Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[I-].[Na+]>CN(C)C=O.O>[CH2:21]([O:20][CH2:19][CH2:18][CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCCOCc2ccccc2)ccc1Br

Procedure:
To a solution of 4-bromo-3-methylphenol (2.5 g) in N,N-dimethylformamide (10 mL) were added cesium carbonate (4.79 g), benzyl 3-bromopropyl ether (2.48 mL) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 60 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(3-benzyloxypropoxy)-1-bromo-2-methylbenzene. This material was dissolved in tetrahydrofuran (100 mL). To the solution was added n-butyl lithium (2.46 mol/L n-hexane solution, 6 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added N,N-dimethylformamide (2.57 mL), and the mixture was allowed to warm to 0° C. and stirred for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(3-benzyloxypropoxy)-2-methylbenzaldehyde. This material was dissolved in ethanol (40 mL). To the solution was added sodium borohydride (506 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-1.5/1) to give the title compound (3.33 g).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].ONC(=O)CCC(N)=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.Cl.[NH:61]1[C:65]([CH2:66][NH2:67])=[N:64][N:63]=[N:62]1>CN(C=O)C.C(N(CC)CC)C>[CH3:3][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:67][CH2:66][C:65]1[NH:64][N:63]=[N:62][N:61]=1)=[O:33])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:1])[CH3:34]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NC(=O)CCC(=O)NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1nnn[nH]1
Reaction time: 1 h

Procedure:
50 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to of 40 mg N-hydroxysuccinamide in 5 mL DMF. 150 mg of dicyclohexylcarbodiimide was added and the mixture was stirred for 1 h. 43 mg of (1H-Tetrazol-5-ylmethyl)amine dihydrochloride was added followed by 1 mL triethylamine. The mixture was stirred for 18 h, filtered through celite, and the solvents removed by evaporation. The resulting residue was purified by reverse phase H.P.L.C. to give the title compound as a white solid; 18 mg.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14]C)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(OCCO)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43 %

Procedure:
6-Amino-9-benzyl-2-(2-methoxyethoxy)purine (100 mg, 0.36 mmol) and bromine (0.25 ml) were dissolved in methylene chloride (100 ml). The solution was stirred at room temperature for 6 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (55 mg, yield 43%).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[C:8](=[O:19])[NH:9][C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)=[O:6])[CH3:3].CN(C)C=O.[CH2:25](Br)[CH:26]=[CH2:27]>O>[CH2:2]([O:4][C:5]([C:7]1[C:8](=[O:19])[N:9]([CH2:27][CH:26]=[CH2:25])[C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(N)c2cc(Cl)ccc2[nH]c1=O
Reactant: C=CCBr
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(C(=O)OCC)c(N)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
To a solution of 8.66 g. (0.03 mole) of the sodium salt of 4-amino-6-chloro-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid ethyl ester in 50 ml. of dimethyl formamide was added 4.84 g. (0.04 mole) of allyl bromide. The reaction mixture was heated on a steam bath for 2 hours and was then cooled to room temperature. The reaction mixture was poured into 500 ml. of water. The reaction mixture was allowed to stand for several hours at room temperature and was then filtered. There was obtained 7.6 g. of product. Recrystallization from ethyl acetate gave 3.4 g. of product, m.p. 144°-146° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:33]([C:34](=[O:45])[NH:35][C:36]3[CH:44]=[CH:43][C:39]4[N:40]=[CH:41][S:42][C:38]=4[CH:37]=3)=[CH:32][C:17]3[N:18]=[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[S:42]1[C:38]2[CH:37]=[C:36]([NH:35][C:34]([C:33]3[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]([F:29])([F:30])[F:31])=[N:18][C:17]=4[CH:32]=3)=[O:45])[CH:44]=[CH:43][C:39]=2[N:40]=[CH:41]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3ncsc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc2ncsc2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1

