Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([OH:23])=O)[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)=[C:5]([CH3:19])[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:47]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1>CN(C=O)C.O>[CH2:47]([N:57]1[CH2:62][CH2:61][N:60]([C:21](=[O:23])[CH2:20][N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=3)=[C:5]([CH3:19])[CH:4]=2)[CH2:59][CH2:58]1)[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: Cc1cc(N(C)CC(=O)O)ccc1Oc1ccc([N+](=O)[O-])cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetic acid (0.93 g, 2.9 mmol) in DMF (40 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol), 1-hydroxybenzotriazole monohydrate (0.54 g, 3.5 mmol), and 1-piperonylpiperazine (0.68 g, 3.08 mmol). The reaction mixture was stirred for 15 hours at room temperature under a nitrogen atmosphere. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→dichloromethane:methanol=100:1), to thereby yield 1.2 g of the title compound.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[NH2:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1.[N+]([C:31]1[C:44]2[C:43](=[O:45])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](=[O:46])[C:35]=2[CH:34]=[CH:33][CH:32]=1)([O-])=O>C(O)C>[CH:20]1[CH:19]=[C:18]2[C:17]([C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:34]4[C:35]5[C:36]([C:37]6[C:42]([C:43](=[O:45])[C:44]=5[CH:31]=[CH:32][CH:33]=4)=[CH:41][CH:40]=[CH:39][CH:38]=6)=[O:46])[C:25]=3[C:24](=[O:26])[C:23]2=[CH:22][CH:21]=1)=[O:27]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
250 ml of quinoline, 100 g of 1-aminoanthraquinone and 25 g of CaO are warmed to 200° to 210° C. in a 1 l sulphonation beaker with an anchor stirrer and shortpath distillation bridge. 120 g of 1-nitroanthraquinone are added in portions in the course of 2 hours, and the mixture is then stirred for another 5 hours at 200° to 210° C. The mixture is allowed to cool to 120° C., and is diluted slowly and under reflux with 500 ml of ethanol. The mixture is then filtered off under suction, and the residue is washed with ethanol and dried. The dry caked filter residue is heated under reflux in 1 l of water with 100 g of ammonium chloride, and is acidified slowly through the reflux condenser with concentrated hydrochloric acid. After filtering off the mixture under suction, washing the residue until the runnings are neutral, and drying, 190.4 g of 80.4% strength 1,1'-dianthraquinonylamine are obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][OH:31]>CN(C=O)C.CS(C)=O.CO>[OH:31][CH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OC[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC[C@H]3CO)n2n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and (S)-pyrrolidin-2-ylmethanol (78 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-25% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (82.8 mg, 81%). Melting point (167.0-197.7° C.). 1H NMR (DMSO-d6) δ: 11.06 (s, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 6.80 (s, 1H), 6.21 (s, 1H), 5.01 (br. s., 1H), 3.99 (t, J=8.2 Hz, 1H), 3.77-3.92 (m, 1H), 3.55-3.62 (m, 1H), 3.49 (dd, J=10.9, 6.6 Hz, 1H), 2.36 (s, 3H), 2.02-2.18 (m, 3H), 1.88-2.00 (m, 1H), 1.46 (s, 6H); ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:20])(=[O:19])[NH2:18].[C:21]([OH:26])(=[O:25])[CH:22]([CH3:24])[OH:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:19])(=[O:20])[NH2:18].[C:21]([O-:26])(=[O:25])[CH:22]([CH3:24])[OH:23]
Reactant: CC(O)C(=O)O
Agent: CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C
Solvent: CCO
Product: CC(O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.5 g of 4-(4-chloro-3-sulfamoylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol 0.7 g of lactic acid were added in 10 ml of ethanol, the mixture was stirred for 3 hours at room temperature and precipitated with diisopropyl ether. After decanting of the solvent the oil was dissolved in water and lyophilized. The result was a colorless, amorphous solid substance that was decomposed from 120° C onwards, γC=N 1630 cm-1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:35]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:39]2C=CC=CC=2N=N1.CN.O1CCCC1>CN(C)C=O.O>[CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:35][CH3:39])=[O:17])=[CH:13][N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (prepared in Example 46, 125 mg, 0.31 mmol), N)N-diisopropylethylamine (0.10 mL, 0.61 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (142 mg, 0.32 mmol) in N,N-dimethylformamide (15 mL) at 25° C. was treated dropwise with a 2.0M solution of methylamine in tetrahydrofuran (0.16 mL, 0.32 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide (83 mg, 64%) as white solid: mp 229.1-231.7° C.; FAB-HRMS m/e calcd for C21H23Cl2N3O2 (M+H)+420.1245, found 420.1247.
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C@H:4]1[C@@H:6]([C:7]([O-:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[Cl:13]/[CH:14]=[CH:15]\[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]([Br:12])=[CH:3][C@H:4]1[C@@H:6]([C:7]([O:9][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([CH2:16]/[CH:15]=[CH:14]\[Cl:13])=[CH:18][CH:19]=2)=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: OCc1ccc(C/C=C\Cl)cc1
Reactant: CC1(C)[C@H](C(=O)[O-])[C@@H]1C=C(Br)Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OCc2ccc(C/C=C\Cl)cc2)[C@@H]1C=C(Br)Br
Reaction time: 0.5 h

