Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:26]1([NH:32][C:33](=[O:34])[S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCS
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCSC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a mixture of 15.69 g (54.8 mmol) of octadecanethiol, 250 ml of acetonitrile, and 5 ml (4.9 g, 62 mmol) of pyridine and under a nitrogen atmosphere, 6.52 g (0.54.8 mmol) of phenylisocyanate were added all at once. The mixture was heated to reflux for 2 hours, then cooled to room temperature. The product crystallized, was collected by filtration, and was recrystallized from acetonitrile to give 19.19 g of S-octadecyl phenylcarbamothioate (Compound PS-1), mp 85.5–86.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-])=O)[CH:10]=2)=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1ccc(C(c2ccc(F)cc2)n2ccnc2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc(C(c2ccc(F)cc2)n2ccnc2)cc1N

Procedure:
A mixture of 6.24 parts of 4-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-2-nitrobenzenamine, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 5.6 parts of 4-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine as a residue (int. 5).
Reaction SMILES: C1(S([CH:10]([C:42]2[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]=2[CH3:50])[CH:11]=[C:12]([CH3:41])[CH:13](Cl)[CH2:14][CH2:15][C:16]([CH3:39])=[CH:17][CH:18]=[CH:19][CH:20]=[C:21]([CH3:38])[CH:22]=[CH:23][CH:24]=[C:25]([CH3:37])[CH:26]=[CH:27][C:28]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=2[CH3:36])(=O)=O)C=CC=CC=1.C[O-].[K+].O>C1(C)C=CC=CC=1>[CH3:50][C:43]1[CH2:44][CH2:45][CH2:46][C:47]([CH3:48])([CH3:49])[C:42]=1/[CH:10]=[CH:11]/[C:12](/[CH3:41])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36]
Reactant: CC(C=CC=C(C)C=CC1=C(C)CCCC1(C)C)=CC=CC=C(C)CCC(Cl)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Yield: 79.8 %

Procedure:
In a 50-ml round-bottom flask 2.01 g (purity: 40.9%, 1.15 mmoles) of 1-phenylsulfonyl-4-chloro-1,18-di(2,6,6-trimethyl-1-cyclohexen-1-yl)-3,7,12,16-tetramethyloctadeca-2,7,9,11,13,15,17-heptaene was reacted with 1.0 g (purity: 80%, 11 mmoles) of potassium methoxide in 4 g of toluene at 30° C. for 2 hours. Then water was added to the reaction mixture. The resulting organic layer was separated and washed with water, followed by removal of the solvent, to give 2.58 g (purity: 19.1%, 0.918 mmole, yield: 80%) of a crude β-carotene. To this product 10 g of water was added. The mixture was heat-refluxed for 10 hours and subjected to extraction with toluene to remove organic substances, followed by recrystallization of the residue from toluene-methanol solvent, to give 44 mg of a dark brown crystal. The crystal thus obtained was confirmed to be β-carotene by comparison with standard sample.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCC1CCOCC1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOCC3)c2n1
Temperature: 60 °C
Yield: 55.8 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.2 g) in anhydrous N,N-dimethylformamide (5 mL) was treated with anhydrous potassium carbonate (0.315 g) and then heated to 60° C. for 1 hour. On cooling to room temperature, to the above was added 4-(2-bromoethyl)tetrahydro-2H-pyran (0.110 g) and the reaction was warmed to 50° C., overnight. The reaction mixture was quenched with water (5 mL) and extracted into ethyl acetate (3 times, 100 mL combined total volume). The separated organic layers were combined and passed through a hydrophobic frit to dry. The organic phase was stripped to give a gum which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (111 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2O.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2[Cl:30]
Reactant: Cc1nc2ccc(Br)cc2c(O)c1S(C)(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(Br)cc2c(Cl)c1S(C)(=O)=O
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 18 %

