Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[C:65]([I:66])[C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:76]>CO.O>[ClH:76].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[C:65]([I:66])[C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(I)n[nH]c54)c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(I)n[nH]c54)c3=O)cc2)CCC1
Yield: 56 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(3-iodo-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (2 mL), water (3 mL) and 1 M HCl (0.1 mL) and chromatographed on a 2 g C18 cartridge {gradient 40 to 80% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (2.1 mg, 56%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].Cl.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:17][CH2:16]1)(=[O:11])=[O:10]
Reactant: c1ccc2c(c1)CCN(CC1CCNCC1)C2
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)ccc1Cl)N1CCC(CN2CCc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
2,5-dichlorobenzene-1-sulfonyl chloride (108.1 mg, 0.44 mmol) was added to a solution of 2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (92.1 mg, 0.40 mmol) and N,N-diisopropylethylamine (206.9.2 mg, 1.60 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4, and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (138 mg, 78%).
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:15]=[N:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24]([NH:27][CH:28]2[CH2:32][CH2:31][O:30][NH:29]2)(=[O:26])=[O:25])[C:18]=1[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].[N:41]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24]([NH:27][CH:28]2[CH2:32][CH2:31][O:30][NH:29]2)(=[O:26])=[O:25])[C:18]=1[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])=[NH:41]
Reactant: N#CNC(=N)N
Reactant: N#CN
Reactant: CC(C)(C)[Si](C)(C)Oc1c(N=C=Nc2ccccc2Br)ccc(Cl)c1S(=O)(=O)NC1CCON1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1c(NC(=N)N(C#N)c2ccccc2Br)ccc(Cl)c1S(=O)(=O)NC1CCON1
Yield: 26 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 1, N-(2-bromophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″-tetrahydroisoxazylaminosulfonyl)phenyl]carbodiimide (385 mg, 0.79 mmol), cyanamide (133 mg, 3.16 mmol) and N,N-diisopropylethylamine (127 mg, 0.95 mmol) were reacted, followed by desilylation with Cesium fluoride (144 mg, 0.95 mmol) to form the desired product (100 mg, 26%). EI-MS m/z 515 (M+).
Reaction SMILES: P([O:4][PH:5]([OH:7])=[O:6])(O)=O.C([C:11]([CH:18]([CH3:20])C)([CH:15]([CH3:17])C)C(C)C)(C)C.BrCCC(Br)C>>[CH3:17][CH:15]1[CH2:11][CH2:18][C:20]1([P:5]([OH:4])(=[O:6])[OH:7])[P:5]([OH:7])(=[O:4])[OH:6]
Reactant: O=[PH](O)O[PH](=O)O
Reactant: CC(C)C(C(C)C)(C(C)C)C(C)C
Agent: CC(Br)CCBr
Product: CC1CCC1(P(=O)(O)O)P(=O)(O)O

Procedure:
Using the procedure of Example I, tetraisopropyl methane diphosphonate was converted to tetraisopropyl 2-methyl cyclobutane-1,1 diphosphonate by reaction with 1,3 dibromobutane at 80° C. for 4 hours. 31P NMR (CDCl3) chemical shift 24.1 ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([C:9]([CH2:12]Br)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:1][C:2]1[C:3]([OH:14])=[C:4]([C:9]([CH2:12][S:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1O
Reactant: COc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Temperature: 60 °C
Yield: 64.8 %

Procedure:
A mixture of methyl 3-bromo-6-bromomethyl-2-hydroxybenzoate (Intermediate 53, 0.6 g), 2-methoxythiophenol (0.518 g) and potassium carbonate (0.766 g) in THF (10 ml) was stirred and heated at 60° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and water and the separated organic layer was washed with potassium hydroxide solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give methyl 3-bromo-2-hydroxy-6-(2-methoxyphenylthiomethyl)-benzoate (0.46 g) as a white solid which was used without further characterisation.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[NH:23][C:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[CH:25][CH:26]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([C:25]1[CH:26]=[C:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)[NH:23][C:24]=1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: c1csc(-c2ccc(-c3cccs3)[nH]2)c1
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 22.7 %

