Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH:12]([F:14])[F:13].C(N(CC)C(C)C)(C)C.Cl.Cl.[O:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH:12]([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:38][CH:35]2[CH2:34][CH2:33][N:32]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH2:37][CH2:36]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)F)c(Cl)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 70 °C
Yield: 95.1 %

Procedure:
A stirred solution of 1-chloro-2-(difluoromethyl)-5-fluoro-4-nitrobenzene (D96, 200 mg, 0.89 mmol) in dimethylformamide (4 ml) at room temperature under argon was treated with N,N-diisopropylethylamine (0.47 ml, 2.7 mmol), followed by 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (D40, 240 mg, 0.94 mmol) and then heated at 70° C. for 1.5 hrs. The reaction mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum to leave an orange solid. This was purified by chromatography on silica gel eluting with 0-20% methanol/ethyl acetate to afford the title compound as a yellow solid (330 mg, 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][Si](C(C)(C)C)(C)C.[Li]C(C)(C)C.[CH3:22][N:23]([CH2:25][CH:26]1[C:32](=[O:33])[CH2:31][CH:30]2[CH2:34][CH:27]1[CH2:28][CH2:29]2)[CH3:24]>C1COCC1.CCCCCC>[CH3:24][N:23]([CH2:25][CH:26]1[C:32]([C:2]2[CH:3]=[C:4]([OH:5])[CH:13]=[CH:14][C:15]=2[F:16])([OH:33])[CH2:31][CH:30]2[CH2:34][CH:27]1[CH2:28][CH2:29]2)[CH3:22]
Reactant: CN(C)CC1C(=O)CC2CCC1C2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC1C2CCC(C2)CC1(O)c1cc(O)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
Cool a solution of (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane (5.81 g, 19.03 mmol) in THF (100 mL) to −78° C. under N2. Then add dropwise a solution of t-BuLi (14.6 mL, 19.03 mmol) in hexane via syringe to the reaction solution. After being stirred at −78° C. for 1 hour, add dropwise a solution of 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one (2.87 g, 15.86 mmol) in THF (1.5 mL) to the reaction mixture and stir the mixture at −78° C. for additional 1 hour. Quench the reaction with 60 mL of diluted HCl (2N), and stir at ambient temperature for 2 hours. Basify the resultant mixture with K2CO3 to pH=9, and extract with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2 to CH2Cl2:MeOH=10:1) to afford 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol as white solid (2.38 g, yield: 51.2%). MS (m/z): 294 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][NH2:15].C(O)C>O>[CH3:14][NH:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: CN
Solvent: CCO
Solvent: O
Product: CCOC(=S)c1cnc(C)nc1NC
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 20 g, 86 mmol) in 250 mL of dichworomethane at 0° C. was added slowly solution of methylamine in ethanol (33%, 35 mL 281 mmol). After stirring for 30 minutes, water (150 mL) was added and the phases were separated. The organic phase was dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure to give 19 g of the ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[SH:16])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[K].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][S:16][C:12]1[N:13]=[N:14][S:15][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:10][CH:9]=1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)c1ccc(-c2snnc2S)cc1
Agent: [K]
Solvent: CCO
Product: CCOC(=O)CSc1nnsc1-c1ccc(C(C)(C)C)cc1
Yield: 83.2 %

Procedure:
A solution of 2.9 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassium salt in 50 ml of ethanol was stirred overnight with 1.67 g of ethyl bromoacetate, then concentrated in vacuo. The residue was taken up in ether, filtered and evaporated in vacuo. The oily residue was dissolved in dichloromethane and purified as described in Example 50, giving an oil which was crystallized from methylcyclohexane, giving 2.8 g of the desired compound as white needles, mp 62.5°-63.5° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 1.21 (t, 3H, J=7.0 Hz, CH3); 1.37 (s, 9H, t-butyl); 4.11 (s, 2H, SCH2); 4.15 (q, 2H, CH2O); 7.55 (s, 4H, C6H4). Infrared absorption spectrum (KBr pellet): 1739(s); 1606(w); 1520(w); 1480(w); 1445(w); 1385(w); 1365(w); 1305(s); 1175(s); 1040(w); 935(s); 840(s).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([Cl:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:51]([NH:50][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:47]([Cl:48])=[CH:46][C:45]=1[F:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)Nc1nc(N)c(Cl)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2Cl)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.42 h

