Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]([NH2:26])=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3[CH:25]=[CH:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:17]=3[NH:26][C:2](=[O:3])[C:1]2=[O:5])=[CH:11][CH:10]=1
Reactant: COc1ccc(Nc2ccc3ccccc3c2N)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of oxalyl chloride (0.12 mL) was added dropwise an anhydrous tetrahydrofuran (10 mL) solution of N2-(4-methoxyphenyl)naphthalene-1,2-diamine (322 mg, 1.22 mmol) under cooling in an ice-bat. The mixture was stirred under cooling in ice-bath for 30 minutes and at room temperature for one hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The obtained solid was filtered. The crude crystal was washed with ethyl acetate and hexane to obtain the titled compound as a slightly off-white crystal (220 mg, yield 56%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:32]([O:33][CH3:34])=[CH:31][C:7]2[CH2:8][C:9](=[O:30])[N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:29])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+].N>C(OC(=O)C)(=O)C.CC(C)=O>[ClH:1].[CH3:2][O:3][C:4]1[C:32]([O:33][CH3:34])=[CH:31][C:7]2[C:8](=[O:36])[C:9](=[O:30])[N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:29])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Agent: Cl
Agent: N
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
1.98 gm (4.0 mmols) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane hydrochloride were suspended in 50 ml of acetic anhydride; the suspension was mixed with 2.5 gm of potassium permanganate, and the mixture was stirred for 20 minutes at 20° C. The reaction mixture was poured into ice water and made alkaline with concentrated ammonia. The precipitated manganese dioxide was suction-filtered off, and the filtrate was extracted several times with methylene chloride. The extract was dried over magnesium sulfate, evaporated in vacuo, and the residue was purified on a silica gel column with methylene chloride +1% of ethanol as the eluant. The product thus obtained was dissolved in acetone, and the hydrochloride was precipitated with ethereal hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH2:22])[C@H:12]1[OH:13].[C:23]([O:27][C:28]([NH:30][CH:31]([C:42](O)=[O:43])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH:22][C:42](=[O:43])[CH:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)[NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])[C@H:12]1[OH:13]
Reactant: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Product: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Yield: 46.7 %

Procedure:
Ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(4-nitrophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (280 mg) was prepared by reacting ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (308 mg) prepared in Example 63 with N-tert-butoxycarbonyl-β-(4-nitrophenyl)-D,L-alanine (310 mg) according to a similar manner to that of Example 64, mp. 170°-180° C. (dec.).
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.Cl[CH2:14][C:15]([N:17]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:16].O>CN(C)C=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([N:17]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:15](=[O:16])[CH2:14][N:6]2[C:2](=[O:12])[C:3]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]3[C:5]2=[O:7])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CCl)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
tert-Butyl 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido] acetate may be prepared in the following manner: phthalimide potassium salt (7.5 g) is added to a solution of tert-butyl 2-[2-chloro-N-(3-methoxyphenyl)acetamido]acetate (6.3 g) in dimethylformamide (100 cc). The mixture is stirred at a temperature in the region of 100° C. for 5 hours and then poured into water (1000 cc). The insoluble product is separated by filtration, washed with water (3×60 cc) and dried in the air. After recrystallisation in diisopropyl ether, tert-butyl 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido]acetate (6.7 g), m p 138° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.CC1C=CC(N=[CH:21][C:22]2[C:23]([NH2:31])=[CH:24][C:25]3[O:29][CH2:28][O:27][C:26]=3[CH:30]=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:9]([C:10]=2[CH:11]=1)=[N:31][C:23]1[CH:24]=[C:25]2[O:29][CH2:28][O:27][C:26]2=[CH:30][C:22]=1[CH:21]=3
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COc1ccc2c(c1)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 44.6 %

Procedure:
Using the procedure of Example 1, 6-methoxyindan-1-one (162 mg, 1 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (255 mg, 1 mmol) to yields 7-methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (130 mg, 44.6% of theory).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:9][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[CH:7]=[O:8]
Reactant: Cc1cc(Br)sc1C=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccccc2)sc1C=O
Yield: 62.8 %

Procedure:
A mixture of 5-bromo-3-methylthiophene-2-carbaldehyde (2.1 g), phenylboronic acid (1.5 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 66%) as a yellow crystal.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][N:5]=[C:4](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][N:5]=[C:4](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCOC(=O)CCc1cnc(/C=C/c2ccccc2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCc1cnc(/C=C/c2ccccc2)nc1Cl
Yield: 53 %

