4; 143.02, C2; 134.59, C6; 127.53, C1; 117.23, C3; 111.67, C5; 63.54, OCH2CH3; 19.70, ArCH3; 14.47, OCH2CH3. Mass spectrum (f.a.b.) calculated 164.083724, found 164.084.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]([CH2:10][CH2:11][OH:12])[CH3:9]>[Pd].C(O)C.CO.N>[CH3:9][N:8]([CH2:10][CH2:11][OH:12])[C:7]1[CH:6]=[CH:5][N:4]=[N:3][CH:2]=1
Reactant: CN(CCO)c1cc(Cl)nnc1Cl
Agent: [Pd]
Agent: N
Solvent: CCO
Solvent: CO
Product: CN(CCO)c1ccnnc1
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (444 mg, 2 mmol) and 10% palladium-on-charcoal catalyst (150 mg) in ethanol (15 ml), methanol (5 ml) and aqueous ammonia (15 ml) was stirred under hydrogen at 3 atmospheres pressure for 4 hours. The catalyst was removed by filtration and the solvent removed from the filtrate by evaporation. The residue was dissolved in methylene chloride, the insoluble material was removed by filtration and the solvent was removed from the filtrate by evaporation. The residue was purified by column chromatography on neutral aluminum oxide eluting with methylene chloride/methanol (95/5 followed by 90/10). The purified product was triturated with petroleum ether, the solid product was collected by filtration and dried under vacuum to give 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (275 mg, 91%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[C:13]([C:18](=O)[CH3:19])[C:12]=2[OH:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]([C:24]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[S:25])[NH2:23].CN(C)C=O>Cl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[C:13]([C:18](=[N:23][NH:22][C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)=[S:25])[CH3:19])[C:12]=2[OH:21])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCn1nc(C(C)=O)c(O)c1-c1ccc(C(C)(C)C)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C(C)=NNC(=S)Nc2ccc(C(=O)O)cc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Yield: 71.6 %

Procedure:
1-[5-(4-tert-Butylphenyl)-1-ethyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.1718 mmol, 49.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.1718 mmol, 36.3 mg) were stirred with dimethylformamide (3 mL) and two drops of concentrated hydrochloric acid at room temperature for 21 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (59 mg, yield 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[CH2:36][C@H:35]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[CH2:36][C@H:35]([NH:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.38 g, 1.2 mmol), HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL) and DIPEA (0.65 mL, 3.7 mmol) was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.435 g, 51%). LCMS calc. for C34H38BrN6O5[M+H]+: m/z=689.2. found: 689.3.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=O)[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[O:5]2.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl:17][C:9]1[C:10]2[C:4](=[CH:3][S:2][CH:1]=2)[O:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[N:8]=1
Reactant: O=C1Nc2ccccc2Oc2cscc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC1=Nc2ccccc2Oc2cscc21

Procedure:
A 1.08 g. portion of thieno[3,4-b][1,5]benzoxazepin-10(9H)-one and 1.15 g. of phosphorus pentachloride in 22 ml. of dry toluene are reacted as described in Example 1, giving 10-chloro-thieno[3,4-b][1,5]benzoxazepine. To this is added 10 ml. of toluene, 7.2 g. of N-ethylpiperazine and 25 ml. of triethylamine. The mixture is heated overnight at 100° C. and concentrated to dryness. The residue is treated as described in Example 3 providing the base compound as a foam which is converted to the fumarate, m.p. 215°-217° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)=[N+]=[N-].[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][CH2:4][CH:5]1[O:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC1CN2C(=O)CC2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC1CN2C(=O)CC2O1