Procedure:
To 3 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.84 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.65 g of 2-amino-6-(t-butylamino)-3-chloro-5-fluoropyridine. The solution was concentrated under reduced pressure to obtain yellow solid residue. To this residue were added 0.7 g of anhydrous potassium carbonate and 3 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 25 minutes and allowed to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 1.06 g of the title compound as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:14]([O:18]C(C)(C)C)(=[O:17])[CH:15]=[CH2:16].C(O)(=O)C=C>>[O:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2](/[CH:16]=[CH:15]/[C:14]([OH:18])=[O:17])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: Brc1ccc(N2CCOCC2)nc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C=CC(=O)O
Product: O=C(O)/C=C/c1ccc(N2CCOCC2)nc1
Yield: 41 %

Procedure:
Following the same procedure as described in Example 2, step 2 (scheme 2), but substituting compound 37 for compound 163, and compound 38 for acrylic acid, title compound 164 was obtained (41% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6]=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[CH:19]([C:20]([OH:22])=[O:21])[CH2:18][C:17](=[O:23])[N:7]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1cccc(C=Nc2ccccc2)c1
Solvent: Cc1ccccc1C
Product: COc1cccc(C2C(C(=O)O)CC(=O)N2c2ccccc2)c1

Procedure:
A solution of 42.3 gm. of 3-methoxybenzylidenaniline, 20 gm. of succinic anhydride and 200 ml. of xylene was refluxed for 16 hours. The crude product was obtained as a solid via the same workup used for example 1B. Recrystallization from ethyl acetate followed by a second recrystallization from acetonitrile provided 21.0 gm. of colorless crystals, m.p. 145°-149°.
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.Cl[C:29]1[C:30]([O:43][CH2:44][C:45]2([CH3:53])[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[CH:14]1([C:29]2[C:30]([O:43][CH2:44][C:45]3([CH3:53])[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC(F)(F)CC1
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC(F)(F)CC1

Procedure:
Following the procedure as described in Example 158 step 3, and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoate with tert-butyl 5-chloro-4-((4,4-difluoro-1-methylcyclohexyl)-methoxy)-2-fluorobenzoate, the title compound was obtained as colorless oil (3.69 g, 99%): MS (ES+) m/z 399.2 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:37])[CH2:19][CH2:20][N:21]2[CH2:26][CH:25]=[C:24]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:37])[CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH2:25][CH2:26]2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCNC(=O)CCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCNC(=O)CCN2CCC(c3c[nH]c4cc(Cl)ccc34)CC2)CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
A mixture of the compound of EXAMPLE 2 (0.383 mmol) and triethylsilane (0.422 mmol) in trifluoroacetic acid (6 ML) was stirred at 0° C. for 2.5 hours. The mixture was diluted with dichloromethane (20 mL) and quenched with sodium hydroxide solution until the pH was 10-13. The mixture was extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 8% methanol, 0.5% ammonium hydroxide in dichloromethane to give the title compound (191 mg, 95%).
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH2:12]([O:14][C:15](=[O:22])[C:16]#[C:17][C:18]([F:21])([F:20])[F:19])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]([C:16]1[N:1]([C:4]2[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:10])[N:2]=[N:3][C:17]=1[C:18]([F:19])([F:20])[F:21])=[O:22])[CH3:13]
Reactant: CCOC(=O)C#CC(F)(F)F
Reactant: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(F)(F)F)nnn1-c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 59.5 %

