Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH2:23][C:24](C)(C)N=3)=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:29]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:22][CH2:23][CH3:24])=[O:29])=[CH:19][CH:20]=2)([OH:14])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)COC(c2ccc(C3(O)CCN(Cc4ccccc4)CC3)cc2)=N1
Reactant: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
1-Benzyl-4-(4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)piperidin-4-ol described in Production Example 7-1 (13.4 g, 36.8 mmol) was dissolved in ethanol (300 mL), then sulfuric acid was added, and the mixture was stirred at 90° C. for 12 hours. The reaction mixture was cooled to room temperature and then the solvent was evaporated under vacuum. The resultant residue was dissolved in dichloromethane, the resultant was washed with a saturated aqueous sodium bicarbonate solution, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum and the resultant residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1). The target fraction was concentrated under vacuum to obtain the title compound (7.23 g, 58%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.[Ag]=O>[CH3:9][N:10]([C:6]1[CH:7]=[CH:8][C:1](=[O:2])[C:3](=[O:4])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ccccc1
Reactant: Oc1ccccc1O
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(C1=CC(=O)C(=O)C=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.2 g (0.02 mole) catechol and 2.0 g (0.019 mole) N-methylaniline were dissolved in 80 ml acetone. Then 18.8 g (0.08 mole) silver oxide was added followed by 20 g anhydrous sodium sulfate. The mixture was stirred at room temperature for 10 minutes and filtered. The residue was washed with several portions of acetone totaling 50 ml. The filtrate was diluted with ligroin (bp 60°-80° C.) and the solid was filtered and washed with ligroin to give 2.6 g (60%). Thin-layer chromatography on Eastman chromogram silica gel sheets showed essentially a single spot with traces of impurities.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[O:19]([C:26]1[CH:27]=[C:28]([CH2:29][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:31]=[CH:32][CH:33]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(Oc3ccccc3)c2)CCCC1=O
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
40% Methanolic Triton B (1.53 mL, 3.4 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (554.6 mg, 2.28 mM) in 5 mL of DMF at 25° C. After 5 minutes, 3-phenoxybenzyl chloride (748.0 mg, 3.42 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed three times with 1N HCl, three times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 563.6 mg (58%) of 9-[(3-phenoxyphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a thick yellow oil. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.4-7.2 (m, 6H), 7.1 (t, 1H, J=8 Hz), 6.95 (m, 2H), 6.8-6.7 (m, 2H), 5.55 (s, 2H), 3.75 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.45 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1653, 1585, 1487, 1465, 1288, 1252, and 1119. MS (ES) m/e 426.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:23]([O-:25])=[O:24])=[C:18](F)[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:33])([F:32])[CH2:30][OH:31].[OH-].[K+]>>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:17]=[C:18]([O:31][CH2:30][C:29]([F:33])([F:32])[F:28])[C:19]([N+:23]([O-:25])=[O:24])=[C:20]([F:22])[CH:21]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Reactant: OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c2)[C@@H]1O
Temperature: 70 °C

Procedure:
To a solution of [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (5.0 g, 12.1 mmol, example 24f) and 2,2,2-trifluoroethanol (24.49 g, 242 mmol) was added pulverized KOH (0.694 g, 12.1 mmol) and the reaction mixture was heated at 70° C. for 3 h. The reaction mixture was evaporated and after addition of ice-water the product was extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound after crystallization from Et2O-hexane as light yellow crystals: TLC (toluene-EtOAc 3:1) Rf=0.17; HPLC RtA=2.28 min; ESIMS [M+H-isobutylene]+=429; 1H NMR (600 MHz, DMSO-d6): δ 7.13 (s, 1H), 7.10 (d, 1H), 6.76 (d, 1H), 5.10 (s, 1H), 5.01 (m, 2H), 3.37 (m, 1H), 3.19 (dd, 1H), 2.92 (dd, 1H), 2.55 (d, 1H), 2.48 (dd, 1H), 2.37 (dd, 1H), 2.31 (d, 1H), 2.25 (dd, 1H), 1.95 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:7])=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: O=C(c1ccc(Cl)cc1)N1CC1
Solvent: Cc1ccccc1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55.4 G. of p-chlorobenzoylaziridine and 26.5 g. of morpholine are boiled in 250 ml. of toluene for 2 hours under reflux. The solution is then cooled to room temperature, whereupon crystals separate out. The solution which crystallizes is allowed to stand overnight in a refrigerator. Thereafter, the product is removed by filtration, washed with toluene and recrystallized from isopropanol, and 75.9 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>>[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:19][CH2:20]1
Reactant: Clc1nc2ccccc2o1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc3ccccc3o2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-benzooxazole following a procedure analogous to that described in Example 19. LC (method 9): tR=1.85 min; Mass spectrum (ESI+): m/z=429 [M+H]+.
Reaction SMILES: Cl[CH2:2][S:3][CH3:4].[C:5]1([C:11]2[NH:16][C:15](=[S:17])[NH:14][C:13](=[O:18])[C:12]=2[CH3:19])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:4][S:3][CH2:2][N:16]1[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:12]([CH3:19])[C:13](=[O:18])[NH:14][C:15]1=[S:17]
Reactant: CSCCl
Reactant: Cc1c(-c2ccccc2)[nH]c(=S)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSCn1c(-c2ccccc2)c(C)c(=O)[nH]c1=S
Yield: 8.1 %