Procedure:
(3RS, 5SR)-3-azidomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (150 mg, 0.89 mmol) was hydrogenated with 100 mg of 10% palladium on activated carbon in 25 ml of ethyl acetate at 50 psi hydrogen pressure at room temperature for 1 hr. After removal of catalyst by filtration, (3RS, 5SR)-3-aminomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one in ethyl acetate was obtained.
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][O:32][C:33]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH:37]([NH2:45])[CH2:38]2>ClCCl>[CH3:31][O:32][C:33]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH:37]([NH:45][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:1])[CH2:38]2
Reactant: COc1ccc2c(c1OC)CCC(N)C2
Reactant: O=C(O)CCCCC(=O)NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccc2c(c1OC)CCC(NC(=O)CCCCC(=O)NCCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-oxo-6-(2-phenylethylamino)hexanoic acid (2.49 g) and carbonyldiimidazole (1.62 g) in dry dichloromethane (100 ml) was stirred under a nitrogen atmosphere for 2 hours at room temperature. A solution of 1,2,3,4-tetrahydro-5,6-dimethoxy-2- aminonaphthalene (2.07 g) in dichloromethane (20 ml) was added and the solution stirred at room temperature for 18 hours. The solution was washed with dilute hydrochloric acid, dilute sodium carbonate solution and water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to leave the sub-title compound which crystallised from isopropanol as colorless flakes (3.8 g), m.p. 191°-193°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15](OC)=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH2:13][CH2:14][CH2:15][OH:16])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)CCc1cc(OC)c(OC)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCCO)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 19 h
Yield: 97.6 %

Procedure:
A solution of methyl 3-(3,4,5-trimethoxyphenyl)propanoate (11.03 g, 0.043 mol) in tetrahydrofuran (20 ml) was added dropwise to a suspension of lithium aluminum hydride (1.6 g, 0.042 mol) in 20 ml of tetrahydrofuran, said suspension having been cooled to 0° C., followed by stirring at room temperature for 19 hours. After the addition of sodium sulfate decahydrate, the resulting mixture was stirred further at room temperature for one hour. Insoluble matter was removed by filtration and the filtrate was concentrated, whereby 9.5 g of the title compound were obtained as colorless oil (yield: 96.8%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Product: COc1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1OC1CCCC1

Procedure:
Prepared by Procedure F and Scheme R using 3-(cyclopentyloxy)-4-methoxybenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 451.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[O:18][CH2:19][C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(O[N:31]1N=N[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=CC=CN=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[O:18][CH2:19][C:20]([NH:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:37]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(COC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of compound 22 (100 mg, 0.34 mmol) in THF (5 mL) at room temperature was added HATU (141 mg, 0.37 mmol) and TEA (0.07 mL, 0.48 mmol) and the resulting reaction mixture was stirred at room temperature for 10 minutes. Thereafter 2-aminopyridine (35 mg, 0.37 mmol) was added to the reaction mixture and the resulting reaction mixture was allowed to stir at room temperature for 5 hours. The reaction mixture was poured onto saturated ammonium chloride and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography (SiO2, 20% EtOAc-Hexanes eluant) provided 80 mg of 23 as a clear oil. (126 mg theoretical, 63% yield). 1H NMR (300 MHz, CDCl3): δ 8.85(br s, 1H), 8.35(m, 1H), 8.15(m, 1H), 7.95(m, 1H), 7.7(m, 1H), 7.65-7.45(m, 2H), 7.45(m, 2H), 7.3-7.2(m, 4H), 7.1-7.0(m, 1H), 5.95(s, 1H), 5.05(d, J=15 Hz, 1H), 4.45(d, J=15 Hz, 1H), 3.65(d, J=17 Hz, 1H), 3.45(d, J=17 Hz, 1H). MS (ES) m/z (MH+) 373
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:16])=[CH:18][CH:19]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: O=C(NCc1ccccn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-(aminomethyl)pyridine via Procedure G. The product was purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-2-ylmethyl)terephthalamide. MS (Q1) 443 (M)+.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=O.[NH3:24]>C(O)CCC>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)(=[O:2])[NH2:24]
Reactant: COC(=O)CCCCn1c(-n2ccnc2)c(C)c2ccccc21
Reactant: N
Solvent: CCCCO
Product: Cc1c(-n2ccnc2)n(CCCCC(N)=O)c2ccccc12

Procedure:
A solution of 4 g of 1-(4-methoxycarbonylbutyl)-3-methyl-2-(1-imidazolyl)indole in 40 ml of n-butanol is saturated with ammonia and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness and the product is crystallized to yield the 1-[4-carbamoylbutyl]-3-methyl-2-(1-imidazolyl)indole.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC1(C)N([O])C(C)(C)CCC1>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Product: CC1(C)COC(=O)C1=O
Reaction time: 3 h
Yield: 93.5 %