Procedure:
A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/e 353.0 (M+1).
Reaction SMILES: CSC.[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH3:11])[CH:10]=1.ClC(O[C:16]1[CH:21]=[CH:20]C=CC=1)=O.C1([Mg]Br)CC1>O1CCCC1.[Cu](I)I>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH3:11])[C:10]=1[CH:20]1[CH2:21][CH2:16]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cncc(Br)c1
Agent: I[Cu]I
Agent: Br[Mg]C1CC1
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cncc(Br)c1C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of copper iodide (1.082 g, 0.0056 mol), dimethyl sulphide (2.78 mL, 0.0380 mol) and 3-bromo-5-methylpyridine (1.0 g, 0.0056 mol) in anhydrous tetrahydrofuran (25 mL) at room temperature was added phenyl chloroformate (0.764 mL, 0.0060 mol) and the mixture was stirred for 40-50 min. To this suspension at −25 to −20° C. was added cyclopropyl magnesium bromide (12.13 mL, 0.0060 mol, 0.5M solution in tetrahydrofuran) over 30-40 min. The mixture was stirred at this temperature for 30 min. and then warmed slowly to room temperature over 1.0-1.5 h. The reaction mixture was quenched with 20% ammonium chloride (25 mL), followed by extraction of the aqueous layer with ethyl acetate (50 mL). The organic layer was washed with 20% ammonium chloride (25 mL), then saturated aqueous sodium chloride solution (25 mL), and dried over anhydrous sodium sulphate. Silica gel chromatography using 0-5% ethyl acetate-hexane gradient yielded crude title compound.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[C:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1)([OH:7])=[O:6].N>[NH2-].[Na+]>[C:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:2]([CH3:3])[C:1]#[N:4])=[CH:14][CH:13]=1)([OH:7])=[O:6]
Reactant: O=C(O)c1ccccc1CCc1ccc(Cl)cc1
Reactant: CCC#N
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: CC(C#N)c1ccc(CCc2ccccc2C(=O)O)cc1
Yield: 43.9 %

Procedure:
Propionitrile (286.5 g.) is added over the course of 40 minutes and with vigorous stirring to a suspension of sodamide (248 g.) [prepared from sodium (139.5 g.) and liquid ammonia (4 liters)] and then 4-(2-carboxyphenethyl)chlorobenzene (117 g.) is added over the course of 10 minutes. The ammonia is allowed to evaporate during a period of 16 hours. The brown residue is taken up in anaesthetic grade diethyl ether (1 liter) and then in water (2 liters) with care. The alkaline aqueous solution is decanted, extracted with diethyl ether (2 × 400 cc.) and then acidified by adding sulphuric acid (d = 1.36; 350 cc.) whilst cooling. The oil which separates out is extracted with methylene chloride (2 × 500 cc.). The organic extracts are dried over anhydrous sodium sulphate (100 g.) and concentrated to dryness under reduced pressure (20 mm.Hg) at 60°C. The residual oil is dissolved in hot diisopropyl ether (120 cc.); on cooling, a product crystallises and is filtered off. 2-[4-(2-Carboxyphenethyl)phenyl]propionitrile (55 g.), melting at 73°C., is thus obtained; after three recrystallisations from ethyl acetate, the product melts at 129°C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[Br:11][C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1>CC(C)=O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH2:8][CH2:9][CH3:10])[CH:13]=1
Reactant: Sc1cccc(Br)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCSc1cccc(Br)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
Reflux a suspension of potassium carbonate (22.4 g), 1-iodopropane (10.3 mL) and 3-bromothiophenol (8.4 mL) in acetone (375 mL) for 5 hours. Cool to room temperature, filter through diatomaceous earth, and concentrate. Dissolve the residue in hexanes, filter through a silica gel plug, and concentrate to give 1-bromo-3-propylsulfanylbenzene (18 g, 95%) as an oil (GC-MS: m/z=231). Add this material (12 g) to a solution of n-butyllithium (57 mmol) in THF (50 mL) at −78° C. Stir for 45 min, add 110 N,N-dimethylformamide (8.1 mL) and warm to room temperature. Stir for 15 min, pour into water (175 mL), and extract into diethyl ether (3×200 mL). Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography) to give the title compound (7.3 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]2[C:14]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:15]=3[S:16][C:7]=12.CO>[Fe].O>[NH2:21][C:17]1[C:15]2[S:16][C:7]3[C:8](=[N:9][CH:10]=[C:11]([C:12]#[N:13])[C:6]=3[NH:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=3)[C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2c(sc3c([N+](=O)[O-])cccc32)c1Nc1cccc(Br)c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2c(sc3c(N)cccc32)c1Nc1cccc(Br)c1
Reaction time: 12 h