Procedure:
Ethyl 3-{4-hydroxy-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate (11.6 g, 38.9 mmol) in POCl3 (30 mL) was heated at 120° C. for 4 h. The solvent was removed in vacuo. The crude residue was then purified by column chromatography (silica gel) using an EtOAc/hexanes (30-50%) gradient to yield the desired compound as a yellow solid (6.6 g, 53%). LCMS (ES+) m/z 317 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[F:20][C:21]([F:30])([F:29])[C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:20][C:21]([F:30])([F:29])[C:22]([NH:24][CH2:25][C:26]([NH:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])=[O:27])=[O:23]
Reactant: O=C(O)CNC(=O)C(F)(F)F
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)CNC(=O)C(F)(F)F)O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
4′-C-Aminomethylthymidine (4) (0.14 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL). N-Trifluoroacetylglycine (0.036 g, 0.21 mmol) and O-(N-succimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TSTU] (0.085, 0.28 mmol) were then added and the solution stirred at ambient temperature. Diisopropylethylamine (0.036 g, 0.28 mmol, 0.05 mL) was then added dropwise to the solution with stirring. After 12 hours the solvent was removed under vacuum and the residue redissolved in dichloromethane:methanol (9:1). Applied solution directly to a silica gel column and eluted with dichloromethane:methanol (9:1). Fractions containing the desired material were pooled and the solvent removed under vacuum to give the title compound (5) as a clear, glassy material (0.28 g, 28% from crude 4). δH(300 MHz, CD3OD) 7.91(1H, s, H-6), 6.27(1H, dd, H-1′), 4.49(1H, dd, H-3′), 3.74(2H, s, glycyl CH2), 3.52(1H, d, H-5′), 3.51(2H, s, 4′-C—CH2), 3.43(1H, d, H-5′), 2.32(2H, m, H-2′), 1.68(3H, s, 5-CH3); ES +ve m/z 425(M+H)+, 442(M+H2O)+, 447(M+Na)+.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.[H-].[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O1CCCC1>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:3]1[C:4]2=[N:9][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:7][C:6](=[O:16])[N:5]2[CH2:17][C@@:2]1([CH3:1])[C:18]([F:21])([F:19])[F:20])=[O:28]
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1C(=O)c1ccccc1Cl

Procedure:
The product can be prepared as described in Example 21, but using 200 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one, 31 mg of sodium hydride at 60% in oil and 115 mg of 2-chlorobenzoyl chloride in 4 ml of tetrahydrofuran. After purification by silica column chromatography (eluent: dichloromethane/methanol: gradient of 100/0 to 97/03), 74 mg of (2S)-1-[(2-chlorophenyl)carbonyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of an ivory-coloured foam, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccs1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccs4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and thiophene-2-carbaldehyde according to the procedure of Example 66. MS (ES) m/z 475.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[N:32]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)n1

Procedure:
Example 68 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 1H, J=8.0 Hz), 7.79 (br s, 1H), 7.66 (t, 1H, J=8.0 Hz), 7.45–7.41 (m, 2H), 7.04–7.00 (m, 2H), 6.89 (d, 1H, J=7.6 Hz), 6.85 (br s, 1H), 3.30 (dd, 2H, J=6.0, 12.0 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.57–2.50 (m, 2H), 2.37–2.32 (m, 4H), 2.01–1.77 (m, 8H), 1.65–1.60 (m, 8H), 1.27 (d, 6H, J=7.2 Hz); ESMS m/e: 509.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[N+:34]([O-])=O)[O:7][C:8]1[C:17]2[C:12](=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([N+:28]([O-])=O)[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[NH2:25])[O:18][C:13]1[C:12]2[C:17](=[C:8]([O:7][C:6]3[CH:31]=[CH:32][C:33]([NH2:34])=[C:4]([NH2:1])[CH:5]=3)[CH:9]=[CH:10][CH:11]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c(Oc4ccc([N+](=O)[O-])c([N+](=O)[O-])c4)cccc23)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2cccc3c(Oc4ccc(N)c(N)c4)cccc23)cc1N
Yield: 99 %

Procedure:
A stirred mixture of 1,5-bis(3,4-dinitrophenoxy)naphthalene (6 g, 0.0122 mole) and 10 percent palladium on charcoal (0.6 g) in absolute ethanol (300 ml) was heated to reflux under nitrogen. A solution of hydrazine hydrate (8 ml) in ethanol (30 ml) was added dropwise over a period of 40 minutes. The reaction mixture was heated at reflux for 6 hours, chilled in an ice bath, and suction filtered through Celite filter aid into one liter of stirred, cold, concentrated hydrochloric acid. The resulting precipitate of hydrazine hydrochloride and the desired tetraamino hydrochloride was collected, partially dried, and dissolved in water (300 ml). Concentrated ammonium hydroxide solution (60 ml) was added and the resulting precipitate collected and vacuum dried to produce 4.5 g (90 percent) of the desired 1,5-bis(3,4-diaminophenoxy)naphthalene. Recrystallization from benzene gave a white product (melting point 230°-231°C).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([O:16]C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.CO.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.9 %

