Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:25].C[OH:27]>>[OH2:27].[CH2:15]([N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:25])[C:11]=2[N:12]=[C:13]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: N
Reactant: CC(C)Cn1c(-c2ccccc2)nc2c(Cl)nc3ccccc3c21
Reactant: CO
Product: CC(C)Cn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Product: O

Procedure:
A mixture of 5.6 g (0.016 mole) of 4-chloro-1-isobutyl-2-phenyl-1H-imidazo[4,5-c]quinoline and 30 ml of a 20% mixture of ammonia in methanol was placed in a metal bomb and heated at 145°-150° C. for about 6 hours. After cooling, the solid was separated by filtration, washed with methanol and dried to provide 3.8 g of crude product. Recrystallization of the solid from ethanol provided 2.4 g of colorless 1-isobutyl-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine hydrate, melting point 194°-205° C. Analysis: Calculated for C20H20N4.1/2H2O: % C, 73.8; % H, 6.5: % N, 17.2. Found: % C, 73.6; % H, 6.2: % N, 17.0
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:17]([N+:22]([O-:24])=[O:23])=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([N+:22]([O-:24])=[O:23])=[C:4]2[C:3]=1[N:29]([CH:26]1[CH2:28][CH2:27]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Reactant: NC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 45 °C
Reaction time: 3 h

Procedure:
The ethyl 2-(3-chloro-2,4,5-trifluoro-6-nitro -benzoyl)-3-ethoxyacrylate prepared in the previous step was dissolved in 200 ml of t-butanol and treated with 5.0 g (88 mmol) of cyclopropylamine. The reaction mixture was warmed to 45° C. and stirred for three hours at that temperature. The solution was then cooled to room temperature and treated with a slurry of 9.4 g (84 mmol) of potassium t-butoxide in 50 ml of t-butanol. The mixture was stirred at 60° C. for five hours; the suspension was filtered, and the solid was washed with water and ether to give 21.7 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:7]([F:14])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:22](=[O:29])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH2:23]>>[F:14][C:7]1[C:8]([CH3:13])([CH3:12])[O:9][C:10]2[C:5]([C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[CH:4][CH:3]=[C:2]([NH:23][C:22](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2
Reactant: CC(C)(C)OC(N)=O
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1F
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(F)=C2c1ccc(F)cc1

Procedure:
The compound obtained in (5) described above (125 mg) and tert-butyl carbamate (145 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (157 mg) as a brown viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[N:8](C(OC(C)(C)C)=O)[C:9](=[O:16])[C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:16])[C:10]3([CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(CCOCC2)c2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2cc(Br)ccc2C12CCOCC2
Reaction time: 5 h
Yield: 103.1 %

Procedure:
A mixture of tert-butyl 6-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carboxylate (preparation 8b, 4.20 g, 11.0 mmol) and a 5M solution of hydrogen chloride in 1,4-dioxane (25 mL) was stirred at room temperature. After 5 hours, the mixture was concentrated in vacuo to give the title compound (3.20 g, 98%) as a pale pink solid.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]4[CH3:43])[C:25]4[CH2:31][CH2:30][N:29]([CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.C(OC1N=C(NC2C=CC(C3N=C(N4CCOC[C@@H]4C)C4CCNCC=4N=3)=CC=2)C=CC=1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.S(OCC(F)(F)F)(C(F)(F)F)(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:43][C@@H:38]1[N:37]([C:24]2[C:25]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]([F:35])([F:34])[F:36])[CH2:28][C:26]=3[N:27]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:17][CH:18]=3)[N:23]=2)[CH2:42][CH2:41][O:40][CH2:39]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(CC(F)(F)F)C2
Agent: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCNC2
Agent: Cl
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(=O)[nH]3)cc2)nc2c1CCN(CC(F)(F)F)C2
Yield: 110 %

