Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH2:35])[CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: NCCOCCCc1cccnc1
Reactant: O=[N+]([O-])c1c(Cl)nc2c(c1Cl)CCCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Temperature: 55 °C
Yield: 94.7 %

Procedure:
A 200 ml round bottom flask was charged with 2,4-dichloro-3-nitro-5,6,7,8-tetrahydroquinoline (10 g, 0.04 mol), triethylamine (6.1 g, 0.06 mol, 1.5 equivalents) and anhydrous N,N-dimethylformamide (100 mL). To this solution was added 2-(3-pyridin-3-ylpropoxy)ethanamine (7.3 g, 0.04 mol). The reaction mixture was heated to 55° C. and maintained overnight with stirring. The reaction was quenched by pouring into water (1000 mL). The reaction mixture was then extracted with a 1:1 solution of hexane/ethyl acetate (4×200 mL). The organics were combined, washed with brine (300 mL) and concentrated to provide 2-chloro-3-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine as an orange syrup (14.8 g, 94%). TLC (10% MeOH/CH2CL2, Rf=0.84).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:32])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:21][C:22]3[N:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[CH3:33][O-:34].[Na+]>CO>[O:31]1[C:24]2[CH:23]=[C:22]([CH2:21][NH:20][CH:17]3[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]4[C:10]5[C:5](=[CH:4][CH:3]=[C:2]([O:34][CH3:33])[N:11]=5)[CH:6]=[CH:7][C:8]4=[O:32])[CH2:15][CH2:16]3)[N:27]=[CH:26][C:25]=2[O:28][CH2:29][CH2:30]1
Reactant: C[O-]
Reactant: O=c1ccc2ccc(Cl)nc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Yield: 30.6 %

Procedure:
A solution of 7-chloro-1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,8-naphthyridin-2(1H)-one (Example 67) (95 mg, 0.21 mmol) in methanol (5 mL) was treated with a solution of sodium methoxide (0.5 M, 1 mL, 0.5 mmol). The reaction mixture was sealed in a tube and heated at 150 C for 1 hour using microwave irradiation. The reaction mixture was concentrated at reduced pressure, partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×10 mL) and chloroform/methanol (4:1) (3×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-50%) gave the product as a colorless solid (29 mg, 31%)
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH:10]([CH2:12][CH2:13][OH:14])[C:9](=[C:15]=[C:16]=C=C)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:20]([O:23][CH2:24]C)(=[O:22])C>CO.Cl[Pd]Cl>[C:1]1([CH:7]2[O:11][CH:10]3[CH2:12][CH2:13][O:14][C:9]3([C:15](=[CH2:16])[C:20]([O:23][CH3:24])=[O:22])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C=C=C=C1CC(c2ccccc2)OC1CCO
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: O
Product: C=C(C(=O)OC)C12CC(c3ccccc3)OC1CCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(5-phenyl-3-vinylidenevinylidene-tetrahydrofuran-2-yl)ethanol (39 mg, 0.18 mmol) was dissolved in 2 mL of methanol, and then was filled with CO gas (1 atm), followed by addition of PdCl2 (2.4 mg, 0.014 mmol) and CuCl2 (73 mg, 0.54 mmol). The solution was stirred for 4 hours at room temperature. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:25, v/v), thus providing products (47 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH3:22])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH3:22])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccc(Cl)cc1
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-9-ethyl-9H-purine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].C(Cl)Cl.[Cl:19][S:20](O)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>CC(OC)(C)C>[Cl:19][S:20]([C:14]1[C:13]([CH3:15])=[CH:12][C:4]([O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[CH3:1])(=[O:22])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: CCC(Oc1cc(C)cc(C)c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCC(Oc1cc(C)c(S(=O)(=O)Cl)c(C)c1)C(=O)O
Temperature: -27 °C
Yield: 54.3 %

Procedure:
A 500 mL 3-neck flask was charged with 3,5-dimethylphenoxybutanoic acid (17) (25 g, 120 mmol) and CH2Cl2 (100 mL). This solution was cooled to −27° C. with mechanical stirring then chlorosulfonic acid (42 g, 360 mmol) was added dropwise over 30 min (temperature reached a max. of −20° C.). The material was stirred for an additional 1 hr at −25° C. then NaHCO3 (20 g, 238 mmol) was added to the reaction mixture. The reaction mixture was then added to 150 g of ice. The reaction mixture was then extracted into EtOAc (750 mL), dried over Na2SO4 (10 g), filtered and then concentrated in vacuo. Two triturations of the crude product with MTBE at 5° C. (50 mL then 25 mL) gave 20.0 g 18 (54% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.ClC(O[CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=O>O1CCCC1>[Cl:35][C:34]([Cl:37])([Cl:36])[CH2:33][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C(=O)N1
Reaction time: 0.5 h

