Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:14][CH:13]=2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:54][N:55]=[CH:56]C(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:54][N:55]([CH3:56])[C:9](=[O:10])[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:14][CH:13]=1)[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCCC1)c1ccc(OCc2ccccn2)cc1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Agent: N
Product: CN(O)C(=O)C(CC1CCCCC1)c1ccc(OCc2ccccn2)cc1

Procedure:
The desired material was prepared according to the procedures described in Example 5 substituting 3-cyclohexyl-2-[4-(pyrid-2-yl-methoxy)phenyl]propionic acid for {[1-(3-[2-naphthylmethoxyl]phenyl)-4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 0.85 (m, 2H), 1.1 (m, 4H), 1.43 (m, 1H), 1.6 (m, 5H), 1.8 (m, 1H), 3.04 (s, 3H), 4.25 (m, 1H), 5.24 (s, 2H), 6.93 (d, J=7Hz, 2H), 7.2 (d, J=7Hz, 2H), 7.33 (m, 1H), 7.5 (d, J=7Hz, 1H), 7.82 (dt, J=7Hz, 2Hz, 1H), 8.58 (m, 1H), 9.8 (bs, 1H). IR (CDCl3): 3620, 3440, 1610 with shoulder 1660 cm-1. MS (DCI/NH3) m/e 369 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.O.[OH-].[Li+].O.Cl>C1COCC1.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2c(F)cccc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(-c2c(F)cccc2F)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate (1.72 g, 6.39 mmol) in THF (40.0 mL), lithium hydroxide monohydrate (1.51 g, 36.0 mmol) was added followed by water (10.0 mL). The mixture was stirred at 60° C. for 5 h. The reaction mixture was then cooled to 0° C., and 6 M HCl was added slowly until the pH reached 2. The mixture was diluted with EtOAc (250 mL), washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-30% MeOH in DCM) to give the title compound as a white solid (1.49 g, 97%). LCMS calc. for C10H6F2NO2S (M+H)+: m/z=242.0. found 242.0.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])=[CH:7][CH:6]=1.Cl(O)(=O)(=O)=[O:20].ClCCl.CO>CC(C)=O.O>[OH:20][CH:2]([CH2:18][OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12](=[O:17])[CH:13]=[CH:14][C:15]2=[O:16])=[CH:9][CH:10]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: O=C1C=CC(=O)N1c1ccc(OCC2CO2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1C=CC(=O)N1c1ccc(OCC(O)CO)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of N-(4-[2,3-epoxypropyl]oxyphenyl)maleimide (200 g, 0.816 mole) in 1360 ml of acetone was added perchloric acid (20 ml) in 660 ml of water. The reaction mixture was refluxed for 2 h, during which the solution became clear yellow (complete conversion on TLC, dichloromethane: methanol 90:10). After cooling, the acetone was removed under reduced pressure. Water was added to the resulting slurry which was stirred for 0.5 h. The solids were filtered off, washed with water and dissolved in THF (tetrahydrofuran). This solution was dried twice over anhydrous sodium sulfate, followed by concentration to dryness.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:11]=1[C:12]([NH:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])=[O:13].C(N(CC)CC)C>O1CCOCC1>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:15]1[N:14]=[C:12]([C:11]2[C:10]([F:9])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[O:13][C:2]1=[O:3]
Reactant: O=C(NNc1ccccc1Br)c1c(F)cccc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=c1oc(-c2c(F)cccc2F)nn1-c1ccccc1Br

Procedure:
2.3 ml (19 mmol) of trichloromethyl chloroformate are added dropwise at 10°-20° C. to a mixture of 5.34 g (16 mmol) of 2,6-difluoro-N'-(o-bromophenyl)-benzhydrazide and 5.50 ml (40 mmol) of triethylamine in 35 ml of dioxan. The reaction mixture is heated at the reflux temperature for a further 3 hours and the solvent and excess reagent are subsequently distilled off under reduced pressure. The residue is taken up in diethyl ether and the solution is washed in each case once with water and sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After crystallization of the residue from acetone/n-hexane there is obtained pure 3-(2-bromophenyl)-5-(2,6-difluorophenyl)-1,3,4-oxadiazol-2(3H)-one, m.p. 111°-114° C.; IR spectrum: 1790 cm-1 ; mass spectrum: 354/352(15), 310/308(7), 171/169(41), 90(100).
Reaction SMILES: C1(=O)OCCC1.[NH2:7][CH2:8][C:9](O)=O.[N:12]1([CH2:18][C:19]([OH:21])=O)[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(CN)O>>[O:21]1[CH2:9][CH2:8][N:7]=[C:19]1[CH2:18][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]
Reactant: O=C(O)CN1CCCC1=O
Reactant: NCC(=O)O
Solvent: NCCO
Solvent: O=C1CCCO1
Product: O=C1CCCN1CC1=NCCO1

