Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[NH:10]1[CH2:17][CH2:16]C[C@H:11]1[C:12](O)=[O:13].C(=O)([O-])[O-].[K+].[K+].N1CCOCC1>CS(C)=O.[Cu]I>[F:9][C:3]1[C:2]([NH2:1])=[CH:7][C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:16][CH2:17]2)=[CH:5][N:4]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Nc1cc(Br)cnc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCN1
Solvent: CS(C)=O
Product: Nc1cc(N2CCOCC2)cnc1F
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A stirred mixture of 3-amino-5-bromo-2-fluoropyridine (0.96 g, 5.02 mmol), L-proline (0.12 g, 1.01 mmol), potassium carbonate (1.39 g, 10.1 mmol), copper(I) iodide (0.096 g, 0.50 mmol), and morpholine (1.31 mL, 15.04 mmol) in dry DMSO (3.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentration the residue was purified on basic alumina (10-50% EtOAc in hexanes) to afford a white solid as 2-fluoro-5-morpholinopyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.96 (1H, t, J=2.6 Hz), 6.75 (1H, dd, J=9.6, 2.7 Hz), 5.25 (2H, br. s.), 3.80 (4H, m), 3.08 (4H, m). Mass Spectrum ESI (pos.) m/e: 198.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10]O)[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1CC(CS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.5 g, 1.93 mmol) and TEA (0.33 gm, 2.89 mmol) in DCM (20 ml), methane sulphonyl chloride (0.38 g, 3.86 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 4 h. Aqueous NaHCO3 solution was added to it and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to offer 4-methanesulfonylmethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow solid (0.45 g, 69%). 1HNMR (400 MHz, CDCl3): δ 1.45-1.50 (Two s, 9H); 1.79-1.85 (m, 1H); 2.42-2.81 (m, 2H); 3.08 (s, 3H); 3.21-3.38 (m, 1H); 3.77 (s, 3H); 4.09-4.4 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][OH:15])[CH:9]1[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>[K]>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][O:15][S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:9]1[C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC(CO)C(c2c(Cl)cccc2Cl)N1Cc1ccccc1
Agent: [K]
Product: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(Cc3ccccc3)C2c2c(Cl)cccc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To 40 g of 1-benzyl-2-(2,6-dichlorophenyl)-3-hydroxymethyl-pyrrolidine-5-one in 67 ml of potassium dried pyridine at 5°-10° was added 23.3 g of tosyl chloride over 30 minutes. After the addition, the mixture was stirred for 3 hours at 15° and then for 13 hours at ambient temperature. The reaction mixture was added dropwise to a stirred ice-water solution and then set at ambient temperature for 72 hours. The light yellow solid was collected by filtration and then air dried. Trituration with ether followed by filtration provided 44.5 g of colorless crystals, m.p. 110°-114°.
Reaction SMILES: [C:1]1([C@H:7]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[O:17])[C:8]([O:10]C(C)(C)C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[C:1]1([C@H:7]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[O:17])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](C(=O)O)c1ccccc1

Procedure:
The solution of tert-butyl (2S)-phenyl[({[4-(4-pyridinyl)phenyl]amino}carbonyl)amino]acetate (50.0 mg) in dichloromethane (1.0 mL) and trifluoroacetic acid (954 μL) was stand at ambient temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue was diluted with chloroform (2 mL), then concentrated. To the residue was added ethyl acetate (2.0 mL) and the precipitated solid was collected by filtration, then washed with ethyl acetate (2.0 mL) to give (2S)-phenyl[({[4-(4-pyridinyl)phenyl]amino}carbonyl)amino]acetic acid trifluoroacetate (39 mg) as off-white crystals.
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:16][CH2:17][C:18]1[CH:37]=[CH:36][C:21]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][C:26]=2[O:34][CH3:35])=[O:23])=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.Br>C(O)(=O)C>[NH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:32])[NH2:33])=[CH:27][C:26]=2[O:34][CH3:35])=[O:23])=[CH:36][CH:37]=1
Reactant: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.7 %

