Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C1(S(Cl)(=O)=O)C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:9]1(=[O:10])[C:3]2([CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[CH2:2][O:11]1
Reactant: O=C(O)C1(CO)CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C1OCC12CCOCC2
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-hydroxymethyl-tetrahydropyran-4-carboxylic acid (3.84 Kg), 4-dimethylaminopyridine (0.6 Kg) in dichloromethane (32 liters) was added triethylamine (4.88 Kg). The mixture was cooled to -20° C., and a solution of benzenesulfonyl chloride (4.66 Kg) in dichloromethane (5 liters) was added over a period of 35 minutes, maintaining the temperature below -10° C. The mixture was stirred at -10° C. for 30 minutes, then 3N hydrochloric acid (10 liters) and water (10 liters) were added with stirring, then the layers allowed to separate. The organic layer was separated, the aqueous layer washed with dichloromethane (16 liters), the combined organics washed with aqueous 5% sodium bicarbonate solution (12 liters), then with water (12 liters), and solvent removed under reduced pressure, to give 2,7-dioxaspiro[3,5]nonane-1-one, a compound of Formula (10a)
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(SCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(Cl)c1=O
Yield: 85.5 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2.2 g (0.01 mol) of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 3.5 g (0.0105 mol) of 4-(4'-trifluoromethylphenoxy) benzyl bromide, and thereto was added 2.1 g (0.02 mol) of anhydrous sodium carbonate to effect reaction at 85° to 90° C. for 4 hours. After the reaction, the reaction liquid was allowed to cool, poured into water and then extracted with benzene. The benzene layer was washed with 5% aqueous solution of sodium hydroxide and then with water, dried over anhydrous sodium sulfate and then freed of benzene by distillation under reduced pressure. The oily residue was incorporated with n-hexane and the precipitated crystals were filtered off to obtain white crystals (yield: 85.5%).
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][C:8]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=O)(=O)C.O.[NH2:29][NH2:30]>C(O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:8]=3[CH2:7][C:6]([CH2:5][OH:4])=[N:30][N:29]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(CC(=O)COC(C)=O)c(C(=O)c2cccc(Cl)c2)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)=NN=C(CO)C2
Reaction time: 8 h
Yield: 77.8 %

Procedure:
6.7 g (17.3 mmoles) of 2-(3-acetoxyacetonyl)-3'-chloro-4,5-dimethoxybenzophenone [(IV), R=CH3 ] are suspended in 70 ml of 99.5% ethanol, then 5.2 l (104 mmoles) of 100% hydrazine hydrate are added under stirring. The reaction mixture is stirred at room temperature for 72 hours, treated with activated carbon, filtered and 82 ml of distilled water are added to the filtrate. Then 4 ml of glacial acetic acid are dropped to the pale yellow solution under cooling with ice-cold water. Upon scratching crystals get separated. The suspension is kept overnight at 1° to 5° C., filtered, washed five times with 5 ml of ice-cold 50% ethanol solution each and the product is dried at a temperature between 80° and 100° C. Thus 4.64 g of crude product are obtained.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1.C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3nc(C(C)C)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)ethanol (1.7 g, 6.08 mmol), methyl 2-(4-hydroxyphenyl)acetate (1.5 g, 9.1 mmol) and triphenylphosphine (2.4 g, 9.1 mmol) were dissolved in THF (30 ml). The mixture was stirred at RT under N2 for 5 min and disisopropyl azodicarboxylate (1.78 ml, 9.1 mmol) was added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with water, dried and evaporated. The crude material was purified by silica gel column (100 g SNAP, 5-25% EtOAc in hexane) to afford the desired product. LC/MS (m/z): 428 (M+H)+.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[CH2:16][CH2:17][CH3:18])[CH:10]=1.Cl>CCO>[CH2:17]([C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:7][C:15]=1[C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1)[CH3:18]
Reactant: NNc1ccccc1
Reactant: CCCC(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Product: CCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A flask is charged with phenylhydrazine (0.873 g, 6.46 mmol) and EtOH (14 mL). 1-Pyridin-3-yl-butan-1-one (0.914 g, 6.13 mmol) is added and the reaction is refluxed for 1 h. After cooling to room temperature, HCl (4M in 1,4-dioxane, 6.45 mL, 25.83 mmol) is added. The reaction mixture is refluxed for 4 h. After cooling to room temperature, the precipitate formed is filtered to afford 3-ethyl-2-pyridin-3-yl-1H-indole as a yellow solid. MS (ESI) m/z 223.0 (M+H)+.
Reaction SMILES: ClC1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]C=1.C([Li])CCC.[I:18][CH2:19][CH2:20]I.[Cl-:22].[NH4+]>C(OCC)C>[Cl:22][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:5][C:19]([I:18])=[CH:20][N:3]=2)=[CH:8][CH:9]=1
Reactant: Clc1csc(-c2ccccc2)n1
Reactant: ICCI
Reactant: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Clc1ccc(-c2ncc(I)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.3 grams (0.012 mole of 2-(4-chloro(phenyl)thiazole in 20 ml of diethyl ether was cooled to -78° C. To this solution was added 4.72 ml of a 2.5 M solution of n-butyllithium in hexanes. This mixture was stirred for 30 minutes. A solution of 3.3 grams (0.012 mole) of 1,2-diiodoethane in 15 ml of diethyl ether was added, and the resultant mixture was allowed to warm to room temperature and stir for approximately 18 hours. Approximately 50 ml of an aqueous, saturated ammonium chloride solution was added, and the resultant mixture was poured into a separatory funnel. The organic phase was washed with water followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:1), to yield 2.6 grams of 2-(4-chlorophenyl)- 5-iodothiazole as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[CH2:9]([I:13])[CH2:10][CH2:11][CH3:12]>C(#N)C>[I-:13].[CH2:9]([N+:6]1[C:5]([CH3:7])=[C:4]([CH3:8])[S:3][C:2]=1[CH3:1])[CH2:10][CH2:11][CH3:12]
Reactant: Cc1nc(C)c(C)s1
Reactant: CCCCI
Solvent: CC#N
Product: CCCC[n+]1c(C)sc(C)c1C
Product: [I-]