Procedure:
The product from Example 163 was treated with 4M HCl in dioxane employing the procedure described for Example 156 to afford 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide as a hydrochloride salt. MS: m/z 538 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:20]/[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)[S@@](N)=O
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(C(F)(F)F)cc1F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (1.17 g, a pale yellow solid) from 2-fluoro-4-(trifluoromethyl)benzaldehyde (800 mg, 4.16 mmol) and (S)-2-methylpropane-2-sulfinamide (606 mg, 5.00 mmol) by the similar manner in Step-1 of Amine-88.
Reaction SMILES: Cl[C:2]1[C:19]2[C:6](=[C:7]3[C:16](=[CH:17][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9](=[O:21])(=[O:20])[NH:8]3)[N:5]=[CH:4][CH:3]=1.[NH3:22]>CO>[O:20]=[S:9]1(=[O:21])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[C:7](=[C:6]3[C:19](=[CH:18][CH:17]=2)[C:2]([NH2:22])=[CH:3][CH:4]=[N:5]3)[NH:8]1
Reactant: O=S1(=O)Nc2c(ccc3c(Cl)ccnc23)-c2ccccc21
Reactant: N
Solvent: CO
Product: Nc1ccnc2c3c(ccc12)-c1ccccc1S(=O)(=O)N3
Yield: 20 %

Procedure:
In a similar fashion using route 48 general procedure 114, 1-chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 305 (90 mg, 0.28 mmol), 7M NH3 in MeOH (5 ml) gave the title compound (17 mg, 20%) after purification by column chromatography eluting with chloroform/MeOH (98:2:1 drop NH3).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:30]1([NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: NN1CCOCC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NN3CCOCC3)ccc21
Yield: 82.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid morpholin-4-ylamide (100 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 4-aminomorpholine (28 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 493.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 9.49 (s, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.78-7.59 (m, 2H), 7.47 (d, 1H), 7.34 (d, 1H), 3.78-3.56 (m, 7H), 2.93-2.84 (m, 4H).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:5]=[N:6][CH:7]=[C:8]([O:10][Si](C)(C)C)[N:9]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].CO>ClC(Cl)C.II>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:5]1[C:4](=[O:3])[NH:9][C:8](=[O:10])[CH:7]=[N:6]1
Reactant: ClCCCCBr
Reactant: C[Si](C)(C)Oc1cnnc(O[Si](C)(C)C)n1
Agent: II
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=c1cnn(CCCCCl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 25 h
Yield: 76.5 %

Procedure:
22.1 g of 3,5-Bis-trimethylsilanyloxy-[1,2,4]triazine (86 mmol) were dissolved in 150 mL of dichloroethane followed by addition of 14.7 g of 1-bromo-4-chloro-butane (86 mmol) and 0.218 g of iodine (0.858 mmol). The reaction mixture was stirred for 25 h at room temperature. Then, 300 mL of methanol were added and the mixture was stirred for an additional 10 minutes. The solvents were evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous phase was extracted several times with dichloromethane. The combined organic layers were washed with 10% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the organic phase was evaporated under reduced pressure. The thus obtained crude product was purified via silica gel chromatography using dichloromethane-methanol 0-10% to yield 13.4 g of the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:24][C:25]1([CH3:41])[O:30][CH:29]([C:31]([NH:33][CH2:34][CH2:35][C:36](O)=[O:37])=[O:32])[C:28]([CH3:40])([CH3:39])[CH2:27][O:26]1>>[CH3:24][C:25]1([CH3:41])[O:30][CH:29]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:37])=[O:32])[C:28]([CH3:40])([CH3:39])[CH2:27][O:26]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 88.8 %

Procedure:
N-(2-Hydroxyethyl)oleamide (0.97 g) and 0.78 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 1.50 g of the title compound (yield: 90%).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C(I)(I)I.O>C1COCC1.O1CCOCC1.CCOCC>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][I:1]
Reactant: COC(=O)CCCCCCC/C=C/I
Agent: IC(I)I
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCCCCC=CI
Reaction time: 12 h
Yield: 62.8 %