Procedure:
To 1.5 g of 4-amidino-2-methoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate, was added 15 ml of acetic acid followed by 1 ml of anisole. To the mixture, while being cooled in ice, was added 3.0 ml of an acetic acid solution containing 30% of hydrogen bromide. The mixture was then stirred overnight at room temperature. The insoluble substance precipitated from the reaction mixture was collected by filtration and recrystallized from a methanol-ethyl ether mixture to obtain 1.1 g of colorless crystals of 4-amidino-2-methoxyphenyl 4-aminomethylbenzoate dihydrobromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cc(C)cc32)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
2-{2-[5-Fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 96 mg, 0.33 mmol), methyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (85 mg, 0.3 mmol) and ytterbium trifluoromethanesulfonate (28 mg, 0.045 mmol) were stirred in acetonitrile (0.4 mL) with some molecular sieves. The resulting mixture was then heated to reflux (80° C.) overnight and then allowed to cool to room temperature. The mixture was poured into ethyl acetate (5 mL) and washed successively with saturated aqueous sodium bicarbonate and aqueous brine. The organic phase was separated, dried over anhydrous sodium sulphate and then concentrated and the residue purified by silica gel column chromatography (10% ethyl acetate in cyclohexane) to give the title compound as a white solid (75 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:32]([O:33][CH3:34])=[CH:31][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:8]=2[CH:7]=1)[N:15]=[CH:14][C:13]([C:18]#[N:19])=[C:12]3[NH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=1[Cl:30].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[I-].[Na+]>COCCOC>[Cl:30][C:22]1[CH:23]=[C:24]([Cl:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=1[NH:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:32]([O:33][CH3:34])=[CH:31][C:9]=3[CH:10]=2)[N:15]=[CH:14][C:13]=1[C:18]#[N:19]
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl

Procedure:
Following procedure 1 of Example 17, a mixture of 0.105 g (0.20 mmol) of 8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.3 mL of morpholine and 0.01 g of sodium iodide in 10 mL of 1,2-dimethoxyethane is heated under reflux for 7 hours. The resulting solid is purified by silica gel chromatography, utilizing a 98:2 to 94:6 gradient of methylene chloride/methanol to give 0.089 g of 4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 205-208° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16](I)[CH2:17][CH2:18][CH3:19].O>CN(C)C=O>[CH2:1]([O:8][C@@H:9]([C@@H:10]([O:12][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:11])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: C[C@H](O)[C@@H](C)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCO[C@@H](C)[C@@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
1.90 g of (2S,3R)-3-benzyloxy-2-butanol was dissolved in 50 ml of dry N,N-dimethylformamide. Thereto was added in small portions 2.53 g of about 60% oily sodium hydride. The mixture was stirred for 1 hour at room temperature. 11.63 g of butyl iodide was dropped with ice cooling. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water. The resulting mixture was extracted with ether three times. The extract was washed with water three times, dried and concentrated. The residue was subjected to Kugel-rohr distillation (1 mmHg) to obtain 2.05 g of (2R,3S)-2-benzyloxy-3butoxybutane.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH:6]=[O:7])([O-:3])=[O:2].[CH2:8](O)[CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([O-:3])=[O:2]
Reactant: OCCO
Reactant: O=CCC[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CCC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask fitted with a Dean-Stark trap and reflux condenser, a solution of 3-nitro-propionaldehyde (138 g, 1.34 mol) in toluene (1 L) was treated with ethylene glycol (83 g, 1.34 mol) and p-toluenesulfonic acid monohydrate (5.0 g, 26 mmol). The mixture was heated at reflux, open to air, for 4 h, and then cooled to rt. A black residue was removed by paper filtration. The filtrate was washed with satd. aq. NaHCO3 (250 mL) and brine (3×100 mL). Charcoal and MgSO4 were added, and the resulting suspension was stirred for 1 h. Filtration and concentration of the filtrate gave the title compound, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): 5.03 (t, J=3.6, 1H), 4.50 (t, J=6.8, 2H), 4.05-3.90 (m, 2H), 3.90-3.80 (m, 2H), 2.44 (td, J=6.8, 3.6, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1.[Cl:14][C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>[OH-].[Na+]>[ClH:14].[CH3:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][C:4]([NH:3][C:15](=[O:16])[O:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[CH:13][C:8]=2[N:9]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-methylbenzothiazole dihydrochloride (530 mg, 2.23 mmol) was dissolved in 1 N NaOH (10 mL) and was extracted with EtOAc (3×20 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in CH2Cl2 (10 mL), p-nitrophenyl chloroformate (586 mg, 2.91 mmol) was added, and the reaction mixture was stirred at rt overnight. The resulting solid was collected by filtration, was washed with CH2Cl2, and was dried under vacuum. This gave 853 mg of the title compound contaminated with some 5-amino-2-methylbenzothiazole. LC-MS: RT=8.49 min, [M+H]+=330.0.
Reaction SMILES: C(S[N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(C)(C)C.SC1SC2C=CC=CC=2N=1>C1C=CC=CC=1>[C:10]1(=[O:11])[NH:6][C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: CC(C)(C)SN1C(=O)c2ccccc2C1=O
Agent: Sc1nc2ccccc2s1
Solvent: c1ccccc1
Product: O=C1NC(=O)c2ccccc21
Yield: 96.5 %