Procedure:
A mixture of 2,4,5-trimethylthiazole (1.3 g, 10 mmol) and n-butyl iodide (7.4 g, 40 mmol) in anhydrous acetonitrile (30 mL) was refluxed for 72 hours and then concentrated under reduced pressure to provide the crude thiazolium salt. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.39 (sextet, J=7 Hz, 2H), 1.65 (m, 2H), 2.43 (s, 6H), 2.96 (s, 3H), 4.25 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22](O)=[C:23]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=3)[C:24](=[O:28])[NH:25]2)=[CH:20][C:19]=1[N+:38]([O-:40])=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:22]1[C:21]2[C:26](=[CH:27][C:18]([Cl:17])=[C:19]([N+:38]([O-:40])=[O:39])[CH:20]=2)[NH:25][C:24](=[O:28])[C:23]=1[C:29]1[CH:30]=[C:31]([CH3:36])[CH:32]=[C:33]([CH3:35])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of (S)-2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.864 g in 38 mL dry tetrahydrofuran) was added 1.56 g of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one [see Example 9] followed by 1.19 g of triphenylphosphine and the mixture stirred at room temperature. To this was added 0.72 mL of diethyl azodicarboxylate (DEAD) and stirring was continued for 64 hours. At this time the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4) to give the title compound, 1.56 g.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([O:10][C:11](=[O:13])[CH3:12])(=O)[CH3:8].[OH:14][C@H:15]([C-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)[CH3:16].[C-:22]1([C@@H:27]([OH:29])C)C=CC=C1.[Fe+2:30]>O>[C:11]([O:10][C@H:7]([C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1)[CH3:8])(=[O:13])[CH3:12].[C-:17]1([C@@H:15]([O:14][C:27](=[O:29])[CH3:22])[CH3:16])[CH:21]=[CH:20][CH:19]=[CH:18]1.[Fe+2:30]
Reactant: C[C@H](O)[c-]1cccc1
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: [Fe+2]
Solvent: O
Product: CC(=O)O[C@@H](C)[c-]1cccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.0 ml of pyridine and 4.0 ml of acetic anhydride were added to 4.00 g (14.6 mmol) of (S,S)-1,1'-bis(1-hydroxyethyl)ferrocene and the resulting solution was stirred overnight at 25° C. After hydrolysis of the excess anhydride using 100 ml of water, the hydrolysis mixture was extracted twice with 200 ml each time of diethyl ether and the combined organic extracts were dried over magnesium sulphate. The solvent was taken off and the residue was dried to constant weight in a high vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].[CH3:23][C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)n1nnc(-c2ccc(Br)cc2)n1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)O
Product: CC(C)(C)c1ccc(-c2nnn(C(C)(C)C)n2)cc1
Temperature: 75 °C
Yield: 54.9 %