Procedure:
In 50 ml of tetrahydrofuran was dissolved 6.2 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and, following addition of 1.2 ml of pyridine, a solution of 5.4 g of 2,2,2-trichloroethyl chloroformate in 30 ml of tetrahydrofuran was added dropwise under cooling at 0°-5° C. The reaction mixture was stirred at the same temperature as above for 30 minutes and under reflux for 5 minutes and then concentrated to dryness under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-ethyl acetate (3:1). The eluate was concentrated under reduced pressure, and the residue was dissolved in a small amount of ethyl ether. After addition of petroleum ether to the solution, the mixture was allowed to stand in a refrigerator overnight to give crystals. Yield 1.1 g.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:30])[N:13]2[CH:16]([C:27]([CH3:29])=C)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]=O.CSC>ClCCl.CO>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:30])[N:13]2[C:16](=[C:27]([OH:31])[CH3:29])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: O=O
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: CC(O)=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Yield: 70.28 %

Procedure:
To a solution of benzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-isopropenylacetate (4.22 g) in dichloromethane and methanol (5:1) is introduced ozonized oxygen until the blue color of the solution does not fade out. Then the solution is mixed with dimethyl sulfide, washed with water, dried, and concentrated. The obtained residue is purified by chromatography over silica gel containing 10% water to give benzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (2.98 g: 70.28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:11]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:32][O:33][C:34]1[CH:40]=[CH:39][C:37]([O-:38])=[CH:36][CH:35]=1.[Na+:41]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O-:9])=[CH:5][CH:4]=1.[Na+:41].[CH3:32][O:33][C:34]1[CH:40]=[CH:39][C:37]([O:38][C:11]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1c(F)cccc1Oc1ccc2c(c1)OCO2
Reactant: COc1ccc(O)cc1
Agent: COc1ccc([O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Oc2ccc(OC)cc2)cccc1Oc1ccc2c(c1)OCO2
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Sodium 4-methoxyphenoxide was prepared as described in part A using 4-methoxyphenol (156 mg, 1.25 mmol) and was dried in vacuo. A solution of ethyl 2-fluoro-6-[3,4-(methylenedioxy)phenoxy]benzoate (304 mg, 1.0 mmol) in DMSO was added to the sodium 4-methoxyphenoxide at 25° C. and the mixture was stirred until all the solid had dissolved (approximately 20 min.). Stirring was continued at 25° C. for an additional 24 hr. The reaction mixture was then warmed to 60° C. and stirred for 2 hr., then stirred for 4 hr. at 80° C. At this time all of the ethyl 2-fluoro-6-[3,4-(methylenedioxy)phenoxy]benzoate had been consumed, as judged by thin layer chromatography (TLC). The reaction was cooled to 25° C., diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The organic extract was washed with water (2×7 ml) and brine (7 ml), dried (MgSO4) and concentrated to give a light yellow oil. The crude product was purified by flash chromatography (SiO2, 50% CH2Cl2 /hexane--CH2Cl2) giving 195 mg of ethyl 2-(4-methoxyphenoxy)-6-[3,4-(methylenedioxy)phenoxy]benzoate. (47% yield, m.p. 84.5-85° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[O:10]1CCC[CH2:11]1>>[CH3:9][C:4]1[N:3]=[C:2]2[NH:1][C:11](=[O:10])[O:8][C:7]2=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(O)c(N)n1
Product: Cc1ccc2oc(=O)[nH]c2n1