Procedure:
To 4 ml of dimethylformamide, 0.17 ml (2.0 mmol) of chloromethylmethylsulfide, 0.47 g (2.0 mmol) of 6-phenylthiothymine, 0.56 ml (2.0 mmol) of triethylamine were added and allowed to react for 22 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was adsorbed on a silica gel column and eluted with chloroform. The eluate was concentrated and crystallized from ethyl acetate to obtain 45 mg of the target compound (Yield: 8%).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[O:19]1[C:23]2([CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:22](=[O:29])[NH:21][C:20]1=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:21]1[C:22](=[O:29])[C:23]2([CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[O:19][C:20]1=[O:30]
Reactant: O=C1NC(=O)C2(CCSCC2)O1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)OC3(CCSCC3)C2=O)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 39.5 %

Procedure:
To a solution of 200 mg (0.52 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 146 mg (0.78 mmoles) of 1-oxa-8-thia-3-aza-spiro[4.5]decane-2,4-dione in 5 ml of DMF, 117 mg (0.846 mmoles) of K2CO3 is added at ambient temperature. After being stirred for 18 hours, the reaction mixture is quenched with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by reverse-phase HPLC to give 85 mg of disired 7-(2,2-dimethyl-propyl)-6-(2,4-dioxo-1-oxa-8-thia-3-aza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (NVP-TAB516-NX) in 32% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[C:50](OC(=O)C)(=[O:52])[CH3:51]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][N:13]([C:50](=[O:52])[CH3:51])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1
Reactant: COc1ccccc1CNC[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1CN(C[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reaction time: 4 h

Procedure:
To a stirring solution of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mol) in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 203.97 grams (87% yield) of analytically pure material.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH:8]([CH2:18][OH:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([CH:18]=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:20][CH:21]=1)#[N:2]
Reactant: CCOC(=O)CCCCC(CO)Cc1ccc(C#N)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCC(C=O)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
A solution of 4.6 g (15.90 mmol) of ethyl 6-(4-cyanobenzyl)-7-hydroxyheptanoate from Example 110A in 250 ml of dichloromethane is mixed with 4.11 g (19.08 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 12 hours. After conversion is complete, 10 g of silica gel are added, and the solvent is cautiously concentrated to dryness in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). 4.09 g (14.23 mmol, 89% yield) of a colorless solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:5]=[CH:6][C:7]=1[N:8]([CH3:10])[NH2:9].[CH3:22]OC(OC)N(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:21])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:5]=[C:6]2[CH:22]=[N:9][N:8]([CH3:10])[C:7]=12
Reactant: COC(OC)N(C)C
Reactant: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1Cl
Solvent: CN(C)C=O
Product: Cn1ncc2nn(-c3cccc(C(F)(F)F)c3)c(=O)c(Cl)c21

Procedure:
In 100 ml. of absolute dimethylformamide (dried over molecular sieves) under a nitrogen atmosphere, are dissolved 9.6 grams of 4-chloro-5-(1-methylhydrazino)-2-(3'-trifluoromethylphenyl)-3(2H)-pyridazinone. To this solution are added 3.9 grams of N,N-dimethylformamide dimethyl acetal and the solution is heated at 110°-120° C. overnight. The progress of the reaction is followed by thin layer chromatography. An additional 3.9 grams of N,N-dimethylformamide dimethyl acetal are added with continued heating to complete the reaction (about 20 hours). The reaction mixture is then evaporated to dryness in vacuo and then column chromatographed on silica gel, eluting with a mixture of benzene-chloroform (50/50), to obtain the title product. (m.p. 156°-158° C.).
Reaction SMILES: [Br:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.Cl>CC(O)C.ClCCl.[Fe]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]([OH:27])([C:23]([F:26])([F:24])[F:25])[C:19]([F:20])([F:21])[F:22])=[CH:16][CH:17]=3)[CH2:7][CH2:6]2)=[C:2]([Br:1])[CH:31]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(Br)c1
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(Br)c1
Yield: 90.8 %