Procedure:
A solution of 5-(4-bromophenyl)-2-(1,1-dimethylethyl)-2H-tetrazole (3.0 g, 10.2 mmol), t-butyl acrylate (2.9 mL, 20.4 mmol), and triethylamine (7.9 mL, 59 mmol) in DMF (93 mL) was deoxygenated with argon, whereupon bis(triphenylphosphine)palladium dichloride (0.5 g, 0.8 mmol) was added. After heating at 75° C. for 12 hours the mixture was concentrated under reduced pressure and the brown residue was filtered through a short column of silica gel eluting with a mixture of hexanes and ethyl acetate (9:1). The eluent was concentrated and then purified by chromatography on a Waters Prep 500 liquid chromatograph fitted with two silica gel cartridges eluting with a mixture of hexanes and ethyl acetate (9:1). The fractions containing product were pooled, concentrated and the residue was recrystallized from hexanes to give 1,1-dimethylethyl 4-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]benzene propenoate (1.6 g, 5.6 mmol) in 55% yield, mp. 118.5°-120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:3])=[O:2].C1(C)C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[C:26]([O:18][CH:15]1[CH2:14][CH2:13][N:12]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:17][CH2:16]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113.6 %

Procedure:
5-Nitro-2-(4-hydroxypiperidin-1-yl)benzonitrile (20 g) was dissolved in pyridine (100 ml). To the solution was added dropwise toluene solution (50 ml) containing benzoyl chloride (12.8 g) under ice-cooling, and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water. The obtained crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 1-(2-cyano-4-nitrophenyl)-4-piperidinyl benzoate (32.3 g), melting point: 143–145° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([Cl:24])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
To a solution of 0.688 mole (219 g.) of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid in 657 ml. of benzene is added 1.376M. (100.4 ml.) of thionyl chloride slowly over 1 hour while heating to about 60° C. The mixture is then heated at reflux for about 8 hours, then evaporated to provide the desired product, 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride as a residue. The structure is verified by means of infrared spectral analysis.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:28]=2[N:29]=[CH:30][N:31]=1)[C@@H:15]1[O:27][C@H:24]([CH2:25][OH:26])[C@@H:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:16]1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:55]=[CH:54][C:37]([C:38](Cl)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:28]=2[N:29]=[CH:30][N:31]=1)[C@@H:15]1[O:27][C@H:24]([CH2:25][O:26][C:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:37]2[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:55][CH:54]=2)[C@@H:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:16]1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
A solution of N6-Benzoyl-3′-O-(2-methoxyethyl) adenosine (11.0 g, 0.285 mol) in pyridine (100 mL) was evaporated under reduced pressure to an oil. The residue was redissolved in dry pyridine (300 mL) and 4,4′-dimethoxytrityl chloride (DMT-Cl, 10.9 g, 95%, 0.31 mol) was added. The mixture was stirred at 25° C. for 16 h and then poured onto a solution of sodium bicarbonate (20 g) in ice water (500 mL). The product was extracted with ethyl acetate (2×150 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate (powdered) and evaporated under reduced pressure (below 40° C.). The residue was chromatographed on silica gel (400 g, ethyl acetate-acetonitrile-triethylamine 99:1:1→95:5:1). Selected fractions were combined, concentrated under reduced pressure and dried at 25° C./0.2 mmHg to give 16.8 g (73%) of foam; TLC homogenous.
Reaction SMILES: [N:1]([C:3]1C=CC=CC=1)=O.[C]=[O:10].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Pd]>[C:11]1([N:1]=[C:3]=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Nc1ccccc1
Reactant: c1ccccc1
Reactant: [C]=O
Agent: [Pd]
Product: O=C=Nc1ccccc1
Temperature: 190 °C