Procedure:
6-Bromo-3-methanesulfonyl-2-methyl-quinolin-4-ol (example C.1) (6 g, 19 mmol) and N,N-dimethyl-p-toluidine (5.5 mL, 38 mmol) were dissolved in toluene (60 mL) and heated under argon to reflux. The phosphorous oxychloride (1.9 mL, 20.9 mL) was added and heating at reflux continued for 6.5 h. The product precipitated spontaneously upon cooling to 20° C., the crystals were filtered off and washed with little toluene. One obtained 4.19 g (66%) of light brown crystals. Since the product is somewhat soluble in toluene, the mother liquor was extracted with 3 N HCl (2×), sat. NaCl (2×). The residue was purified by chromatography on silica gel in dichloromethane. One obtained 1.17 g (18%) of additional material. MS: m/z=333/335 (M).
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[CH:12][C:11]([F:16])=[CH:10][C:9]=3[C:8]([O:17]COC)=[N:7][C:6]=2[N:5]([CH3:21])[N:4]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24]C1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:16][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:3]([CH2:2][N:22]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[N:4][N:5]([CH3:21])[C:6]=3[NH:7][C:8](=[O:17])[C:9]=2[CH:10]=1
Reactant: COCOc1nc2c(c(CBr)nn2C)c2ccc(F)cc12
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1nc(CN2CCCC2)c2c3ccc(F)cc3c(=O)[nH]c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
After the completion of the reaction, the reaction solution was allowed to cool to room temperature, and the precipitated solid was removed by filtration. The filtrate was concentrated, and the residue was filtrated using silica gel (hexane:ethyl acetate=2:1). The filtrate was concentrated to give 1-bromomethyl-7-fluoro-5-methoxymethoxy-3-methyl-3H-pyrazolo[3,4-c]isoquinoline (0.50 g) as crude crystals. The crude crystals (0.50 g) of 1-bromomethyl-7-fluoro-5-methoxymethoxy-3-methyl-3H-pyrazolo[3,4-c]isoquinoline, piperidine (0.30 g) and potassium carbonate (0.39 g) were dissolved in acetonitrile (20 mL), and the reaction solution was stirred at room temperature for 2 days. After the completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give 7-fluoro-3-methyl-1-(pyrrolidin-1-ylmethyl)-3H-pyrazolo[3,4-c]isoquinolin-5(4H)-one (0.079 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:11]1(C(C2C(CCC3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(B(O)O)C=CC=CC=1.N1C=CC=CC=1>CC(N(C)C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: OC(c1cn(-c2ccccc2)nc1CCc1ccccc1)C1CCCCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OB(O)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (14.4 g) synthesized in Example 1, (3) was dissolved in dimethylacetamide (200 mL), phenylboronic acid (25.0 g), copper acetate (36.4 g) and pyridine (32 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1, volume ratio) to give the title object compound (11.4 g, 53%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[CH2:20]([NH2:26])[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[O:25]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][NH:26][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:3]
Reactant: NCC1CCCO1
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: O=C(NCC1CCCO1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4,4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline to afford the urea.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH:2]=[CH2:3].[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.[OH-].[K+]>C(O)C.Cl.CO>[CH2:1]([N:4]1[C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[NH:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=CCNC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: C=CCn1c(=O)cc(C)[nH]c1=O
Reaction time: 288 h

Procedure:
To allylurea (25 g, 0.25 mol) in ethanol (10 mL) was added ethyl acetoacetate (31.86 mL, 0.25 mol) and 10 drops conc. HCl. After 12 days at room temperature, concentration gave an oil which was dissolved in MeOH. KOH (22.5 g, 0.34 mol) was added and the solution refluxed for 1 hour. After neutralization, the resulting solid 1 was collected. Yield 2.7 g (7%). NMR (CDCl3) δ: 2.16 (3H, s), 4.52 (2H, d), 5.18 (1H, d), 5.23 (1H, d), 5.60 (1H, s), 5.82–5.93 (1H, m), 10.3 (1H, s).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]1[O:19][C@@H:18]1[CH2:20]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C(OCC)(=O)C>CC(=O)CC>[O:19]1[CH2:17][C@H:18]1[CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: c1cc2c(cc1OC[C@@H]1CO1)OCO2
Yield: 57.4 %

Procedure:
A mixture of sesamol (2.49 g, 18.02 mmol), potassium carbonate (2.74 g, 19.83 mmol) and (2S)-(+)-glycidyl-3-nitrobenzenesulfonate (4.67 g, 18.02 mmol) in 2-butanone (50 mL) was heated to reflux for 18 h. To the cooled reaction mixture was added 35 mL of ethyl acetate and the solids were remove by vacuum filtration. The filtrate was evaporated in vacuo and the residue was taken up into ethyl acetate (65 mL). The solution was washed with aqueous sodium bicarbonate (2×), and water (2×), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 50% diethyl ether/hexane) to leave 2.01 g of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1.[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1.O>CN(C)C=O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]([CH2:35][CH:32]2[CH2:34][CH2:33]2)[C:18](=[O:20])[C:17]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1
Reactant: BrCC1CC1
Reactant: O=C(Nc1ccc(-c2ccccc2Cl)[nH]c1=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(-c2ccccc2Cl)n(CC2CC2)c1=O)OCc1ccccc1
Reaction time: 4 h
Yield: 38.2 %