Procedure:
Iron (94 mmol, 5.24 g) (reduced powder) was added to a suspension 2-(4-((4-(2-bromo-4-nitrophenoxy)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (9.40 mmol, 5.24 g) in 2-propanol (100 mL) containing concentrated hydrochloric acid (1 mL) and the mixture refluxed for 4.5 hours. The mixture was cooled, diluted with dichloromethane and filtered through dicalite. The filtrate was washed with sodium carbonate solution, the organic phase dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (4.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH3:14][N:15]1CCCC1=O.O>[C-]#N.[Zn+2].[C-]#N.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.C(OCC)(=O)C>[CH2:11]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: CN1CCCC1=O
Reactant: CCCOCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOCCc1ccc(C#N)cc1
Temperature: 125 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
1-Bromo-4-(2-propoxy-ethyl)-benzene described in Preparation Example 195 (790 mg, 3.2 mmol), zinc cyanide (380 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium (190 mg, 0.16 mmol) were added to N-methylpyrrolidinone (10 mL), and this mixture was stirred at 125° C. for 4 hours. This reaction mixture was allowed to cool, and water (50 mL) and ethyl acetate (50 mL) were added thereto. This mixture solution was filtered through Celite pad. The organic layer was separated, then, washed with water (3 times) and brine, and then, concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1), and the title compound (120 mg, 0.62 mmol, 19%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Brc1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To the suspension of 4-(4-bromo-phenyl)-1H-indole (1.20 g, 4.41 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (54 mL) was added pyridinium tribromide (4.23 g, 13.23 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was suspended in water (300 mL) for 0.5 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (1.12 g, 88%) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:12]([NH2:13])=[CH:11][C:9](=[O:10])[N:8]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.N([O-])=O.[Na+].C(O)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:33]([NH2:35])=O>>[CH:15]1([CH2:14][N:8]2[C:9](=[O:10])[C:11]3[NH:35][CH:33]=[N:13][C:12]=3[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]2=[O:7])[CH2:17][CH2:16]1
Reactant: NC=O
Reactant: Nc1cc(=O)n(CC2CC2)c(=O)n1CC1CC1
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 100 °C

Procedure:
1,3-Di-cyclopropylmethyl xanthine was prepared using an analogous procedure to that described in Chem. Berichte 88, 1306-1312, 1955: 20.2 g (0.0855 mol) of 1,3-di-cyclopropylmethyl-6-amino-uracil was dissolved in 100 ml of formamide, then 5.9 g sodium nitrite was added and at 60° C. 13.4 ml formic acid was added slowly with stirring. After the colour had changed from yellow to violet, the mixture was heated up to 100° C. and 3.1 g of sodium dithionite (Na2S2O4) was added in small portions.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@H:13]3[C:8]3[C:9]2=C([CH:5]=[CH:6][CH:7]=3)N1.[H-].[Na+].CI.[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>O>[CH3:2][CH:11]1[N:10]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:8]3[C:9]2=[C:27]([CH:5]=[CH:6][CH:7]=3)[N:28]([CH3:29])[C:30]1=[O:31]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)C(=O)N4C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of ethyl 2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (from Example 211, Step A) (500 mg, 1.6 mmol) in DMF (20 mL) at rt was added NaH (147 mg, 3.6 mmol), MeI (0.25 mL, 4.0 mmol) and stirred at 25° C. for 3 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 1,3-dimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (350 mg, 64%) as an oil. MS [M+H]+ 328. 1H NMR (CDCl3, 300 MHz): δ 7.18 (d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.63 (d, 1H, J=7.7 Hz), 4.90 (m, 1H), 4.51 (m, 1H), 3.20 (m, 5H), 3.49 (m, 1H), 3.42 (s, 3H), 2.91 (m, 1H), 2.80 (m, 1H), 1.61 (d, 3H, J=7.0), 1.28 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:17]=[CH:18][C:19]1[S:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[N:28]=1>CN(C)C=O>[CH3:33][O:32][C:31]1[CH:30]=[CH:29][C:16]([CH:17]=[CH:18][C:19]2[S:20][C:21]3[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[N:28]=2)=[CH:15][C:14]=1[O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCBr
Reactant: COc1ccc(C=Cc2nc3c(s2)NCCCC3)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cc(C=Cc2nc3c(s2)NCCCC3)ccc1OC
Reaction time: 1 h
Yield: 15.4 %

Procedure:
Amyl bromide (0.49 ml) and potassium carbonate (0.46 g) were added to a solution (20 ml) of 2-(3-hydroxy-4-methoxy-styryl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (1.00 g) in dimethylformamide, and the whole was stirred for 1 hr. at 100°. After cooling, the reaction mixture was washed with water, dried and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel, and recrystallized from isopropyl ether to give the title compound (0.19 g, 15.4%). m.p. 124-125°.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)=O.[C-:28]#[N:29].[K+]>CN(C=O)C.O>[C:28]([CH2:6][CH2:7][CH2:8][C:9]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:29]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCOS(C)(=O)=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCC#N
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of ethyl 2-(3-methanesulfonyloxypropyl)-3-benzyloxybenzoate (19.42 g, 31.7 mmol) and potassium cyanide (2.28 g, 35 mmol) in DMF (50 ml) was heated at 100° C. for 8 hr. The mixture was cooled, diluted with water (250 ml), and extracted three times with ethyl acetate. The ethyl acetate extracts were dried with brine, and concentrated in vacuo. The crude product was chromatographed on silica gel using methylene chloride as the eluent to give the product as an oil (5.25 g, 53%).