Procedure:
11.8 Grams (0.05 mole) of N-(tert-butylthio)phthalimide and 8.5 grams (0.05 mole) of 2-mercaptobenzothiazole in 200 ml of benzene are stirred at 70° C for 6 hours. The reaction mixture is cooled and filtered to obtain 7.1 grams of phthalimide (white solid, m.p. 231° C). The benzene is stripped from the filtrate by evaporation to give a solid residue. The residue recrystallized from methanol gives 9.3 grams of 2-(tert-butyldithio)benzothiazole, m.p. 80.0°-80.5° C. Another 3.0 grams of product are obtained upon concentration of the alcoholic filtrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
0.072 mol (12.6 g) of 4-chloro-2-nitrophenol, 40 ml of acetone and 9.72 g of potassium carbonate are introduced into a 250 ml three-necked flask equipped with a stirring system, a thermometer and a condenser. The mixture is brought to 40° C and 9.72 g of dimethyl sulphate are then added drop by drop; the mixture is heated under reflux for 5 hours; the potassium sulphate is separated; the acetone solution is concentrated under reduced pressure and the 4-chloro-2-nitroanisole is precipitated. It is separated and then crystallized in a water/acetone mixture.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH3:10])[CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:11][C:12]1[C:13]2[C:14]3[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16](S)[C:15]=3[CH:22]=[CH:23][CH:24]=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:37].Cl.Cl>C(O)C>[ClH:37].[ClH:37].[Br:11][C:12]1[C:13]2[C:14]3[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:9][CH2:8][CH:7]([CH3:10])[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:15]=3[CH:22]=[CH:23][CH:24]=2
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Reactant: CC(CN)Cn1ccnc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: CC(CNC1=Nc2ccc(Br)c3cccc1c23)Cn1ccnc1

Procedure:
The free base of the title compound was prepared by the procedure of Example 55, employing 2.8 grams of 3-(1H-imidazol-1-yl)-2-methylpropanamine, 5.3 grams of 6-bromobenz(cd)indol-2-thiol, 6.45 grams of mercuric acetate, and 500 ml of ethanol. The crude free base was purified by the chromatographic procedure of Example 46, 5.5 grams of product being obtained. This was converted to the dihydrochloride salt by treatment with excess 2.3N ethanolic hydrogenchloride, followed by precipitation with acetone. The yield was 1.2 grams and the mp 180° C. with decomposition.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(COc2ccc(CC3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
4-{4-[4-(Trifluoromethyl)benzyloxy]benzyl}piperidine-1-carboxylic acid tert-butyl ester (2.64 g, 5.9 mmol), dichloromethane (5 ml) and trifluoroacetic acid (5 ml) were mixed and stirred at room temperature for 2 hours. After concentrating the reaction mixture, dichloromethane was added to the residue, and 5 N sodium hydroxide was further added, followed by vigorous stirring. The organic layer was separated, washed with water, dried over sodium sulfate, and then concentrated to afford the title compound as a colorless powder (2.06 g, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([O:30][CH3:31])[CH:19]=1>>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1cc(N)ccc1-c1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Product: COc1cc(NCc2cncn2Cc2ccc(C#N)cc2)ccc1-c1ccccc1

