Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:3][CH:2]=1.Cl[CH2:25][S:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[N:30]1[CH:31]=[CH:32][C:27]([S:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[O:23])=[CH:28][CH:29]=1
Reactant: ClCSc1ccncc1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCCSc1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2n(CSc2ccncc2)c(=O)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a solution of 491 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2,4(1H,3H)-dione and 287 mg (1.8 mmol) of 4-chloromethylthiopyridine in 15 ml of dimethylformamide, 0.27 ml (1.8 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexane=2:1 to 4:1 to ethyl acetate) to give 0.315 g of the desired product (46.7% yield, colorless oil).
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].[C:6]([C:8]1[CH:17]=[CH:16][C:11]([NH:12][C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=1)#[N:7].O>C(O)C.C(O)(=O)C>[Cl:1][C:10]1[CH:9]=[C:8]([C:6]#[N:7])[CH:17]=[CH:16][C:11]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: [O-]Cl
Reactant: CC(=O)Nc1ccc(C#N)cc1
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(C#N)cc1Cl
Reaction time: 96 h
Yield: 82.3 %

Procedure:
An aqueous solution (200 ml) of calcium hypochlorite (21 g) was added to a solution of p-cyanoacetanilide (12.5 g) in ethanol (27 ml), acetic acid (27 ml), and water (27 ml). The mixture was stirred for 4 days and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated to give a powder of 2'-chloro-4'-cyanoacetanilide (12.5 g).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].Cl.[F:11][C:12]([F:22])([F:21])[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1>>[F:22][C:12]([F:11])([F:21])[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:16][CH2:15]1
Reactant: COC(=O)C(Br)CCBr
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: Cl
Product: COC(=O)C1CCN1C1CCN(CC(F)(F)F)CC1
Yield: 8 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with 1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride 18G yielded methyl 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-2-carboxylate as a light brown solid (8%). MS ISP (m/e): 281.1 (100) [(M+H)]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C:7]1=[O:16].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>C1(C)C=CC=CC=1>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C:7]1=[O:16]
Reactant: O=C1OC2(CCCCC2)CN1Cc1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: O=C1OC2(CCCCC2)CN1Cc1cccc(-c2ccccn2)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
3-(3-Iodo-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (0.148 mmol, 55 mg), 2-tributylstannanyl-pyridine (0.222 mmol, 81.72 mg), tetrakispalladium(0) (0.03 mmol, 34.2 mg) were combined and dissolved in toluene (5 mL). The reaction mixture was left to stir at 110° C. overnight. It was then filtered through silica and the filtrate was concentrated in vacuo. The residue was purified by SPE flash column chromatography using silica gel and ethyl/acetate/hexanes (0˜50%) as eluent. The product was impure by NMR. Therefore, it was dissolved in dichloromethane, and 2M hydrogen chloride in diethyl ether (10 mL) was added. This solution was concentrated in vacuo, the residue was dissolved in water (10 mL) and washed with hexanes. The aqueous layer was then neutralized using sodium bicarbonate and washed with dichloromethane. The organic layer was concentrated in vacuo to give the final product was a pale yellow gum (10 meg, 21%). 1H NMR (300 MHz, CDCl3): δ (ppm)=8.71 (m, 1H), 7.92 (m, 2H), 7.77 (m, 2H), 7.49 (m, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 4.53 (s, 2H), 3.14 (s, 2H), 1.78 (m, 4H), 1.51 (m, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[S:17][C:16]=2[CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:19]=[C:18]([CH:20]=[O:21])[S:17][C:16]=2[CH:22]=1
Reactant: OCc1cc2ccc(Br)cc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
To a −78° C. solution of oxalyl chloride (1.30 mL, 14.9 mol) in CH2Cl2 (20 mL) is added a solution of dimethyl sulfoxide (2.13 mL, 29.9 mmol) in CH2Cl2 (10 mL). The mixture is stirred for 5 minutes and a solution of (6-bromo-benzo[b]thiophen-2-yl)-methanol (2.91 g; 12.0 mmoles) in CH2Cl2 (30 mL) is added. The mixture is stirred at −78° C. for 30 minutes and triethylamine (8.34 mL, 60.0 mmol) is added. The mixture is stirred for 1 hour while warming to room temperature. The reaction mixture is quenched with water (50 mL). The organic layer is separated and concentrated under reduced pressure to a residue. The residue is purified via silica gel chromatography eluting with 20% EtOAc/Hexanes to provide the title compound (2.58 g, 89%). 1H NMR (400 MHz, CDCl3): δ 10.4 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.79 (d, 1H), 7.52 (d, 1H).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][N:29]=3)[N:26]=2)=[CH:19][NH:18][N:17]=1.S(O[CH:44]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]1)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][N:29]=3)[N:26]=2)=[CH:19][N:18]([CH:48]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47]2)[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: CC(C)c1nnc2ccc(-c3c[nH]nc3-c3ccc(F)cc3F)nn12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3cn(C4CCN(C(=O)OC(C)(C)C)C4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a round bottom flask was added NaH (0.065 g, 1.6 mmol), DMF (4 mL) and 6-(3-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.500 g, 1.47 mmol, Example #L.1.1). The reaction mixture was stirred for about 30 min at ambient temperature. tert-Butyl 3-(tosyloxy)pyrrolidine-1-carboxylate (0.652 g, 1.91 mmol, prepared according to US 2002/0151712, Example #34c) was added and the reaction mixture was stirred for about 30 min at ambient temperature. The reaction mixture was heated to about 75° C. for about 1 h. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), dried with MgSO4, filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 90:10) to give the title compound (0.446 g, 60%) as a mixture of regioisomers: LC/MS (Table 1, Method g) Rt=3.66 min; MS m/z: 510.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:24]#[N:25])[C:22](Cl)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:39])[NH:33][C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)(Cl)Cl.CO>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:24]#[N:25])[C:22]([N:36]3[CH2:37][CH2:38][C@H:34]([NH:33][C:32](=[O:39])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:35]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c3c(cccc3c1Cl)C(=O)N(OCc1ccccc1)C2=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(C#N)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Yield: 63.9 %