Procedure:
To a suspension of CrCl2 (454 mg, 3.75 mmol, 7.0 eq.) in THF (1.5 mL) at 23° C. was added dropwise a solution of (E)-methyl 10-iododec-9-enoate (100 mg, 0.537 mmol, 1.0 eq.) and iodoform (422 mg, 1.07 mmol, 2.0 eq.) in dioxane (9.2 mL). After stirring for 12 h, the reaction mixture was diluted with Et2O (10 mL) and poured into water (10 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×15 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo. Purification of the crude product by flash chromatography (hexanes→hexanes:EtOAc 9:1) provided 10-iodo-9-decenoate methyl ester as a yellow oil (105 mg, 0.337 mmol, 63%). 1H NMR indicated an E:Z ratio of 10:1.
Reaction SMILES: [CH2:1]=[CH: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].[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH:21]=[CH:20]1>>[CH:1]([CH:20]1[CH2:21][C:22](=[O:23])[O:24][C:19]1=[O:25])=[CH: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]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Temperature: 200 °C
Yield: 53.5 %

Procedure:
One thousand and eight grams (4.0 moles) of 1-octadecene and 490 grams (5.0 moles) of maleic anhydride were placed in a 2 liter stirred autoclave equipped with a thermocouple. The reaction was carried out by heating the mixture at 200° C. for 4 hours, and the cooled product was transferred to a 2 liter round bottom flask equipped with a magnetic stir bar, a thermometer, and a distilling head mounted on a Vigreux Column. Unreacted starting materials were removed at 200° C. and 10 torr, leaving the product ODSA (750 grams) in the pot. It was typically a tan solid (m.p. 40°-55° C.) with strong adsorption in its IR spectrum at 1860 and 1785 cm-1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([OH:10])(=[S:9])[CH3:8].CS(O[CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)(=O)=O>CO.CN(C=O)C.O>[C:7]([S:9][CH:20]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19]1)(=[O:10])[CH3:8]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
Potassium carbonate (4.42 g, 31.96 mmol) was suspended in dry MeOH (20 mL) and thioacetic acid (2.28 g, 29.96 mmol) was added. The mixture was stirred vigorously for 10 mins, concentrated and diluted in dry DMF (30 mL). tert-Butyl 3-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (2.65 g, 9.99 mmol) dissolved in dry DMF (20 mL) was added and the reaction mixture was heated to 60° C. for 3.5 h. The reaction mixture was diluted with water (350 mL) and extracted with EtOAc (2×150 mL) The organic phases were dried with MgSO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system (25+M column, isocratic run heptane/EtOAc (60:40)) affording the title compound (0.592 g, 24.2%) (the product is a mixture of cis and trans isomers). 1H NMR (500 MHz, CDCl3): δ 1.41 (d, 18H), 1.66 (d, 1H), 1.74-1.86 (m, 2H), 2.20-2.26 (m, 2H), 2.29 (s, 3H), 3.10-3.26 (m, 2H), 3.30-3.43 (m, 4H), 3.46-3.54 (m, 1H), 3.66-3.74 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 28.68, 30.82, 31.25, 32.34, 36.16, 41.09, 44.88, 51.60, 55.37, 79.67, 154.43; Mass Spectrum: M+H+ 241.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.Cl[CH2:21][CH2:22][CH3:23]>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:21][CH2:22][CH3:23])[CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: CCCCl
Product: CCCn1cnc2c1c(=O)n(CC1CC1)c(=O)n2CC1CC1

Procedure:
1,3-Di-cyclopropylmethyl-7-n-propyl xanthine was prepared from 1,3-di-cyclopropylmethyl xanthine and 1-chloropropane using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:14]O>OS(O)(=O)=O>[CH3:14][O:12][C:11]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)=[O:13]
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c2cc(Cl)ccc12

Procedure:
1 g of 6-chloro-1H-indole-3-carboxylic acid were heated at reflux in MeOH with 3 drop of concentrated H2SO4 overnight. Concentration in vacuo afforded the title compound in quantitative yield.
Reaction SMILES: [OH-].[Al+3:2].[OH-].[OH-].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6]>>[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Al+3:2].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Al+3:2]
Reactant: O=S(=O)(O)O
Agent: [Al+3]
Agent: [OH-]
Product: O=S(=O)([O-])[O-]