Procedure:
The titled compound was prepared from the product of Step 5 and 1-amino-3-methoxy-4-phenylbenzene using the procedure described in Step 3 of Example 1.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[O:10]1[CH2:25][CH:11]1[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[CH:23]C=CC=1)[CH2:14][CH:15]1[O:17][CH2:16]1>O>[CH2:18]([N:13]1[CH2:14][CH:15]([CH2:16][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:17][CH:11]([CH2:25][OH:10])[CH2:12]1)[CH2:19][CH2:24][CH3:23]
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: CCCCN1CC(CO)OC(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
An amount of 125 g of benzyl alcohol is stirred and 0.3 g of finely cut sodium metal (0.013 mole) is added and the mixture then stirred under nitrogen for 2.5 hours. Then with stirring, 27.79 g of N,N-bis(2,3-epoxypropyl)benzylamine (0.15 mole) is added to the reaction mixture and stirring at room temperature continued for 0.5 hour, followed by heating the mixture at reflux for 16 hours. The mixture is then cooled to room temperature and poured into 400 ml of water. The aqueous mixture is extracted with 2×250 ml portions of chloroform, and the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the colorless oil vacuum distilled through a 10 cm vigreux distilling column. The fraction distilling at b.p. 196°-199° @0.4 mm is collected yielding 28.6 g (65%) of the title compound.
Reaction SMILES: BrC1C=C2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[C:4](C(O)=O)C=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NCC(OC(C)(C)C)=O>>[C:16]1([NH:15][C:8](=[O:11])[CH2:7][CH2:6][C:5]#[CH:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(Br)cc2c1CCC2=O
Agent: CC(C)(C)OC(=O)CN
Product: C#CCCC(=O)Nc1ccccc1

Procedure:
The procedure for Example 41 was used, substituting 4-pentynoic acid for 6-bromo-4-carboxy-1-indanone and aniline for t-butyl glycinate to provide Example 645. MS (ESI): m/z 174 (M+H)+.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:15][CH2:14][CH2:13][C:12]([CH2:17][OH:18])([OH:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CCO>[ClH:1].[OH:18][CH2:17][C:12]1([OH:16])[CH2:13][CH2:14][CH2:15][NH:9][CH2:10][CH2:11]1
Reactant: OCC1(O)CCCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OCC1(O)CCCNCC1

Procedure:
A solution of tert-butanol of N-methylmorpholine-N-oxide and osmium tetroxide was added to a mixture of 1-benzyl-4-methyleneazepane hydrochloride and THF-water and stirred at room temperature for 24 hours. Then the reaction solution was processed with 4M hydrochloric acid (HCl)-ethyl acetate (EtOAc) solution to give 1-benzyl-4-(hydroxymethyl)azepane-4-ol hydrochloride. 10% palladium carbon was added to a solution of EtOH of the obtained 1-benzyl-4-(hydroxymethyl)azepane-4-ol hydrochloride and stirred for six hours at room temperature under the hydrogen atmosphere to give 4-(hydroxymethyl)azepane-4-ol hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=O.Cl.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]2[N:4]([C:16]([C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[F:13])=[N:18][N:19]=2)[N:3]=1
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Reactant: NNC(=O)c1ccccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Yield: 43.8 %

Procedure:
A mixture of 3,6-dichloro-4-(1,1-dimethylethyl)pyridazine (20 g, 0.097 mol), 2-fluorobenzhydrazide (22.6 g, 0.145 mol) and triethylamine hydrochloride (20 g, 0.0145 mol) in dioxan (1.2 l) was stirred and heated at reflux under a stream of nitrogen for 4 days. Upon cooling the volatiles were removed in vacuo and the residue was triturated with dichloromethane (200 ml), filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 0%→25% ethyl acetate/dichloromethane to give the title compound (12.95 g. 44%) as a white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ1.57 (9H, s), 7.26-7.35 (2H, m), 7.53-7.60 (1H, m), 7.89-7.93 (1H, m), 8.17 (1H, s); MS (ES+) m/e 305 [MH]+, 307 [MH]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([CH2:14][O:15][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC1CCCC1
Product: Brc1ccc(OCC2CCCC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and cyclopentylmethanol by the method of Example 10 (b).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.O.S(=O)(=O)(O)[OH:21]>C(OCC)(=O)C>[OH:21][CH:2]([CH2:18][OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:13])=[O:14])[S:11][C:7]=2[CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1nc2ccc(OCC(O)CO)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2,3-Epoxypropoxy)benzothiazole-2-sulfonamide (1.21 gm, 4.25 mmol) was dissolved in ethyl acetate (35 mL) and added to water (25 mL) containing concentrated sulfuric acid (2.5 mL). This two phase mixture was stirred at room temperature overnight and then was poured into water and repeatedly extracted with 5% methanol/ethyl acetate (V/V). The extracts were dried (Na2SO4) and evaporated. The residue (1.2 gm) was dissolved in methanol and allowed to sit overnight to give 1.0 gm of impure product. This material was purified by chromatography on silica gel, eluting with 1% methanol/ethyl acetate (V/V). The combined fractions containing product were evaporated and the residue was triturated with methanol to give material which was recrystallized from methanol/ethyl acetate (0.3 gm), m.p. 183°-185° C.