Procedure:
To a solution of (1R)cis 3(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (0.11 g) in CH2Cl2 (3 ml) cooled to 0° is added successively 4(Z-3-chloroallyl) benzyl alcohol (0.070 g) in CH2Cl2 (2 ml), N,N1 dicyclohexylcarbodiimide (0.076 g) in CH2Cl2 (2 ml), and 4-dimethylamino pyridine (0.010 g). This mixture is stirred for 30 minutes at 0°, then for 16 hours at 20°. The resulting precipitate is filtered off, the filtrate evaporated under reduced pressure and the residue chromatographed on florisil. The fraction eluted by 7% diethyl ether in petroleum ether bp 60°-80° C. ether in petrol is evaporated to a residue of 4(-3-chloroallyl)benzyl (1R)-3(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (0.15 g) 91% nD20 1.5684.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.CCCCCC.C([Li])CCC.[C:24](=[O:26])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:24]([OH:26])=[O:25])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: COc1cc(Br)c2[nH]ccc2c1
Reactant: O=C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C(=O)O)c2[nH]ccc2c1
Temperature: -78 °C
Yield: 59.1 %

Procedure:
A mixture of 7-bromo-5-methoxy-1H-indole (1.2 g) and THF (12 mL) was stirred at −78° C. under an argon atmosphere. To the reaction mixture was added dropwise an n-butyllithium n-hexane solution (1.65 M, 9.6 mL) at −50° C. or lower. The reaction mixture was stirred for 0.5 hour under ice-cooling. The reaction mixture was cooled to −78° C., and dry ice (10 g) was added thereto, followed by slowly warming to room temperature. The reaction mixture was poured into a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (THF/hexane=20→60%) to obtain 5-methoxy-1H-indole-7-carboxylic acid (0.60 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH2:3]([O:10][N:11]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
Sodium hydride (0.97 g of 80% in mineral oil, 32 mmol) was added to a solution of tert-butyl N-benzyloxycarbamate (6.53 g, 29 mmol) in N,N-dimethylformamide (45 mL). A gas evolved and the mixture was stirred for 20 minutes. Isobutyl bromide (3.5 mL, 32 mmol) was added and the reaction mixture was heated at 70° C. for 1.5 hr. The reaction was quenched with water (about 50 mL) then extracted twice with diethyl ether. The extracts were combined, washed with water (5 small portions), dried over magnesium sulfate and then concentrated under vacuum to provide 7.63 g of tert-butyl N-benzyloxy-N-(2-methylpropyl)carbamate as a faintly brown oil.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1[C:10]2[CH2:11][C:12]3[N:17]4[CH:18]=[CH:19][N:20]=[C:16]4[C:15](=[O:21])[NH:14][C:13]=3[C:22]=2[CH:23]=[CH:24][CH:25]=1)=[O:8])=[O:4].Cl>O1CCOCC1>[O:21]=[C:15]1[NH:14][C:13]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:9]([C:7]([NH:6][CH2:5][C:3]([OH:4])=[O:2])=[O:8])[C:10]=3[CH2:11][C:12]=2[N:17]2[CH:18]=[CH:19][N:20]=[C:16]12
Reactant: COC(=O)CNC(=O)c1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)c1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Yield: 83.5 %