Procedure:
--[(2-oxazolin-2-yl)methyl]-2-pyrrolidone, for example, can be obtained by condensation of pyrrolidone and chloroacetic acid to form 2-pyrrolidone acetic acid, where m =I in the above formula (II), or, alternatively, by condensing butyrolactone with glycine, and the starting carboxylic acid condensed with ethanolamine and cyclodehydrated to form 1-[(2-oxazolin-2-yl)methyl]-2-pyrrolidone.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(C(=O)O)cc1
Yield: 97.4 %

Procedure:
A mixture of 2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid ethyl ester of Step A (3.7 g, 14.4 mmol) in tetrahydrofuran (40 mL) and 1 N sodium hydroxide (30 mL, 30 mmol) was heated at reflux overnight. After cooling, the reaction mixture was concentrated in vacuo, and the residue was acidified with 2N hydrochloric acid to give a white solid which was collected by filtration and dried under vacuum to provide the title compound (3.2 g, 97.4%) as a white solid, m.p. 250–253° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(Cl)Cl>C1(C)C(C)=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:15]=[C:16]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Nc1ccc(Br)cc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: Brc1ccc(-n2c(-c3ccccc3)nc3ccccc32)cc1
Yield: 50.2 %

Procedure:
2.1 g (5.7 mmol) of N-[2-(4-bromophenylamino)phenyl]benzamide was suspended in 30 mL of xylene. After the addition of 0.6 g (2.9 mmol) of p-toluenesulfonic acid monohydrate, the mixture was subjected to azeotropic dehydration under reflux for 3 hours. After allowing the reaction solution to cool, ethyl acetate, methylene chloride, and water were added to the reaction solution, and an insoluble component was removed by filtration. The organic phase was extracted from the mother filtrate, washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.0 g of 1-(4-bromophenyl)-2-phenyl-1H-benzimidazole as a slightly pinkish white crystal (yield: 52%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH:23]2[C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1>O1CCOCC1.CC(O)(C)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:48]1([CH3:51])[CH:49]=[CH:50][C:45]([NH:44][C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]3[C:28](=[O:37])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)[C:5]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:46][CH:47]=1
Reactant: COc1ccc(-c2ccc3nc(Cl)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Reactant: Cc1ccc(N)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(-c2ccc3nc(Nc4ccc(C)cc4)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.4 %

Procedure:
A white suspension of 2-chloro-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine (104 mg, 0.2 mmole), K2CO3 (64 mg, 0.46 mmole), and p-toluidine (46 mg, 0.43 mmole) in a mixture of 1,4-dioxane/t-BuOH 5:1 (2 ml) was stirred at room temperature under nitrogen for 5 minutes. Thereafter, tetrakis(triphenylphosphine)palladium(0) (26 mg, 23 μmole) was added and the reaction mixture was heated at reflux under a N2 atmosphere for 48 hours. Upon cooling, the mixture was diluted with water and extracted three times with ethyl acetate (brine added). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography on silica using an ethyl acetate/n-hexane mixture as the mobile phase (in a ratio gradually ranging from 1:1 to 3:1), resulting in the pure title compound (30 mg, yield 25%) which was characterized by its mass spectrum as follows: MS (m/z): 590 ([M+H]+, 100).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[C:23]1[CH2:24]CNC[CH:28]=1>>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[C:23]1[CH2:24][CH2:3][N:2]([CH2:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:1][CH:28]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Product: C1=C(c2cc3ccccc3s2)CCN(Cc2c[nH]c3ncccc23)C1