Procedure:
The procedure of Example 14 is repeated using 12.3 parts of nitrosobenzene, 80 parts of benzene, 10 parts of 5% palladium on carbon and 0.44 part of stannic chloride. After carbon monoxide is introduced to a pressure of 4,000 p.s.i., the pressure vessel is heated at 190°C. for 5 hours. Phenyl isocyanate is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1)=[N+:25]=[N-:26]
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OCCCCCCBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
10 g of [4-(6-bromo-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone are dissolved in 200 ml of DMF and, after the addition of 14.7 g of sodium azide, the mixture is stirred at 90° C. for 24 hours, filtered and the filtrates are concentrated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution. The organic phase is dried and concentrated. There are obtained 9.2 9 of [4-(6-azido-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone, MS: m/e 401 (M+H+, 1Br).
Reaction SMILES: [OH:1][CH:2]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)[C:3]#[CH:4].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc[nH]3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(1H-pyrrol-2-yl)-1-propyne (212 mg, 1.75 mmol) (from Example 30 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (125 mg, 0.39 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (42 mg) (Aldrich) and CuI (20 mg) (Aldrich) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(1H-pyrrol-2-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: N1C2C3C(CN[C:6](=[O:13])C=3C=CC=2)=C1.C1NC=CC2C=1C1=CC=NC1=CC=2.[CH3:27][O:28][C:29]([C:31]1[C:32]2[CH:33]=[CH:34][NH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1)=[O:30].CN(C=O)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[CH3:27][O:28][C:29]([C:31]1[C:32]2[C:33]([CH:6]=[O:13])=[CH:34][NH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1)=[O:30]
Reactant: O=C1NCc2c[nH]c3cccc1c23
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CN(C=O)c1ccccc1
Agent: c1cc2c(ccc3cc[nH]cc32)n1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12

Procedure:
The starting material for the compounds of this invention is the amide, 3,4-dihydropyrrolo[4,3,2-de]isoquinolin5(lH)-one (2). The preparation of this starting material is described in detail in our copending patent application of Philipp et al., Ser. No. 413,417 now U.S. Pat. No. 3,950,343 and entitled "Pyrroloisoquinoline Derivatives". Briefly a preferred preparation of this starting material involves treating 4-indolecarboxylic acid methyl ester, F. C. Uhle, J. Amer. Chem. Soc., 71, 761 (1949), with N-methylformanilide in the presence of phosphorus oxychloride according to the conditions of the Vilsmeier reaction to obtain 3-formylindole-4-carboxylic acid methyl ester, converting the latter compound to its corresponding oxime, catalytically reducing the oxime in the presence of hydrochloric acid and palladium on charcoal to obtain 3-(aminomethyl)indole-4-carboxylic acid methyl ester hydrochloride and finally treating the latter compound with sodium methoxide to give the desired starting material of formula 2.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C@@H:12]([CH2:25][NH2:26])[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[BH4-].[Na+].C(N(C(C)C)CC)(C)C.[C:47](Cl)(=[O:49])[CH3:48].C(=O)(O)[O-].[Na+]>C(O)C.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])[C@@H:12]([CH2:25][N:26]([C:47](=[O:49])[CH3:48])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Cl
Reactant: C[C@@H](c1ccccc1)N1CCc2c(sc(N)c2C(=O)OC(C)(C)C)[C@@H]1CN
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N(Cc1ccccc1)C[C@H]1c2sc(N)c(C(=O)OC(C)(C)C)c2CCN1[C@@H](C)c1ccccc1
Yield: 46.7 %

Procedure:
A solution of 2-amino-7-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic aicd tert-butyl ester (400 mg, 1.03 mmol) and benzaldehyde (105 mg, 1.03 mmol) was heated to 50° C. in ethanol (20 ml) for 1 hour in the presence of molecular sieves (4 A, 7 ml). The reaction mixture was cooled on an ice bath before sodium borohydride (78 mg, 2.06 mmol) was added in three portions over 45 min. The cooling bath was removed and the reaction mixture was allowed to reach room temperature. The mixture was filtered through a plug of Celite and the filter cage was washed with dichloromethane (3×25 ml). The solvent was removed in vacuo and the residue was redissolved in ethyl acetate (50 ml), washed with sodium bicarbonate (50 ml) and dried (MgSO4). The solvent was removed in vacuo before the product was dissolved in dichloromethane (20 ml). The solution was cooled on an ice bath before di-isopropyl-ethyl amine (267 mg, 2.06 mmol) was added followed by drop wise addition of acetyl chloride (81 mg, 1.03 mmol) in dichloromethane (1 ml). The reaction mixture was stirred 1 hour at 0° C. before sodium bicarbonate (20 ml) was added. The mixture was extracted with dichloromethane (2×10 ml) and the combined organic fractions were dried (MgSO4). The crude product was purified by flash column chromatography (petrol ether/ethyl acetate (3:1)), which afforded 250 mg (46%) of 7-(S)-((acetyl-benzyl-amino)methyl)-2-amino-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.