Procedure:
Following the procedure of Example B2, 2-benzyloxy-6-chloro-5-cyano-benzo[de]isoquinoline-1,3-dione (0.20 g, 0.55 mmol, from Example A2), (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.11 g, 0.60 mmol), triethyl amine (0.11 g, 1.1 mmol) were reacted at ambient temperature for 5 hours. Column chromatography of the crude product on silica using chloroform/methanol (20:1) gave 0.18 g of the title compound.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:17]2[CH2:20][CH:19]([OH:21])[CH2:18]2)=[CH:4][CH:5]=1
Reactant: OC1CNC1
Reactant: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 1.5 h

Procedure:
The reaction mixture of 22.30 g (70.5 mmol) of 1-[bromo(4-chlorophenyl)methyl]-4-chlorobenzene, 5.67 g (77.6 mmol) of azetidin-3-ol (2) and 18.4 mL (105.75 mmol) of N,N-diisopropylethylamine in 250 mL of acetonitrile was rapidly stirred for 1.5 h at rt to 91° C. Reaction mixture was concentrated to remove solvents and residue was purified by silica gel chromatography with hexanes/ethyl acetate/ammonia (2M in MeOH)=100/30/0.5 to afford the title compound; 1NMR(CDCl3) δ 2.03 (br s, 1H), 2.81 (m, 2H), 3.55 (m, 2H), 4.34 (s, 1H), 4.50 (m, 1H), 7.29 (m, 4H), 7.34 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: Clc1ccnc2ccc(Br)cc12
Solvent: O
Product: Brc1ccc2nccc(N3CCOCC3)c2c1
Temperature: 150 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
A mixture of 6-bromo-4-chloro-quinoline (1.0 g, 4.12 mmol) and morpholine (9.98 g, 114.6 mmol) was heated to 150° C. in a sealed tube and stirred for 2 days. Then, the brown suspension was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.06 g (87.7% yield) of 6-bromo-4-morpholin-4-yl-quinoline as a light brown solid: EI-LRMS m/e calcd for C13H13BrN2O (M+) 293.1, found 293.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:19]([Cu])#[N:20]>CN(C)C=O.O>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:19]#[N:20])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[CH2:14][CH3:15]
Reactant: N#C[Cu]
Reactant: CCCN(CCC)c1nccc2ccc(Br)cc12
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)c1nccc2ccc(C#N)cc12
Temperature: 25 °C