Procedure:
A mixture of 4-(3-bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile (0.213 g, 0.5 mmol), iron powder (0.168 g, 3.0 mmol) ammonium chloride (0.325 g, 6.0 mmol), methanol (90 mL) and water (90 mL) is heated at reflux temperature with vigorous stirring under nitrogen for 12 hours. The final mixture is concentrated, and the residue is extracted with ethyl acetate (5×20 mL). The extract is dried over sodium sulfate, evaporated, and re-dissolved in a small volume of chloroform/methanol/DMSO. Purification by silica gel chromatography, eluting with 20:1 chloroform/methanol, yields 6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile as a brown solid, m. p. 256-258° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][OH:21])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.I[CH3:23]>C1COCC1>[CH3:23][O:21][CH2:20][C:19]#[C:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][O:3]1)[N:10]=[CH:11]2
Reactant: OCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Sodium hydride (60% in mineral oil, 0.42 g, 10.5 mmol) was added to a solution of 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-ol (1.01 g, 3.94 mmol; Intermediate 19) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then iodomethane (1.67 g, 11.8 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1:30) to afford the title compound (0.714 g, yield 67.3%). 1H NMR (DMSO-d6, 300 MHz): δ 8.21 (s, 1H), 7.93 (s, 1H), 7.73 (d, 1H), 7.47-7.45 (m, 1H), 5.85-5.83 (m, 1H), 4.38 (s, 2H), 3.76-3.71 (m, 2H), 3.35 (s, 3H), 2.40-2.37 (m, 1H), 2.03-1.94 (m, 2H), 1.73-1.72 (m, 1H), 1.57-1.55 (m, 2H). LCMS: 271 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[Mg+2].[Cl-]>O1CCCC1.COCCO>[CH2:22]([O:21][C:19]([C:18]1[C:9]2=[C:8]3[C:13](=[CH:12][CH:11]=[CH:10]2)[CH2:14][CH2:15][CH:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:7]3[CH:17]=1)=[O:20])[CH3:23]
Reactant: c1ccc2c(c1)CCC(C1CCCC1)N2
Reactant: CCOC(=O)C(=O)CBr
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: COCCO
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2C1CCCC1
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a solution of 2-cyclopentyl-1,2,3,4-tetrahydroquinoline (4.0 g, 20 mmol) in tetrahydrofuran (15 ml) was added ethyl bromopyruvate (˜90% purity; 1.38 ml, 9.9 mmol) and the reaction stirred for 15 h. The resulting precipitate was filtered and washed with tetrahydrofuran (20 ml). The filtrate was evaporated in vacuo. The resulting residue was dissolved in tetrahydrofuran (10 ml) and 2-methoxyethanol (10 ml) and the solution added dropwise to a refluxing solution of magnesium (II) chloride (1.05 g, 11 mmol) in 2-methoxyethanol (10 ml). The reaction mixture was refluxed for 2 h and then a further portion of magnesium (II) chloride (1.05 g, 11 mmol) added and refluxing continued overnight. The reaction was cooled and the solvent removed in vacuo. The resulting brown oil was dissolved in dichloromethane (150 ml) and washed with 2 M HCl (50 ml), saturated potassium carbonate (50 ml) and brine (50 ml). The organics were dried (MgSO4), filtered and the solvent removed in vacuo. The resulting oil was purified by flash chromatography using 33-67% (v/v) dichloromethane in heptane to give 4-cyclopentyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (1.45 g, 4.9 mmol).
Reaction SMILES: [CH:1]([C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)=O.C(OC(=O)C)(=O)C.Cl[C:25](Cl)([F:30])[C:26]([O:28][CH3:29])=[O:27]>[Zn].[Cu]Cl.O1CCCC1>[F:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:1][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: O=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 31.5 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.16 g), molecular sieve 4A (1.1 g), tetrahydrofuran (18 ml), 1-formyl-1-(4-trifluoromethoxyphenyl)cyclopropane (1.08 g), acetic anhydride (0.6 ml) and methyl dichlorofluoroacetate (0.86 g) to yield the title compound (0.45 g, 34%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C1C=CC=CC=1>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][N:18]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CN(C)CCCN
Solvent: c1ccccc1
Product: CN(C)CCCN=Cc1ccc2ccccc2c1
Yield: 93.4 %

Procedure:
Interaction of 15.6 g of 2-naphthaldehyde and 10.2 g of 3-dimethylaminopropylamine in 80 ml. of benzene following the procedure described in Example 1 yields 22.4 g of oily product; boiling point 146°-149° C. at 0.1-0.2 mm. of Hg. The material solidifies when stored in the cold, melting point 29°-31° C.