Procedure:
Step 1—Synthesis of (S)-6-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine (pk). To a solution of (S)-6-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine hydrochloride salt (ms) (51 mg, 0.094 mmol) in Acetonitrile (1.0 mL) and N,N-Diisopropylethylamine (0.10 mL, 0.57 mmol) was added trifluoroethanol triflate (0.020 mL, 0.14 mmol) at room temperature, and the reaction mixture was microwaved at 140° C. for 30 minutes, followed by the addition of a second portion of Trifluoroethanol triflate (0.030 mL, 0.21 mmol). The resultant reaction mixture was microwaved at 140° C. for 20 minutes. The reaction mixture was diluted with Ethyl acetate, and washed by NaHCO3, water, and brine till pH 7. The orange organic solution was evaporated after dried over Magnesium sulfate. The residue was purified on a silica gel column to give the desired product (pk) (61 mg, 110% yield) as yellow powder: 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J=8.4 Hz, 2H), 7.46 (m, 5H), 7.39 (t, J=7.5 Hz, 2H), 7.32 (t, J=7.2 Hz, 1H), 6.55 (s, 1H), 6.45 (d, J=7.8 Hz, 1H), 6.31 (d, J=7.9 Hz, 1H), 5.38 (s, 2H), 4.11 (m, 1H), 4.06-3.80 (m, 4H), 3.80-3.47 (m, 4H), 3.20 (q, J=9.4 Hz, 2H), 3.05-2.95 (m, 1H), 2.86 (m, 1H), 2.82-2.68 (m, 2H), 1.33 (d, J=6.6 Hz, 3H); LC-MS m/z=591 (M+H).
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24].CO.C(O)C>CCCCCCC>[Cl:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:23]([NH:25][CH2:26][C:27]([N:4]1[CH2:5][CH2:6][C:2]([CH3:1])([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1)=[O:28])=[O:24].[CH2:3]([NH:4][CH2:5][CH3:6])[CH3:2]
Reactant: CC1(N2CCC(c3ccccc3)CC2)CCNC1
Reactant: O=C(O)CNC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CO
Solvent: CCO
Solvent: CCCCCCC
Product: CC1(N2CCC(c3ccccc3)CC2)CCN(C(=O)CNC(=O)c2ccc(Cl)c(Cl)c2)C1
Product: CCNCC
Yield: 0.2 %

Procedure:
The title compound was prepared (as a mixture of two enantiomers) from 1-(3-methylpyrrolidin-3-yl)-4-phenylpiperidine and 2-(3,4-dichlorobenzamido)acetic acid using general procedure G. HPLC (Table 1, Method b) Rt 2.13 min; m/z: (M+H)+ 474. From the mixture, the enantiomers were isolated via chiral preparative RP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.2% diethylamine modifier at 15 mL/min, column temperature 50° C.; UV detection monitored at 254 nm; Daicel OD-H column, 20×250 mm, 5 um particle) to yield two isomers, (S)- and (R)-3,4-dichloro-N-(2-(3-methyl-3-(4-phenylpiperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)benzamide. The absolute stereochemistry of the isomers was not assigned. Isomer 1 eluted at Rt 11.5-14 min. Isomer 2 eluted at Rt 14.8-18 min.
Reaction SMILES: C([O:8][CH:9]1[CH2:14][O:13][CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.[OH:15]C1COCOC1.OCC(CO)O.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>Cl.N1C=CC=CC=1>[OH:8][CH:9]1[CH2:14][O:13][CH2:12][O:11][CH2:10]1.[C:28]([OH:35])(=[O:15])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(COC2COCOC2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: OC1COCOC1
Solvent: OCC(O)CO
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1