Procedure:
A solution of 7-bromo-N,N-dipropylisoquinolin-1-amine (350 mg, 1.1 mmol) and CuCN (204 mg, 2.2 mmol) in N,N-dimethylformamide (2 mL) was stirred at reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organics were washed with saturated sodium chloride, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to provide 1-(dipropylamino)isoquinoline-7-carbonitrile (279 mg, which was used without any further characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](I)[N:11]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>C(NC(C)C)(C)C.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:32]#[C:31][CH2:30][CH2:29][OH:33])[N:11]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc(I)n(CCCc3ccccc3)c2-c2ccncc2)cc1
Reactant: C#CCCO
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: OCCC#Cc1nc(-c2ccc(F)cc2)c(-c2ccncc2)n1CCCc1ccccc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-(4-fluorophenyl)-2-iodo-1-(3-phenylpropyl)-5-(4-pyridyl)imidazole (1.42 g, 2.74 mmol) and 3-butyn-1-ol (0.289 g, 4.1 mmol) in diisopropylamine (10 mL) was added bis(acetato)-bis(triphenylphosphine) palladium (0.102 g, 0.14 mmol), followed by the addition of copper(I) iodide (0.052 g, 0.274 mmol). The mixture was stirred at 75° C. for 4 h. The reaction mixture was then cooled to room temperature and quenched with water (100 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extract was washed with water (2×30 mL), brine (30 mL), and dried with Na2SO4. After removal of solvents, the crude product was obtained as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1cccs1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3cccs3)c3ccccc23)CC1
Reaction time: 15 h

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 4 g (15 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 30 mL of a freshly prepared 2-bromomethyl-thiophene 0.61M solution in anhydrous ethyl ether. After standard work-up, 5.6 g (100% of yield) of the expected product was obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][N:12]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
NaH (37 mmol, 2 equiv.) was taken up in DMF (25 ml) and cooled to 0° C. 6-Nitro-1H-indole (18.5 mmol, 1 equiv.) was added in portions, and the mixture was stirred for 1 h at 25° C. The reaction mixture was cooled to 0° C. again, ethyl bromoacetate (22.22 mmol, 1.2 equiv.) was added dropwise, and the mixture was stirred for 2 h at 25° C. The reaction mixture was then poured into ice-water and extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with sat. NaCl solution (30 ml), dried over Na2SO4 and concentrated under reduced pressure. The product was crystallized from hexane and was used in the next step without being purified further. Yield: 57%
Reaction SMILES: C([Li])CCC.CCCCCC.C(OP([CH2:20][C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(OCC)=O)C.[CH2:29]([O:31][C:32]1[C:33](/[C:46](/[CH2:51][CH3:52])=[C:47](/[F:50])\[CH:48]=O)=[CH:34][C:35]2[C:36]([CH3:45])([CH3:44])[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[C:40]=2[CH:41]=1)[CH3:30]>C1COCC1.CN1CCCN(C)C1=O>[CH2:29]([O:31][C:32]1[C:33](/[C:46](/[CH2:51][CH3:52])=[C:47](/[F:50])\[CH:48]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:34][C:35]2[C:36]([CH3:44])([CH3:45])[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[C:40]=2[CH:41]=1)[CH3:30]
Reactant: CCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium and hexane (16.4 mL, 1.6 M, 26.2 mmol) was added over 20 minutes down the side of the flask into a stirring solution of ethyl 4-(diethoxyphosphoryl)-3-methylbut-2-enoate (6.92 g, 26.2 mmol referenced in text in THF (75 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (1.11 mL, available from Aldrich Chemical Co.) at −78° C. After 30 min, the mixture was treated with a solution of (E)-3-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enal (Intermediate 5, 3.55 g, 8.02 mmol) in THF (25 mL). The resulting solution was stirred for 2 h at 0° C. and then cooled again to −78° C. The reaction was quenched at −78° C. by adding saturated aqueous ammonium chloride. The solution was warmed to room temperature, and the products were extracted three times with ether. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound after purification by silica gel chromatography using a 94:6 mixture of hexane:ethyl acetate.
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)(=O)C>[O:4]1[C:5]2[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][C:6]=2[NH:7][CH2:2][CH2:3]1
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: NCc1ccc2c(c1)NCCO2
Yield: 63.6 %