Procedure:
Methyl 5-benzyloxy-2-methoxybenzoate (3.72 g) was dissolved in a mixed solvent of THF (30 ml) and methanol (30 ml), and 1N aqueous sodium hydroxide solution (27.3 ml) was added to the mixed solution. The mixture was stirred at room temperature for 2 days, and 1N aqueous hydrochloric acid solution (40 ml) was added. The precipitate was collected by filtration and washed with water to give 5-benzyloxy-2-methoxybenzoic acid (3.10 g, 88%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)([OH:24])N.[O-]Cl=O.[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:24])=[O:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
4-(2-Formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.50 g, 1.72 mmol) is dissolved in 80 mL of dioxane and 20 mL of H2O. The mixture is cooled to 4° C. and then sulfamic acid (1.36 g, 14.00 mmol) is added in one portion. The mixture is stirred for an additional 30 min and then 3 mL of a solution of NaClO2 (0.343 g, 3.80 mmol) is added in a drop-wise portion. The reaction is quenched by the addition of 50 mL of H2O and 50 mL of brine. The resulting mixture is extracted with 3×100 mL of CH2Cl2. The combined organic phase is washed with 2×50 mL of brine, dried with MgSO4, filtered and concentrated to give 500 mg of 4-(2-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH2:11].Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1>COCCOC>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: CC1CCCC(C)N1CCN
Solvent: COCCOC
Product: CC1CCCC(C)N1CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 81.4 %

Procedure:
2-(2,6-Dimethyl-1-piperidinyl)ethylamine (280) (0.66 g, 4.3 mmol) was added to a stirred solution of chloride 21 (314 mg, 1.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 38 (389 mg, 80%) as a yellow solid: mp (MeOH) 173-175° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.47 (br s, 1H, NH), 3.50-3.55 (m, 2H, CH2N), 2.96-3.03 (m, 4H, CH2N, CH2), 2.87-2.91 (m, 2H, CH2), 2.48-2.57 (m, 2H, CH2N), 2.10-2.18 (m, 2H, CH2), 1.64-1.69 (m, 1H, CH2), 1.53-1.58 (m, 2H, CH2), 1.33-1.38 (m, 1H, CH2), 1.24-1.31 (m, 2H, CH2), 1.20 (d, J=6.3 Hz, 6H, 2×CH3); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.6, 114.7, 57.2 (2), 47.5, 39.4, 34.3, 33.1 (2), 32.3, 25.8, 24.4, 21.7 (2). Anal. calcd for C19H27N5O: C, 66.8; H, 8.0; N, 20.5. Found: C, 66.8; H, 7.8; N, 20.6%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([NH2:11])=[CH:8][CH:9]=[CH:10][C:2]1=2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1OCCO2
Solvent: CCO
Product: CC(=O)Nc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-5-amine (Intermediate B3, 4.5 g, 30 mmol) in ethanol (50 mL) at room temperature was slowly added acetic anhydride (3.0 g, 30 mmol). After the addition was over, the mixture was stirred at room temperature for 5 minutes. The resulting suspension was concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to afford the product N-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (5.5 g, yield 95%). 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (s, 1H), 7.44-7.46 (d, 1H, J=8.0 Hz), 6.71-6.75 (t, 1H, J=8.0 Hz), 6.59-6.61 (d, 1H, J=7.6 Hz), 4.23-4.30 (m, 4H), 2.06 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH:5]=O.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH2:5][NH:22][C:21]1[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(C)(CNc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methyl-3-oxo-propionic acid methyl ester (2.35 g, 6.71 mmol) in methanol (25 mL) was added 4-fluoroaniline (0.53 mL, 5.59 mmol) and acetic acid (0.16 mL, 2.80 mmol). A solution of sodium cyanoborohydride (188 mg, 2.99 mmol) in methanol (25 mL) was added dropwise and the reaction mixture stirred for 3 hours at room temperature post addition. The solvent was removed in vacuo and the residue dissolved in DCM (50 mL). The organic solution was treated with aqueous sodium carbonate solution (20 mL, 1N), stirred for 20 min, and the aqueous layer removed. Concentration of the organic layer followed by purification of the residue using flash chromatography (SiO2, DCM) afforded the title compound as a yellow oil (970 mg, 53%).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](Cl)(=O)=O)=[CH:3][CH:2]=1.[C:12]1([S:18](Cl)(=O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18][S:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: c1ccc(SSc2ccccc2)cc1
Yield: 93 %

Procedure:
One proceeds according to Example 1 except that p-toluene sulfonyl chloride is replaced by benzene sulfonyl chloride as starting material. Thus 10 g of phenyl-disulfide are obtained, yield 93%. Mp.: 58°-60° C.