Procedure:
A mixture of 1 g 9-(methoxycarbonylmethylcarbamoyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 50 ml of dioxane and 15 ml of concentrated hydrochloric acid is heated at reflux for 24 hours. The reaction mixture is concentrated on a rotary evaporator, ethyl ether is added to the evaporation residue and filtration is carried out. The solid obtained is triturated in 20 ml of distilled water, filtered, washed with distilled water (20 ml) and then with ethyl ether and dried at 60° C. under vacuum (1 mm Hg; 0.13 kPa). 0.8 g of N-[(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)carbonyl]glycine is obtained in the form of a yellow solid containing 0.66 mol of hydrochloric acid and melting above 260° C (Analysis; % Calculated C: 55.13, H: 3.66, Cl: 6.78, N: 16.07, O: 18.36; % Found C: 55.1, H: 3.6, Cl: 6.2, N: 15.8, O: 18.3).
Reaction SMILES: [CH3:1][C:2](OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])(C)C)=[O:39])[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([O:28][CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][CH2:41][CH2:44][CH2:1][CH3:2])=[O:39])[CH2:36][CH2:37]3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOC(=O)N1CCC(Oc2cc3c(Cl)ncnc3cc2OC)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g), 4-hydroxy-1-tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tent-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate as a white solid (10.3 g); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.56-1.69 (m, 2H), 1.93-2.04 (m, 2H), 3.20-331 (m, 2H), 3.60-3.70 (m, 2H), 4.00 (s, 3H), 4.89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8.86 (s, 1H); Mass Spectrum (M+H)+ 394.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].C1(C)C=CC=CC=1.[CH:18]1([C:23]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:29])[C:24](OCC)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC>[CH:18]1([C:23]([C:30]#[C:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([OH:29])[C:24]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCC1
Reactant: OC1CN2CCC1CC2
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(OC1CN2CCC1CC2)C(O)(C#Cc1ccccc1)C1CCCC1

Procedure:
3-Quinuclidinol (3.8 g., 0.030 mole) and about 0.05 g. of sodium were refluxed in 50 ml. of toluene, in a flask equipped with a reflux head, until all the sodium reacted. Then, ethyl α-cyclopentyl-α-phenylethynylglycolate (5.4 g., 0.02 mole) in 35 ml. of solvent was added dropwise over an hour period. No temperature drop was noted in the reflux head. The reaction mixture was refluxed for about 18 hours and then about 40 ml. of solvent was distilled from the reaction flask over a four hour period. The reaction mixture was cooled, and dry 20°-40° petroleum ether was added. A tarry solid formed and was filtered. The solid was treated with hot hexane to yield 3.2 g. (45%) of crude product melting about 115° C. The pure compound, m.p. 137°-39°, was obtained by recrystallization from hexane.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([OH:27])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([OH:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[P:29]([O:36]CC)([O:33][CH2:34]C)[O:30][CH2:31]C>>[CH3:31][O:30][P:29]([CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([OH:27])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([CH3:14])([OH:15])[CH3:13])=[CH:7][CH:6]=1)(=[O:36])[O:33][CH3:34]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(O)C(=O)c1ccc(C(CCBr)c2ccc(C(=O)C(C)(C)O)cc2)cc1
Product: COP(=O)(CCC(c1ccc(C(=O)C(C)(C)O)cc1)c1ccc(C(=O)C(C)(C)O)cc1)OC
Yield: 106.8 %