Procedure:
5 g (38.4 mmol) of pantolactone were reacted with 3.6 g (15.5 mmol) of trichloroisocyanuric acid as described in Example 13. In contrast to Example 13, 60 mg (0.25 mmol) of TEMPO derivative C were used as the catalyst. The reaction had finished after 3 hours. After recrystallization of the crude product there were obtained 4.6 g (93%) of ketopantolactone, m.p. 69°-70° C., GC content: 100% (area percent).
Reaction SMILES: [Cl-].[C:2]1([N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([N+]2C=CC=CC=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH2:29][O:30][C:31]([NH:33][CH2:34][CH2:35][C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]([OH:47])=[O:46])[CH:43]=3)[NH:38][CH:37]=2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O>[C:2]1([N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([O:46][C:45]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[NH:38][CH:37]=[C:36]3[CH2:35][CH2:34][NH:33][C:31](=[O:32])[O:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:47])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Reactant: O=C(NCCc1c[nH]c2ccc(C(=O)O)cc12)OCc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc12)OCc1ccccc1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of 1-[(diphenylamino)carbonyl]pyridinium chloride (1.1 g) in water (10 ml) was added rapidly to a stirred solution of 3-[2-[[(phenylmethoxy)carbonyl]amino]ethyl]-1H-indole-5-carboxylic acid (1 g) and triethylamine (0.6 ml) in water (15 ml). After 0.5 hour, an amorphous yellow solid (1.7 g) was filtered off. A sample (0.5 g) was crystallised from a mixture of ethyl acetate and cyclohexane to give the title compound (0.3 g) as a cream crystalline solid m.p. 137°-138.5° C.
Reaction SMILES: [C:1]([C@H:4]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:5]12[CH2:6][C:7]([OH:9])=[O:8])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[N:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:14]3)(O)=[O:2].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([NH:35][C:1]([C@H:4]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:5]12[CH2:6][C:7]([OH:9])=[O:8])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[N:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:14]3)=[O:2])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C(=O)O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O

Procedure:
A sample of 17β-carboxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one (2.03 g, 4.86 mmol), from part F, is coupled with t-butyl amine as described in Example 1, part A, to give crude 17β-N-t-butylcarbamoyl-6-t-butylcarboxy-6-azaandrost-4-en-3-one which is dissolved in methylene chloride (30 mL) and treated with trifluoroacetic acid (4 mL) at room temperature. After 3 hrs the reaction is concentrated, methylene chloride (50 mL) and saturated aqueous bicarbonate (50 mL) added, the layers separated, methylene chloride washed with saturated aqueous NaCl, dried over MgSO4, concentrated and chromatographed on silica gel (0-10% methanol/methylene chloride) to give 17β-N-t-butylcarbamoyl-6-azaandrost-4-en-3-one as a white solid; yield: 1.04 g (57%). Recrystallization from methylene chloride/hexanes gives an analytical sample as a white crystalline solid; m.p. 186°-189° C. Anal. Calcd. for C23H36N2O2 ·3/8H2O; C, 72.83; H, 9.77; N, 7.38. Found C, 72.95; H, 9.85; N, 7.22.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[CH2:9]2)[N:5]=[C:4]([CH:16]([O:18]C)[CH3:17])[N:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH:10]([CH3:15])[NH:11][CH:12]([CH3:14])[CH2:13]2)[N:5]=[C:4]([CH:16]([OH:18])[CH3:17])[N:3]=1
Reactant: COC(C)c1nc(Cl)nc(N2CC(C)NC(C)C2)n1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1CN(c2nc(Cl)nc(C(C)O)n2)CC(C)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To an ice-cold solution of 2-chloro-4-(3,5-dimethyl-piperazin-1-yl)-6-(1-methoxy-ethyl)-[1,3,5]triazine, prepared in Example 2 above, (2.2 mmol, 631 mg) in methylene chloride (7 mL) was added boron tribromide (1 M in methylene chloride, 11.04 mmol, 11 mL) and the reaction was stirred for 2 h. After the reaction was allowed to come to room temperature, methylene chloride (10 mL) was added to it followed by a small quantity of water (1 mL) to quench the unreacted boron tribromide. Sufficient saturated aq. sodium bicarbonate was added to raise the pH of the reaction solution to 8. The methylene chloride layer was collected, dried, filtered and the filtrate was evaporated to dryness to obtain a residue, which was purified by silica gel chromatography (eluent, 98:2 methylene chloride-methanol) to obtain 1-[4-chloro-6-(3,5-dimethyl-piperazin-1-yl)-[1,3,5]triazin-2-yl]-ethanol (65%, 392 mg); mp 126-128° C.