Procedure:
1.24 g (10 mmol) of 2-amino-3-hydroxy-6-methylpyridine are introduced into a three-necked round-bottomed flask. The contents are placed under argon. 20 ml of anhydrous tetrahydrofuran and then 2.43 g (15 mmol) of 1,1-carbonyldiimidazole are added. The mixture is heated to reflux for 6 hours. The reaction medium is evaporated. The crystals obtained are washed with water, filtered off and redissolved in hot methanol. The solution is filtered and re-evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:17][CH:16]=[C:15]([C:18]([OH:20])=O)[C:11]=3[N:12]=[CH:13][N:14]=2)=[C:5]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:4]=1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:18]([C:15]2[C:11]3[N:12]=[CH:13][N:14]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:21][CH2:22][CH2:23][O:24][CH3:25])[C:10]=3[NH:17][CH:16]=2)=[O:20])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)O)c[nH]c12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A74) and commercially available trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1I.[CH3:13][N:14](C)C=O.[Cu](C#N)C#N>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:13]#[N:14]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Cl)ccc1I
Agent: N#C[Cu]C#N
Solvent: O
Product: N#Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 140 °C

Procedure:
100 g of 2-trifluoromethyl-4-chloro iodobenzene, 200 ml of dimethylformamide and 58.7 g of copper cyanide are introduced at 20° C., the reaction medium is heated for 3 hours at 140° C., left to cool down to 20° C., then poured into 600 ml of ice-cooled demineralized water. After filtering, rinsing with 3×200 ml of isopropyl ether, the aqueous phase is decanted and reextracted with 3×200 ml of isopropyl ether. The organic phases are combined and washed with 200 ml of demineralized water and dried. In this way 66.64 g of expected product is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:12][CH2:11][C:10](=[O:27])[N:9]1[CH2:28][CH:29]=[CH2:30])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:12][CH2:11][C:10](=[O:27])[N:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCN1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of [2-allyl-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3,7-dioxo-[1,2]diazepan-1-yl]-acetic acid tert-butyl ester (5b) (380 mg, 0.89 mmol) and 20% palladium (II) hydroxide on carbon (Pearlman's catalyst) (80 mg) in ethanol (10 mL) was stirred under hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite and the filtrate was evaporated in vacuo to give 380 mg (99.5% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.05-1.09 (t, 3H), 1.47 (s, 9H), 1.71-1.82 (m, 2H), 2.33-2.46 (m, 1H), 5 2.46-2.53 (m, 1H), 3.00-3.09 (m, 1H), 3.43-3.60 (m, 2H), 3.95-4.00 (d, 1H), 4.10-4.18 (m, 1H), 4.54-4.58 (d, 1H), 5.40-5.45 (m, 1H), 7.70-7.76 (m, 2H), 7.80-7.85 (m, 2H). Analytical HPLC: 13.53 min. LC-MS (ES+): m/e=430 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([CH3:39])[CH2:38][O:37]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:39][C:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)([OH:37])[CH3:38])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CC1(c2ccc(F)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(C)(O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 80 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (2 g), 2-(4-fluorophenyl)-2-methyloxirane (1.2 g), potassium carbonate (1.4 g) and DMF (20 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.8 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11](C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1Cc2cc(-c3ccccn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: Fc1cc2c(cc1-c1ccccn1)CNCC2c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
To an ice-cold solution of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (282 mg, 0.73 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (313 mg, 1.46 mmol) in 1,2-dichloroethane (10 mL) was added 1-chlorethyl chloroformate (0.32 mL, 1.46 mmol) drop wise. The mixture was stirred for 15 minutes and then heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated, and filtered through a pad of silica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (10 mL), and heated to reflux for 1 hour. The mixture was cooled, concentrated, neutralized with aqueous saturated sodium bicarbonate and ethyl acetate, and then purified by column chromatography (methylene chloride to 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give 4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline as yellow oil (13 mg, 5%): 1H NMR (CDCl3, 500 MHz) δ 8.72 (d, J=4.7 Hz, 1H), 7.77-7.75 (m, 3H), 7.39 (d, J=8.3 Hz, 1H), 7.27-7.24 (m, 2H), 6.99 (dd, J=8.3, 2.0 Hz, 1H), 6.68 (d, J=11.9 Hz, 1H), 4.21-4.07 (m, 3H), 3.41 (dd, J=12.9, 5.3 Hz, 1H), 3.05 (dd, J=12.9, 6.4 Hz, 1H); ESI MS m/z 373 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[F:22])[C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=3[N:9]=2)=[C:4]([OH:27])[CH:3]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[F:22])[C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=3[N:9]=2)=[C:4]([O:27][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1
Reactant: ICC1CCCC1
Reactant: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3ccccc32)c(F)c1
Product: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3ccccc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 4-[2-(4-chloro-2-hydroxy-phenyl)-benzoimidazol-1-ylmethyl]-3-fluoro-benzonitrile and iodomethyl-cyclopentane (CAS Reg. No. 27935-87-1). Light yellow sticky solid (35%). MS (Turbo Spray): m/z=460.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]#[N:9])[CH2:3][CH2:2]1.[CH3:16][CH2:17][N:18](CC)CC.ClCC#N>C1COCC1>[C:17]([CH2:16][N:1]1[CH2:6][CH2:5][C:4](=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]#[N:9])[CH2:3][CH2:2]1)#[N:18]
Reactant: N#CC(=C1CCNCC1)c1ccccn1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCN1CCC(=C(C#N)c2ccccn2)CC1
Reaction time: 16 h
Yield: 71.4 %