Procedure:
1-(4-{3-Bromo-1-[4-(2-hydroxy-2-methylpropionyl)phenyl]propyl}phenyl)-2-hydroxy-2-methylpropan-1-one (5.0 g, 0.0112 moles) is reacted with 4.6 grams of triethyl phosphite following the procedure of Example 23 to give 5.7 g (98% yield) of {3,3-bis-[4-(2-hydroxy-2-methylpropionyl)phenyl]propyl}phosphonic acid dimethyl ester, a yellow oil. The ester is reacted with trimethylsilyl bromide in chloroform and methanol, following the procedure of Example 22, to give 5.0 g of the title compound, an amorphous solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].N[C:46]1[CH:47]=C(C#CCCCO)C=C[CH:51]=1>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:51]=[CH:46][CH:47]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: Nc1cccc(C#CCCCO)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCO)c5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 47 in place of 8-aminooctanol. ES/MS calcd. for C36H33N4O6S+ 649.2. Found m/z=649.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[CH2:10][CH3:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[C:4]([CH3:9])[C:3]=1[CH2:10][CH3:11]
Reactant: CCc1c(Br)ccc(N)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1c(Br)ccc(NC(C)=O)c1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3.86 g of the bromide prepared in Example 212a in 48 ml pyridine, 2.04 ml of acetic anhydride was added dropwise at 0° C. and stirred for 20 hours at 25° C. The reaction mixture was concentrated in vacuo and the crude product thus obtained was purified by column chromatography on silica gel with hexane/0-100% ethyl acetate. In this manner, 3.73 g of the title compound was obtained.
Reaction SMILES: C(OCC)(=O)C.Cl.COC[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[N:16][CH:17]=1>C(O)C>[F:30][C:28]([F:29])([F:31])[O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][CH2:18][C:15]2[N:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: COCOc1ccc(COCc2ccc(OC(F)(F)F)cc2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(COCc2ccc(OC(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.7 %

Procedure:
2 N hydrogen chloride-ethyl acetate solution (20 ml) was added to an ethanol solution (20 ml) of 5-methoxymethoxy-2-(4-trifluoromethoxybenzyloxymethyl)pyridine (2.3 g) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and a sodium hydrogen carbonate aqueous solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. The result was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1). The result was concentrated to dryness under reduced pressure to afford the title compound as a white solid (2.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:20][CH3:21])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[NH3:1].[CH2:20]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:3]=2)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]1)[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCN1CCC(CC)(c2cccc(N)c2)CC1
Solvent: c1ccncc1
Product: CCCCCCN1CCC(CC)(c2cccc(NS(C)(=O)=O)c2)CC1
Product: N
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.7 %

Procedure:
To 4-(3-aminophenyl)-4-ethyl-N-hexylpiperidine (Preparation 64, 50.0 mg, 0.174 mmol) in anhydrous pyridine (4 ml) under nitrogen at 0° C. was added methanesulfonyl chloride (0.2 ml, 1.18 mmol). The solution was stirred at room temperature for 48 h. Ice (5 g) was added and, after 30 min, the reaction mixture was extracted with dichloromethane (10 ml). The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give the crude product which was purified by silica (5 g) column chromatography, eluting with ethyl acetate:hexane:0.880 ammonia (40:60:1), then ethyl acetate:0.880 ammonia (100:1) and then methanol:ethyl acetate:0.880 ammonia (10:89:1) to give the title compound as an oil (20 mg, 29%).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].[H-].[Na+].[H][H].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][N:16]=1>C(#N)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:9]2[CH2:8][CH2:7][S:6][C:5]2=[CH:4][N+:1]([O-:3])=[O:2])=[CH:17][N:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])C=C1NCCS1
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])C=C1SCCN1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.8 %

Procedure:
2-Nitromethylenethiazolidine (2.9 g) was dissolved in dry acetonitrile (30 ml), and 60% sodium hydride (0.9 g) was added at room temperature in a stream of nitrogen. Subsequently, the mixture was stirred at room temperature until the generation of hydrogen ceased. Then, a solution of 2-chloro-5-pyridylmethyl chloride (3.2 g) in dry acetonitrile (5 ml) was added at room temperature, and the mixture was stirred at room temperature for 1 day. Acetonitrile was then distilled off under reduced pressure, and dichloromethane was added to the residue. The mixture was then washed with water. Dichloromethane was distilled off from the dichloromethane layer. The remaining oil was purified by silica gel column chromatography to give the desired 3-(2-chloro-5-pyridylmethyl)-2-nitromethylenethiazolidine (1.6 g). mp. 177°-179° C.