Procedure:
In another method of preparing the 5-benzyloxy-1,3-dioxane, the starting material was 5-hydroxy-1,3-dioxane (Tetrahedron 7, 10-18 (1959)). The latter was prepared by first reacting glycerol with trioxymethylene, in the presence of HCl as a catalyst to form a mixture of cyclic acetals (J. Am. Chem. Soc. 50, 3124 (1928)) which was then esterified with benzoyl chloride, in the presence of pyridine, yielding on recrystallization the benzoate 5-hydroxy-1,3-dioxane melting at 71°-72° C (J. Am. Chem. Soc. 50, 3120 (1928)). This ester was then split by reaction with sodium methylate in chloroform, to produce the purified 5-hydroxy-1,3-dioxane which was taken off as a cut boiling at 95°-96° C at 22 mm. Three grams (0.029 mol) of the latter product and 100 ml of benzene were placed in a flask equipped with a stirrer, condenser, thermometer and addition funnel. While stirring, 1.1 g of sodium hydride was added portionwise; hydrogen evolved. Next, after the resulting slurry had been kept at room temperature for 1/2 hour without further addition of ingredients while stirring continued, 3.65 g of benzyl chloride was added dropwise over a fifteen minute period. When all the benzyl chloride had been added the mixture was heated to 80° C and maintained at this temperature for 24 hours while stirring continued. The slurry thus obtained was then washed twice with 100 ml portions of water and the resulting organic layer was dried over MgSO4. This drying agent was then filtered off and the solvent was removed under reduced pressure, yielding an oil which was then distilled under reduced pressure to give a fraction (5-benzyloxy-1,3-dioxane) boiling at 80°-82° C at 0.15 mm and having an estimated purity of about 85%.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([CH3:30])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>C(OCC)(=O)C>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:14])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CCC(=O)OCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a mixture of N-t-butoxycarbonyl-N-methyl-β-alanine (6.097 g) and triethylamine (4.18 ml) in ethyl acetate (60 ml) was added 2-bromoacetophenone (5.972 g) portionwise at 0°-5° C. After being stirred over night at ambient temperature, the solvent was evaporated and the resulting residue was dissolved in ethyl acetate (200 ml). The solution was washed with 0.5N hydrochloric acid (200 ml), water (200 ml) aqueous sodium bicarbonate (200 ml), water (200 ml) and brine (200 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave N-t-butoxycarbonyl-N-methyl-β-alanine phenacyl ester (8.54 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[CH:6][C:3]=1[C:4]#[N:5].C([OH:21])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:21])[NH:14]3)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: N#Cc1cc(-c2cccc3c2CC(=O)N3)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To the suspension of 2-fluoro-5-(1H-indol-4-yl)-benzonitrile (2.68 g, 11.34 mmol) in t-BuOH:ethanol:acetic acid (72 mL:43 mL:23 mL) was added pyridinium tribromide (10.91 g, 34.1 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (55 mL). Zinc dust (4 g, 61.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 1.93 g (68%) of 2-fluoro-5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=1)=[C:9]([OH:29])[C:8]2=[O:30])(=[O:3])[CH3:2].C1(=O)[O:36][C:34](=[O:35])[CH2:33]C1>Cl.C(O)(=O)C.O.N1C=CC=CC=1>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[O:11][C:12]3[C:7]([C:8](=[O:30])[C:9]=2[OH:29])=[CH:6][C:5]([NH:4][C:1]([CH2:2][CH2:33][C:34]([OH:36])=[O:35])=[O:3])=[CH:14][CH:13]=3)=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(OCc4ccccc4)cc3)c(O)c(=O)c2c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)Nc1ccc2oc(-c3ccc(O)cc3)c(O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.3 %

Procedure:
A mixture of the protected flavonol (11) (600 mg, 1.49 mmol) in aqueous HCl (36%, 38 mL) and acetic acid (38 mL) was heated under reflux for 2 h. The mixture was then cooled on ice and diluted with water. The resulting suspension was centrifuged and the collected solid washed with water, then freeze-dried to afford the salt as a crude yellow solid (457 mg). A mixture of the crude yellow product and succinic anhydride (179 mg, 1.79 mmol) in pyridine was stirred at room temperature for 4 h. Water (1 mL) was added and the mixture was acidified with 2 M HCl. The mixture was left to stand at room temperature for 30 min, and the resulting suspension was centrifuged and the collected solid was washed with water, freeze-dried and recrystallised from DMF/water to afford the succinamic acid (2) as a brown powder (211 mg, 38.2%), m.p. 256-257° C. Anal. Calcd. for C19H16NO7.½H2O: C, 60.32; H, 4.26; N, 3.70. Found: C, 59.99; H, 4.53; N, 3.90. 1H NMR (399.7 MHz, d6-DMSO) δ 2.55-2.60 (m, 4H, CH2CH2); 6.93 (app. d, 2H, J=9.2 Hz, H3′,5′); 7.69 (d, 1H, J7,8 8.8 Hz, H8); 7.85 (dd, 1H, J5,7 2.8, J7,8 8.8 Hz, H7); 8.09 (app. d, 2H, J=9.2 Hz, H2′,6′); 8.43 (d, 1H, J5, 7 2.8 Hz, H5); 9.33 (s, 1H, NH); 10.11, 10.31 (2 br s, 2×1H, 2×OH); 12.21 (br s, 1H, CO2H). 13C NMR (100.5 MHz, d6-DMSO) δ 25.16, 28.78 (2C, CH2CH2); 31.06, 67.05, 112.65, 115.46, 118.80, 121.45, 122.06, 125.11, 129.55, 135.80, 137.57, 146.01, 150.38, 159.11 (14C, Ar); 170.40, 172.33, 173.86 (3C, 3×C═O).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[C:15]([O-])(=[S:17])[CH3:16].[K+]>C1COCC1>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3][CH:2]2[C:15](=[S:17])[CH3:16]
Reactant: CC([O-])=S
Reactant: CC1(C)CCC(Br)c2cc(Br)ccc21
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=S)C1CCC(C)(C)c2ccc(Br)cc21