Procedure:
Acetic anhydride (75 μL, 1.75 mmol) was dissolved in 2 mL of anhydrous methylene chloride and stirred for 2 minutes at 0° C. under nitrogen. To this stirred mixture was added boron trifluoride etherate (185 μL, 1.5 mmol ), followed by the addition of 1.5 mmol 2,5-dithienylpyrrole in 1 mL of anhydrous methylene chloride. The resultant dark green solution was stirred at 0° C. for 15 minutes and room temperature for 1 hour. The solution was diluted with chloroform (50 mL) and washed four times with water (10 mL), twice with saturated sodium bicarbonate (10 mL), and finally twice with water (10 mL). The organic phase was evaporated and the residue was chromatographed on a silica gel column (50 g). Elution with 30% ethyl acetane in hexane gave 93 mg (68%) of 3-acetyl-2,5-dithienylpyrrole.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:19]=[C:13]2[C:14]([O:16][C:17](=[O:18])[C:12]2=[CH:11][CH:10]=1)=[O:15].[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([SH:31])[CH:25]=[CH:24]2.CN(C=[O:36])C>>[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31][C:10]1[CH:11]=[C:12]([C:17]([OH:16])=[O:18])[C:13](=[CH:19][CH:9]=1)[C:14]([OH:36])=[O:15])[CH:25]=[CH:24]2
Reactant: Sc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(Sc2ccc3cc(Br)ccc3c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Triethylamine (3.1 ml) was added dropwise to a stirred mixture of 5-bromophthalic anhydride (5-bromo-1,3-dihydro-2-benzofuran-1,3-dione; 4.54 g), 6-bromo-2-naphthalenethiol (European Patent Application No. 0409413, Example 19; 5.25 g) and DMF (50 ml) and the mixture was stirred at ambient temperature for 10 minutes. The mixture was heated at 60° C. for 1 hour and then stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was suspended in methanol (60 ml). The mixture was basified by the addition of 2M aqueous sodium hydroxide solution and the mixture was heated to reflux for 1 hour. The mixture was cooled ambient temperature and partitioned between water (300 ml) and diethyl ether. The aqueous layer was acidified by the addition of concentrated hydrochloric acid and extracted with ethyl acetate (2×100 ml). The combined extracts were washed with water and with brine, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether to give 4-(6-bromonaphth-2-ylthio)phthalic acid (6 g, 74%) as a pale yellow solid;
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:26])[NH:17][C@@H:18]1[CH2:23][CH2:22][C@@H:21]([CH2:24][OH:25])[O:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([O:15][C:16](=[O:26])[NH:17][C@@H:18]1[CH2:23][CH2:22][C@@H:21]([CH:24]=[O:25])[O:20][CH2:19]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CO)OC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C=O)OC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
To a solution of oxalyl chloride (3.5 ml) in DCM (25 ml) cooled to −78° C., was added drop wise a solution of DMSO (3.5 ml) in DCM (25 ml). After 15 minutes stirring, a solution of (3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (prepared as described in Eur. J. Org. Chem. (2003), 2418-2427; 3 g) in DCM (25 ml) was added drop wise. The reaction was stirred 1 h and a solution of triethylamine (15 ml) in DCM (15 ml) was added dropwise. The reaction proceeded for 1 hour, with warming to 0° C. Saturated sodium bicarbonate (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (Hex/EtOAc 1:2) to afford the title aldehyde (2.5 g) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1.CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCCBr)cc1
Reactant: N[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(CCCN[C@H]2CC[C@@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Reaction time: 48 h
Yield: 9.8 %

Procedure:
A mixture of cis and trans 4-(4-benzyloxy-phenyl)-cyclohexyl-amine (preparation see under example 43a, 1.25 g, 4.44 mmol), K2CO3 (1.23 g, 8.88 mmol), 1-(3-Bromo-propyl)-4-methyl-benzene (1.18 g, 4.44 mmol) and 2-butanone was stirred at 80° for 48 h. Water was then added and the products were extracted with EtOAc. The organic layer was dried (Na2SO4), evaporated and the residue was purified by chromatography (SiO2, CH2Cl2—MeOH—aq. NH3 140:10:1) to give cis-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-p-tolyl-propyl)-amine (180 mg; 10 %) as a light yellow solid (MS: m/e=414.4 (M+H+))and trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-p-tolyl-propyl)-amine (38 mg; 2%) as a light yellow solid (MS: m/e=414.4 (M+H+)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].O[CH:11]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:11]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: CCCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: Oc1cc(Cl)ccc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1Cl
Temperature: 50 °C
Reaction time: 20 h
Yield: 51.2 %