Procedure:
Cesium carbonate (1.07 g, 3.30 mmol) was added to a solution of benzyl 6-(2-chlorophenyl)-2-oxo-1,2-dihydropyridin-3-ylcarbamate (J. Med. Chem. 1994, 37, 3303-3312) (585 mg, 1.65 mmol) and cyclopropylmethyl bromide (0.19 mL, 1.98 mmol) in N,N-dimethylformamide (5 mL). After 4 h, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes) gave the title compound (258 mg). MS 409.0 (M+1).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH:29]([CH3:31])[CH3:30]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:29]([CH3:31])[CH3:30]
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: CC(C)Br
Product: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(C)C)c(OC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 356 and 2-bromopropane, white powdery 3-[2-(3-difluoromethoxy-4-isopropoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]([S:28]([CH3:27])(=[O:30])=[O:29])[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Compound 52 (0.16 g, 0.605 mmol) was dissolved in anhydrous THF (5 mL). To the clear solution were sequentially added triethylamine (0.18 mL, 1.21 mmol) and 4-dimethylaminopyridine (15 mg, 0.121 mmol). The mixture was cooled to about −10° C. for 15 min by a methanol-ice bath. To the cold solution was slowly added methanesulfonyl chloride (51 μL). The solution was further stirred at the temperature (about −10° C.) for an additional 30 min, then allowed to slowly warm up to room temperature by removing the cooling bath. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0–35%) and hexanes (100–65%), to afford 0.212 g (83%) of the product 53 as a white solid. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.52–1.70 (m, 4H), 2.68 (t, J=7.4 Hz, 2H), 3.13–3.18 (m, 2H), 3.40 (s, 6H), 4.53 (br s, 1H), 7.27 (s, 4H). m/z (APCI)=321 [C17H28N2O6S2-Boc+H]+.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.[BH4-].[Na+].[Cl-].[Na+].CCOCC>CO>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCC(C)(C)c1ccc(C2=CC(O)CCC2)c(O)c1
Reaction time: 0.5 h

Procedure:
To a -18° C. solution of 70.0 g (0.20 mol) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclohex-2-enone in 200 ml of methanol is added 7.6 g (0.20 mol) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to one liter of saturated sodium chloride-one liter of ether. The ether extract is washed once with 500 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 500 g of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=2)[CH2:21]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Cc1ccc(C2CCCNC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (36 mg, 0.16 mmol), 3-(4-methylphenyl)piperidine.HCl (35 mg, 0.16 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 9 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 20 mg of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=O)=[O:12].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][CH2:17][C:18]([N:45]1[CH2:44][CH2:43][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:47][CH2:46]1)=[O:20])=[O:12]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1nc2ccccc2s1
Reaction time: 8 h

Procedure:
To a solution of (S)-5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoic acid (˜4.41 mmol) in DMF (8 mL) at RT were added N-Boc-piperazine (820 mg, 1 equiv.), DIEA (1.2 mL, 1.5 equiv.), and HBTU (2.00 g, 1.2 equiv.) The reaction was allowed to stir overnight, and the crude was purified by RP-HPLC (5-100% ACN in H2O) to give (S)-tert-butyl 4-(5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate as a white solid (801 mg, 27% over 2 steps). LRMS (M+Na+)=699.4.
Reaction SMILES: [Cl:1][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:14]C(N)=O.Cl>O>[ClH:1].[NH2:14][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC12CC3CC(C)(C1)CC(Cl)(C3)C2
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Product: CC12CC3CC(C)(C1)CC(N)(C3)C2
Reaction time: 0.08 h

Procedure:
1.99 grams of 1-chloro-3,5-dimethyl-adamantane were heated with 0.9 gram urea for about 40 minutes at 220° C. The heating was carried out in a closed vessel in an oil bath with a thermostat. After cooling, the reaction product was pulverized and made into a paste with 50 ml. water. The water phase was brought to a pH between 3 and 5 by dropwise addition of concentrated HCl. The acidified water phase was extracted with two 10-ml. ether portions. Next the water phase was brought to a pH between 12 and 13 by addition of sodium hydroxide, and stirred for 5 minutes. After stirring, the alkaline water phase was extracted with four portions of ether, 10 ml. each. The combined ether extracts were dried over potassium hydroxide. By bubbling dried hydrogen chloride through the solution, 1-amino-3,5-dimethyl-adamantane hydrochloride was precipitated. The yield was 1.7 grams (78% of the theoretical yield). The product did not melt until 300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[C:26]3([CH2:27][CH2:28][N:29]([C:6](=[O:7])[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=4)[CH2:30][CH2:31]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC3(CC2)C(=O)NCN3c2ccccc2)cc(OC)c1OC

Procedure:
The title compound, MS: m/e=426.4 (M+H+), was prepared in accordance with the general method of example 1 from 3,4,5-trimethoxybenzoyl chloride and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].Br[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>COCCOCCOC>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[N:12]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)CCBr
Reactant: CCn1ncc2c3[nH]c4ccnn4c(=O)c3cnc21
Agent: [Na]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n3nccc3n(CCC(C)C)c12

Procedure:
7.6 g. of 3-ethyl-3,11-dihydro-6H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one (0.03 mol. ) are refluxed with stirring in 100 ml. of diethyleneglycol dimethylether together with 1.4 g. of sodium (0.06 mol.). After this time, 11.5 g. of 1-bromo-3-methylbutane (0.075 mol.) are added and the mixture is refluxed for 16 hours. The solvent is distilled off and the residue is crystallized with methanol, filtered and washed with water to obtain 3-ethyl-3,11-dihydro-11-(3-methylbutyl)-6H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one, yield 4.1 g. (42%); m.p. 167°-168° (isopropanol).