Procedure:
Reaction of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine and 4-(benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine in an analogous manner to Example 4 gave the title compound, m.p. 241°-246° C. (dec.); (Found: C, 72.85; H, 5.54; N, 12.06; C21H19N3S requires C, 73.01; H, 5.54; N, 12.16%); δH (DMSO-d6) 2.51 (2H, br s, tetrahydropyridinyl CH2), 2.67 (2H, m, tetrahydropyridinyl CH2), 3.14 (2H, m, tetrahydropyridinyl CH2), 3.76 (2H, s, CH2N), 6.19 (1H, br s, CH=CR), 7.03 (1H, m, ArH), 7.31 (2H, m, 3'-H and ArH), 7.74 (1H, d, J 8 Hz, ArH), 7.86 (1H, d, J 8 Hz, ArH), 8.05 (1H, d, J 8 Hz, ArH), 8.20 (1H, m, ArH), and 11.45 (1H, br s, NH); m/z (CI+, NH3) 346 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23](O)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 53.7 %

Procedure:
N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-fluoro benzohydrazide was prepared using 4-fluorobenzoic hydrazide (4.4 mmol, 1.1 equiv.) and (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (4.0 mmol, 1.0 equiv.) as described previously in the preparation of intermediate 5a. The crude golden yellow solid was recrystallized using hot methylene chloride to provide the desired product as a light yellow solid (870 mg, 54% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.85 (br. s., 1H), 9.5 (br. s., 1H), 8.02 (dd, J=5.4, 8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.5 Hz, 1H), 5.59 (br. d, J=6.8 Hz, 1H), 4.70 (br. s., 1H), 4.24 (m, 1H), 4.12 (dd, J=4.9, 7.3 Hz, 1H), 2.35 (s, 3H), 1.38 (d, J=6.3 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H18ClFN4O3 [M]+ 404.82. found 405.4; TLC Rf=0.38, 100% EtOAc, vanillin stain.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:31]#[N:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCC#N)c(-c3ccccc3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (63.0 mg) and triethylamine (22.8 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (18.9 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was added to sodium cyanide (14.7 mg) in dimethylformamide (2 mL) and the mixture was stirred at 60° C. for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1–5:1) to give 6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]hexanenitrile as an yellow oil (58.5 mg).
Reaction SMILES: [NH:1]([C:3]1[C:4]([O:11][CH3:12])=[N:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)[NH2:2].[F:13][C:14]([F:26])([F:25])[C:15](=O)[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:10][O:9][C:6]1[N:5]=[C:4]([O:11][CH3:12])[C:3]([N:1]2[C:15]([C:14]([F:13])([F:25])[F:26])=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:2]2)=[CH:8][N:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)C(F)(F)F
Reactant: COc1ncc(NN)c(OC)n1
Product: CCOC(=O)c1cc(C(F)(F)F)n(-c2cnc(OC)nc2OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using 5-hydrazinyl-2,4-dimethoxypyrimidine (Step 46.8) and ethyl 5,5,5-trifluoro-2,4-dioxopentanoate at 100° C. for 2 hr. The crude product was purified by silica gel column chromatography (hexane/30% EtOAc). tR: 1.09 min (LC-MS 2); ESI-MS: 347 [M+H]+ (LC-MS 2); Rf=0.31 (hexane/30% EtOAc).
Reaction SMILES: [F:1][C:2]1[C:14]([Sn](C)(C)C)=[CH:13][C:5]2[CH2:6][C:7](=[O:12])[CH:8]3[CH2:11][CH:10]([C:4]=2[CH:3]=1)[CH2:9]3.[I:19]I.BrC1C(F)=CC2C3CC(C(=O)CC=2C=1)C3.[SnH4]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:14]([I:19])=[CH:13][C:5]2[CH2:6][C:7](=[O:12])[CH:8]3[CH2:11][CH:10]([C:4]=2[CH:3]=1)[CH2:9]3
Reactant: C[Sn](C)(C)c1cc2c(cc1F)C1CC(C1)C(=O)C2
Reactant: II
Agent: O=C1Cc2cc(Br)c(F)cc2C2CC1C2
Agent: [SnH4]
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cc(I)c(F)cc2C2CC1C2
Yield: 45 %