Procedure:
2,5-Dichlorophenol (163 mg, 1.00 mmol) and (3-hydroxyheptyl)methylcarbamic acid, 1,1-dimethylethyl ester (360 mg, 1.47 mmol) were dissolved in tetrahydrofuran (10 ml). To the resulting solution was added tributylphosphine (0.380 ml, 1.50 mmol) and then 1,1′-(azodicarbonyl)dipiperidine (380 mg, 1.50 mmol). The solution was then heated to 50° C. under nitrogen for 3 h, and then allowed to stir at room temperature for a further 20 h. The mixture was then filtered and poured into sodium hydrogen carbonate solution. The mixture was extracted with diethyl ether three times and the combined organic fractions were washed with brine, then dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 10% ethyl acetate/isohexane as eluent to give 200 mg (51%) of the title compound as an oil.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11](=[O:22])[N:12]([C:14]3[C:19]([C:20]#[N:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:13]=2)OC1.Br[C:25]1[N:29]2[N:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[N:33][C:28]2=[N:27][CH:26]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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>[OH:37][C:34]([C:32]1[CH:31]=[N:30][N:29]2[C:25]([C:8]3[CH:9]=[CH:10][C:11](=[O:22])[N:12]([C:14]4[C:19]([C:20]#[N:21])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH:13]=3)=[CH:26][N:27]=[C:28]2[N:33]=1)([CH3:36])[CH3:35]
Reactant: CC1(C)COB(c2ccc(=O)n(-c3ncccc3C#N)c2)OC1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cnn2c(-c3ccc(=O)n(-c4ncccc4C#N)c3)cnc2n1
Temperature: 95 °C

Procedure:
To a degassed mixture of 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-oxo-2H-[1,2′]bipyridinyl-3′-cabonitrile (from step f), 2-(7-bromo-imidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (from step d) (0.23 g), dry 1,4-dioxane (5 ml), and 2 M aqueous sodium carbonate (3 ml), was added tetrakis(triphenylphosphine)palladium(0) (0.12 g). The mixture was heated at 95° C. under a nitrogen atmosphere for 24 h. After cooling to 25° C., the reaction was diluted with ethyl acetate, and the organic phase separated. The solvent was evaporated at reduced pressure and the residue purified by chromatography (silica gel, 5% MeOH/CH2Cl2) to give the title compound, crystallised from hot isopropanol as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.98 (1H, s), 8.97 (1H, d, J 2.0), 8.62–8.68 (2H, m), 8.40 (1H, s), 8.32 (1H, dd, J 2.7, 9.8), 7.85 (1H, dd, J 5.1, 7.8), 6.83 (1H, d, J 9.8), 5.75 (1H, s), 1.54 (6H, s); MS (ES+) m/z 374 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([OH:34])(=O)=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[NH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([NH2:35])(=[O:34])=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1
Reactant: N
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(N)(=O)=O)n2C)n(CCC)c1=O
Yield: 70 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 0.6 ml of conc. aqueous ammonia. The resulting crude crystals were recrystallized from dioxane/water to give 670 mg (yield 70%) of Compound 9 as yellow needles.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[H][H].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Br)=[N:23][CH:24]=1>CN(C)C=O.CO>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[N:7]2)=[N:23][CH:24]=1
Reactant: [H][H]
Reactant: BrCc1ccc(Br)cn1
Reactant: CCCCc1n[nH]c(CCCC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nc(CCCC)n(Cc2ccc(Br)cn2)n1
Temperature: 3 °C
Yield: 69 %

Procedure:
Under nitrogen 3.19 g (18 mmol) of solid 3,5-dibutyl-1H-1,2,4-triazole from step 3 was added in small portions of 25 mmol of sodium hydride in 45 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to 3° C. and treated with a solution of the crude 5-bromo-2-bromomethylpyridine from step 2 (17 mmol) in 20 ml of dry DMF. The reaction was allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) was added to destroy any unreacted sodium hydride and the DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO4). Silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 4.16 g (69% from triazole) of 5-bromo-2-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine as a brown oil: NMR (CDCl3) δ0.88 (t, J=7 Hz, 3H), 0.93 (t, J=7 Hz, 3H), 1.23-1.46 (m, 4H), 1.59-1.78 (m, 4H), 2.63-2.74 (m, 4H), 5.30 (s, 2H), 6.92 (d, J=8 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H), 8.61 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:19])[C:9]2[C:14]([C:15](=[O:18])[C:16]=1[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:3])=O.ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.[CH2:39]([NH2:42])[CH2:40][NH2:41]>ClC(Cl)C.ClCCl>[NH2:41][CH2:40][CH2:39][NH:42][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:19])[C:9]2[C:14]([C:15](=[O:18])[C:16]=1[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:3]
Reactant: NCCN
Reactant: CC1=C(CCCC(=O)O)C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC1=C(CCCC(=O)NCCN)C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 58.7 %