Procedure:
Employing the above-described procedure for the conversion of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene naphthalene (Compound F) to the dibromonaphthalene derivative (Compond I), 3.5 g (14.6 mmol) of (Compound F), 2.86 g (16.1 mmol) of N-bromosuccinimide and 150 mg (0.62 mmol ) of benzoylperoxide gave crude 4,6-dibromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I). To a solution of this crude dibromonaphthalene derivative (Compound I) in 50 ml of THF was added 5.38 g (47.1 mmol) of potassium thioacetate. The mixture was refluxed for 6 hours under argon atmosphere, filtered through celite and concentrated in vacuo. Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as red oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[N:14]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:13][C@@H:12]([S:28]C(=O)C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][CH2:9][C@H:10]1[N:14]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:16])=[O:17])[CH2:13][C@@H:12]([SH:28])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)S[C@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=S(=O)(c1ccc2ccccc2c1)N1C[C@@H](S)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.2 %

Procedure:
S-Acetyl deprotection: To a solution of (3S,5S)-thioacetic acid S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl] ester (1.2 g) in methanol (17 ml) was added sodium methanolate (28%-solution in methanol, 0.55 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 h, and acetic acid (0.17 ml) was added. The reaction mixture was concentrated, and the residue was extracted with EtOAc. The organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:3 and 1:2 as eluents to obtain (3S,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol (0.59 g) as a slightly coloured syrup, MS: 414 (MH+).
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH:11][CH:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>C1(C)C=CC=CC=1>[OH:11][CH:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24].[OH:11][CH:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24].[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Reactant: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(O)CCCCCCCCCCC(=O)[O-]
Product: CCCC[Sn+2]CCCC
Yield: 97 %

Procedure:
A mixture of dibutyltin oxide, 31.2 g (0.125 mole), 12-hydroxystearic acid, 75 g (0.25 mole), and 250 ml toluene were mixed and reacted as described in Example 1. Removal of toluene yielded 125 g (97% yield) of dibutyltin bis(12-hydroxystearate), a cream colored brittle solid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][C:6]1[N:7]=[CH:8][C:9]([C:12]([NH:14][NH2:15])=O)=[N:10][CH:11]=1.[OH-].[Na+].I[CH3:19]>C(O)C.O.CO>[CH3:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[N:2]([CH3:1])[C:3]([S:4][CH3:19])=[N:15][N:14]=2)=[CH:8][N:7]=1
Reactant: CI
Reactant: CN=C=S
Reactant: Cc1cnc(C(=O)NN)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CSc1nnc(-c2cnc(C)cn2)n1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Methanol (25 mL) was added to a mixture of methyl isothiocyanate (1.052 g, 14.4 mmol) and 5-methylpyrazine-2-carbohydrazide (2.192 g, 14.4 mmol). The resulting mixture was heated at 60° C. for 1 h, and concentrated in vacuo. The residue was dissolved in aqueous sodium hydroxide solution (0.8M, 20 mL, 16 mmol) and the resulting solution was heated at 60° C. for 19 h, then cooled to room temperature. Aq. NaOH (6M, 2.6 mL, 15.6 mmol) was added followed by iodomethane (1.24 mL, 19.8 mmol) in ethanol (31 mL) plus additional water (5 mL rinse) and the resulting mixture was stirred 1 hour at room temperature. The product was partitioned between water (added 30 mL) and dichloromethane (300 mL). The aqueous layer was extracted with dichloromethane (4×100 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL) and dried over sodium sulfate. Removal of the solvent in vacuo followed by flash chromatography (silica gel, 2-3% methanol in dichloromethane) yielded the title compound (2.559 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([S:23]([C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1)(=[O:25])=[O:24])[C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([C:17](OC)=[O:18])=[CH:16][C:12]=2[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:34]>>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]([C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([C:17](=[O:18])[NH2:34])=[CH:16][C:12]=2[CH:11]=1)[S:23]([C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1)(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1cc2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2s1
Product: CC(C)(C)OC(=O)CN(c1ccc2sc(C(N)=O)cc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
250 mg methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-benzo[b]thiophen-2-carboxylate are dissolved in 30 ml ammonia-saturated methanol and stirred for 24 hours at ambient temperature. Then the solution is heated to 80° C. in a pressurised vessel for 8 hours. Then the solvent is eliminated in vacuo and the residue is extracted from diisopropylether. The product thus obtained is chromatographed on silica gel with cyclohexane/ethyl acetate (9:1 to 1:4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Cl.[NH2:13][CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NCC1(O)CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1(O)CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 4-bromo-1-flouro-2-nitrobenzene (Wako Pure Chemical Industries, Ltd.), 1-(aminomethyl)cyclohexanol hydrochloride (J. Med. Chem. 1981, 24, 7-12.) and N,N-diisopropylethylamine.