Procedure:
To a solution of 2-(piperidin-4-ylidene)-2-(pyridin-2-yl)acetonitrile (560 mg, 2.8 mmol) in THF (20 mL) was added NEt3 (5 mL, 38 mmol) and chloroacetonitrile (3 mL, 47 mmol) and the reaction was stirred 16 h. The resulting precipitates were filtered away and the filtrate concentrated to dryness. The residues was purified by silica gel chromatography (Biotage 40-short, 50% EtOAc/hexanes to 100% EtOAc/hexanes) to yield 52 (470 mg, 2.0 mmol, 71%) as a yellow solid. 1H NMR: (500 MHz, CDCl3) δ 8.64 (br d, J=4.9 Hz, 1H), 7.77 (ddd, J=7.9, 7.6, 1.9 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.27 (dd, J=7.6, 4.9 Hz, 1H), 3.58 (s, 2H), 2.94 (t, J=5.8 Hz, 2H), 2.91 (t, J=5.8 Hz, 2H), 2.83 (t, J=5.8 Hz, 2H), 2.67 (t, J=5.8 Hz, 2H); LC/MS: (ES+) m/z (M+H)+=239; HPLC Rt=0.99 min., column 0, conditions B.
Reaction SMILES: Cl[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[K+].C(OCC)(=[O:18])C>O>[OH:18][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Yield: 100 %

Procedure:
3-chloro-2-nitrobenzoic acid (30 g, 0.15 mol) and KOH (120 g, 2.14 mol) were dissolved in water (150 mL). The mixture was heated at reflux for 12 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The pH of mixture was adjusted to 3. The resulting mixture was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (40 g, 100%) as a brown solid. 1H NMR (400 MHz, DMSO): δ 11.193 (s, 1H), 7.476 (t, 1H), 7.367 (d, 1H), 7.268 (d, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([NH2:14])=[N:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C1COCC1>[CH2:17]([NH:19][C:20]([NH:14][C:12]1[NH:11][C:10]2[CH:15]=[CH:16][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]=2[N:13]=1)=[O:21])[CH3:18]
Reactant: CCN=C=O
Reactant: Nc1nc2cc(-c3ccccc3)ccc2[nH]1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3ccccc3)ccc2[nH]1

Procedure:
To a solution of 7 (40 mg, 0.19 mmol) in THF (1 mL) was added ethyl isocyanate (27 μL, 0.34 mmol) as a solution in THF (0.5 mL). The reaction was heated to reflux overnight then concentrated in vacuo. The crude product was purified by preparative HPLC to afford Ia-84.
Reaction SMILES: [Br:1][C:2]1[S:18](=O)[C:5]2[O:6][CH:7]=[CH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C([O-])(O)=O.[Na+]>COCCOCCOC>[Br:1][C:2]1[S:18][C:5]2[O:6][C:7](=[S:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: O=S1C(Br)=CC2=C1OC=CN=C2c1ccccc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Product: S=C1CN=C(c2ccccc2Cl)c2cc(Br)sc2O1
Temperature: 0 °C

Procedure:
(a) 0.1 Mol=35.8 gm of 7-bromo-5-(o-chlorophenyl)-thieno-[2,3-e]-4,1-oxazepinone were heated with 350 ml of diglyme, 24 gm of P2S5 and 19 gm of NaHCO3 for 30 minutes at 60° C. Subsequently, the reaction mixture was poured over about 1 liter of ice water, whereby a crystalline precipitate was formed, which was suction-filtered off, washed with water and dried. 37 gm=99% of theory of 7-bromo-5-(o-chlorophenyl)-thieno-[2,3-e]-4,1-oxazepine-2-thione were obtained M.p. from 200° C. (decomp.).