Procedure:
To a rapidly stirred solution of crude of 3-fluoro-2-(trimethylstannyl)-6,7-dihydro-5H-5,7-methanobenzo[7]annulen-8(9H)-one (3.09 g at 37% purity LCMS-UV215) in chloroform (20 mL) at room temperature was introduced dropwise a solution of iodine (1.488 g, 5.86 mmol, 1.0 equivalent with respect to number of moles 5-bromo-4-fluorotricyclo[8.1.1.02,7]dodeca-2(7),3,5-trien-9-one used for stannane synthesis in previous synthetic step, as a saturated solution in chloroform). Following addition of the iodine solution, the reaction mixture was evaporated directly onto silica gel in vacuo. The dry-loaded material was purified by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) to furnish the title compound (0.835 g, 2.64 mmol, 45% over 2 steps) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 2.08-2.14 (m, 2H), 2.87-2.96 (m, 2H), 3.22-3.28 (m, 1H), 3.48 (td, J=8.28, 3.63 Hz, 1H), 4.11 (s, 2H), 6.78 (d, J=8.51 Hz, 1H), 7.53 (d, J=6.31 Hz, 1H); M+H=317
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:29][S:30][C:31](SC)=[N:32][C:33]#[N:34].CCOCC>C(O)(C)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:31](=[N:32][C:33]#[N:34])[S:30][CH3:29])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CSC(=NC#N)SC
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)C1=C(COCCNC(=NC#N)SC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 4 h

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.3 g) and dimethyl N-cyanoimidodithiocarbonate (2 g) in isopropanol (15 ml) were allowed to stand at room temperature for 4 hours. Ether (30 ml) was then added and the mixture was stood at room temperature overnight. The crystalline precipitate was filtered, washed with ether and dried, yield of the title compound 5.0 g, m.p. 177°-179°.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:38][CH2:37][C:36]([F:40])([F:39])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:40][C:36]1([F:39])[CH2:37][CH2:38][N:34]([CH:32]2[CH2:33][N:30]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:31]2)[CH2:35]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1(F)CCN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)(F)C4)C3)n(C)c2n1
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 1-azetidin-3-yl-3,3-difluoropyrrolidine (46 mg, 0.28 mmol) and 4 Å powdered molecular sieves in DCE (6 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.52 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording 589 as an orange foam (97 mg, 69%). LCMS (method I): RT 2.74 min [M+H]+ 538.2 1H NMR (CDCl3, 300 MHz): δ 8.00 (m, 1 H), 7.75 (m, 1 H), 7.27 (m, 2 H), 4.42-4.27 (m, 4 H), 3.87-3.84 (m, 9 H), 3.54 (t, J=6.5 Hz, 2 H), 3.32-3.30 (m, 3 H), 3.19 (t, J=6.5 Hz, 2 H), 2.89 (t, J=13.1 Hz, 2 H), 2.70 (t, J=6.9 Hz, 2 H), 2.29-2.28 (m, 2 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C[Sn]([N:5]=[N+:6]=[N-:7])(C)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:40]=[CH:39][C:24]4[O:25][CH2:26][C:27]5[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=5[CH:29]([S:30][CH2:31][CH2:32][C:33]#[N:34])[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:40]=[CH:39][C:24]4[O:25][CH2:26][C:27]5[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=5[CH:29]([S:30][CH2:31][CH2:32][C:33]5[NH:34][N:7]=[N:6][N:5]=5)[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: N#CCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: Clc1ccc2ccc(COc3ccc4c(c3)C(SCCc3nnn[nH]3)c3ccccc3CO4)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.6 %

Procedure:
1.25 g of trimethyltin azide was added to 1.4 g of 2-(7-chloroquinolin-2-yl)methoxy-11-(2-cyanoethylthio)-6,11-dihydrodibenz[b,e]oxepine dissolved in 40 ml of xylene and the mixture was refluxed under heating for 8.5 hours. After cooling, 1.5 ml of conc. hydrochloric acid was added to the mixture and the mixture was stirred at room temperature for 15 minutes and then adjusted to about pH 4 with a 1N-sodium hydroxide aqueous solution. Crystals precipitated were applied to silica gel column chromatography to obtain 70 mg of the title compound as light orange powder.