Procedure:
2-(3-carboxypropyl)-3-methyl-1,4-naphthoquinone (1.00 g, 3.9 mmol) and N-hydroxysuccinimide (534 mg, 4.64 mmol) were dissolved in dichloroethane (80 ml). WSC (EDC) (890 mg, 4.64 mmol) was added to the mixture, and the mixture was stirred for 4 hours. 2.59 ml of ethylenediamine (2.33 g, 38.7 mmol) was dissolved in dichloromethane (10 ml), and the above reaction mixture was added thereto dropwise in 15 minutes. The mixture was stirred as it was at room temperature for 2 nights. Dichloromethane (300 ml) was added to the reaction mixture, and the reaction mixture was washed with water (500 ml×1). An organic layer was dried using sodium sulfate. A solvent was removed under reduced pressure, and the mixture was purified using a silica gel chromatography (silica gel: Fuji Silysia NH-DM1020; dichloromethane:methanol=96:4) and recrystallized (dichloromethane:hexane), to thereby obtain a yellow brown powder of 2-{3-[N-(2-aminoethyl)aminocarbonyl]propyl}-3-methyl-1,4-naphthoquinone (yield: 686 mg, 2.29 mmol, 58.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:28]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])=[O:29])=[CH:23][CH:22]=1.O[Li].O>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:28]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])=[O:29])=[CH:23][CH:22]=1
Reactant: CC(C)(C)CS(=O)(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)CS(=O)(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1
Reaction time: 8 h
Yield: 94.2 %

Procedure:
Dissolve 7-chloro-6-[4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (605 mg, 1.14 mmol) in methanol (8 mL) and add LiOH H2O (478 mg, 11.4 mmol). Stir the reaction mixture overnight. Partition the mixture between water and chloroform. Extract the aqueous phase three times with chloroform and chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1; 50 mL/min) to obtain 7-chloro-6-[4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (467 mg, 94%). MS (APCI+) m/z: 435 (M+H)+.
Reaction SMILES: OC[C@@H](N)CC(C)C.COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:34])[C:30]=1[N+:31]([O-:33])=[O:32])[NH2:27].[CH3:35][C:36]1[CH:37]=[C:38]([N:46]=[C:47]=[S:48])[CH:39]=C(C)[C:41]=1[N+]([O-])=O>>[CH3:34][C:29]1[CH:28]=[C:26]([N:27]=[C:47]2[NH:46][C@@H:38]([CH2:37][CH:36]([CH3:41])[CH3:35])[CH2:39][S:48]2)[CH:25]=[C:24]([CH3:23])[C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1cc(N=C=S)cc(C)c1[N+](=O)[O-]
Reactant: Cc1cc(N)cc(C)c1[N+](=O)[O-]
Agent: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(N=C2N[C@@H](CC(C)C)CS2)cc(C)c1[N+](=O)[O-]

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 3,5-Dimethyl-4-nitroaniline was converted to 3,5-Dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 3,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C@H:9]1[C@H:13]([CH2:14][OH:15])[O:12][CH2:11][O:10]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].[CH2:23]([OH:25])[CH3:24]>>[C:16]([O:7][CH2:8][C@H:9]1[C@H:13]([CH2:14][O:15][C:23](=[O:25])[CH3:24])[O:12][CH2:11][O:10]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCO
Reactant: OC[C@@H]1OCO[C@H]1CO
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1OCO[C@H]1COC(C)=O

Procedure:
200 ml of pyridine was added to crude (4S,5S)-4,5-bis(hydroxymethyl)-1,3-dioxolane obtained in Example 14 to dissolve the latter. An excessive amount of acetic anhydride (200 g) was added dropwise under cooling with ice. After several hours of reaction, ethyl alcohol was added dropwise to decompose the excessive acetic anhydride. The reaction mixture was concentrated by evaporator to remove almost all pyridine. The concentrate was extracted with the addition of 500 ml of ethyl acetate. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate, then with water, dried, and concentrated by evaporator. The residue was purified by silica gel column chromatography (eluent, benzene:ethylacetate=9:1) to obtain 90.0 g of the title compound as a colorless liquid.