Procedure:
The aluminum hydroxide obtained as an intermediate product in the above method 2) or a highly aluminous clay mineral is reacted with sulfuric acid to obtain aluminum sulfate. Then, aluminum hydroxide is precipitated by neutralization with ammonia, followed by filtration, drying and calcining to afford alumina gel.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:40][CH2:39][CH2:38][CH2:37][N:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)=[O:16])[CH2:6][CH2:5]2
Reactant: NCCCN1CCOCC1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCN1CCOCC1)O2
Reaction time: 2 h

Procedure:
To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (511 mg, 2.1 mmol) in 10 mL THF was added 356 mg CDI and stirred for 2 h. 3-morpholino-propylamine (438 μl, 432 mg, 3.0 mmol) in 10 mL THF was added dropwise and stirred overnight. The reaction was concentrated, dissolved into 70 mL CH2Cl2, the organics washed once with 50 mL saturated NaCl solution, dried over Na2SO4 and concentrated to brown oil. Flash chromatography yielded 6-hydroxy-2,5,7,8-tetramethyl-N-(3-morpholinopropyl)chroman-2-carboxamide as a pale brown solid.
Reaction SMILES: C(O)C(C)(C)C.[H-].[Na+].C(OC([N:16]1[CH2:22][CH2:21][C:20]2[C:23](SCC3N=NC(Cl)=CC=3)=[C:24](Cl)[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=O)(C)(C)C>C1COCC1.O>[CH2:21]1[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17][NH:16][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nn3)c2CC1
Agent: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a stirred solution of neopentyl alcohol (105 mg, 1.19 mmol) in THF (5 mL) at ambient temperature add sodium hydride (31 mg, 95%, 1.19 mmol) and continue stirring for 3 h at ambient temperature. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (315 mg, 0.59 mmol) in THF (1 mL) and continue stirring overnight at ambient temperature and then at 60° C. for 1 h. Dilute with water, extract the reaction mixture three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give 3-tert-butoxycarbonyl-7-chloro-6,6-(2,2-dimethyl-propoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (81 mg, 28%). MS (APCI+) m/z: 492 (M+H)+, 392 (M+H-Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white powder. MS (APCI+) m/z: 392 (M+H)+, m/z: 322 (M+H—C5H11)+.
Reaction SMILES: [C:1]([C:4]1([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]>CO.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[C:8]([NH:7][C:4]1([C:1](=[O:3])[NH2:2])[CH2:6][CH2:5]1)=[O:18]
Reactant: NC(=O)C1(NC(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1(NC(=O)c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To the suspension of N-(1-carbamoylcyclopropyl)-3-nitrobenzamide (0.28 g, 1.123 mmol) in methanol (5 ml), Pd—C (0.05 g) was added under nitrogen and stirred the reaction mixture under hydrogen atmosphere at room temperature. After 2 hr, reaction mixture was filtered and concentrated under vacuum to afford solid compound (0.2 g, 81%).
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].CN(C)C(=N)N(C)C.[CH:38]([C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH:42]=[CH:43][NH:44]2)=O>ClCCl>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[O:4][CH2:2][CH3:3])=[CH:38]/[C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH:42]=[CH:43][NH:44]2)[CH3:10]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1cccc2[nH]ccc12)OCC
Reaction time: 16 h
Yield: 107.2 %

Procedure:
To a solution of 35.01 g (81.6 mmol) of (1,2-diethoxy-2-oxoethyl)triphenyl phosphonium chloride in 200 ml of dichloromethane was added at 0° C. 11.01 ml (87.1 mmol) of tetramethyl guanidine and the mixture was warmed to 22° C. The mixture was treated with 7.9 g (54.4 mmol) of 4-formyl-indole and stirring was continued at 40° C. for 16 h. The mixture was treated again with 10.0 g (23.3 mmol) of the Wittig salt and 8.0 ml (24.0 mmol) of tetramethyl guanidine and stirring was continued at 40° C. for 24 h after which time the conversion was complete. The reaction mixture was poured into crashed ice and then extracted twice with MeCl2. The organic layer was washed with water, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, 95:5 to 4:1) to give 15.12 g of the title compound as a light yellow solid.