Procedure:
3,4-Dihydro-2H-1,4-benzoxazine-6-ylmethyl)amine: a solution of 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carbonitrile (1.3 g ) in anhydrous TBF (20 mL) was slowly added to a stirred and ice -cooled solution of lithium aluminum hydride (30 mL, 1 M solution in THF). With continued cooling water (5 mmol) and sodium hydroxide (5 mL, 20% solution), water (20 mL) and ethyl acetate (30 mL) were added in succession. The organic solution was decanted from the white residue. The residue was washed twice with ether, all the organic solution were combined then dried over anhydrous sodium sulfate. Filtration and concentration followed by drying in vacuo afforded 3,4-dihydro-2H-1,4-benzoxazine-6-ylmethylamine (0.78 g,): 1H NMR (400 MHz; DMSO-D6): 6.52 (d, 1H); 6.49 (s, 1H); 6.37 (d, 1H); 5.6 (br s, NH); 4.05 (t, 2H); 3.4 (m, 2H).
Reaction SMILES: C(OC[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[C:8]=1[S:16]([CH3:19])(=[O:18])=[O:17])C.FC(F)(F)C(O)=O>ClCCl>[CH3:19][S:16]([C:8]1[C:9]2[O:15][CH2:14][O:13][C:10]=2[CH:11]=[CH:12][C:7]=1[CH2:6][OH:5])(=[O:17])=[O:18]
Reactant: CCOCOCc1ccc2c(c1S(C)(=O)=O)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1c(CO)ccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
571 mg of 1-[(ethoxymethoxy)methyl)-2-(methylsulfonyl)-3,4-methylenedioxybenzene was dissolved in 2 ml of dichloromethane, 2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), to give 308 mg of the title compound as a colorless oil.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccnc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-fluoro-3-nitropyridine (2.5 g, 17.6 mmol), 4-fluorobenzyl-amine (4.40 g, 35.2 mmol), and N,N-diisopropyl-N-ethylamine (4.55 g, 35.2 mmol) in anhydrous acetonitrile (30 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue partitioned between water and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 15% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the 2-(4-fluorobenzylamino)-3-nitropyridine intermediate as yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21](O)=O)=[CH:20][C:8]=2[N:7]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[SH:42]>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21]3[S:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)=[CH:20][C:8]=2[N:7]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccc1S
Reactant: CC(=O)OCc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 117.5 %

Procedure:
A 4-neck flask (500 mL) equipped with a reflux condenser was charged with 2-acetoxymethyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid (5.98 g, 18.79 mmol), anhydrous tetrahydrofuran (158 mL), and oxalyl chloride (2.86 g, 22.50 mmol), and anhydrous N,N-dimethylformamide (1 mL) was then added dropwise at room temperature, after which the reaction mixture was stirred at 50° C. for 5 hours. After being allowed to cool to room temperature, the solvent was distilled off under reduced pressure to give a pale yellow residue, which was taken up in anhydrous tetrahydrofuran (100 mL), and then 2-aminobenzenethiol (2.35 g, 18.79 mmol) was added, and this was stirred for 19 hours at 50° C. This was allowed to cool to room temperature, and after the precipitated crystals were filtered off, they were successively washed with distilled water and dried under reduced pressure with heating to yield the title compound (9.00 g, quant.) as a white solid.