Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=1>C1COCC1>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: O=c1cc(CBr)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(Cn2cc(I)cn2)cc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (19 mg, 0.48 mmol, 60 wt %) was added to a solution of 4-iodo-1H-pyrazole (47 mg, 0.24 mmol) in THF (2 mL) at 0° C. After 30 minutes, 4-(bromomethyl)pyridin-2(1H)-one (30 mg, 0.16 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/MeOH) to afford 4-((4-iodo-1H-pyrazol-1-yl)methyl)pyridin-2(1H)-one. MS ESI calc'd. for C9H9IN3O [M+H]+ 302. found 302. 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.05 (s, 1H), 7.61 (s, 1H), 7.32 (d, J=6.8 Hz, 1H), 5.93-5.90 (m, 2H), 5.19 (s, 2H).
Reaction SMILES: C([Si](C)(C)OCC1C=CC(NC(=O)CCN(C)[C@H]2CC[C@H](OC(C3SC=CC=3)(C3SC=CC=3)C([O-])=O)CC2)=C(Cl)C=1)(C)(C)C.Cl.[OH:46][C:47]([C:80]1[S:81][CH:82]=[CH:83][CH:84]=1)([C:75]1[S:76][CH:77]=[CH:78][CH:79]=1)[C:48]([O:50][C@H:51]1[CH2:56][CH2:55][C@H:54]([N:57]([CH2:59][CH2:60][C:61]([NH:63][C:64]2[CH:69]=[C:68](OC)[C:67]([CH2:72][OH:73])=[CH:66][C:65]=2[Cl:74])=[O:62])[CH3:58])[CH2:53][CH2:52]1)=[O:49]>O1CCCC1>[OH:46][C:47]([C:75]1[S:76][CH:77]=[CH:78][CH:79]=1)([C:80]1[S:81][CH:82]=[CH:83][CH:84]=1)[C:48]([O:50][C@H:51]1[CH2:56][CH2:55][C@H:54]([N:57]([CH2:59][CH2:60][C:61]([NH:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:72][OH:73])=[CH:66][C:65]=2[Cl:74])=[O:62])[CH3:58])[CH2:53][CH2:52]1)=[O:49]
Reactant: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO
Agent: CN(CCC(=O)Nc1ccc(CO[Si](C)(C)C(C)(C)C)cc1Cl)[C@H]1CC[C@H](OC(C(=O)[O-])(c2cccs2)c2cccs2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CN(CCC(=O)Nc1ccc(CO)cc1Cl)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1

Procedure:
Obtained as a beige foam (91%) starting from trans-4-((3-(4-((tert-butyl(dimethyl)-silyloxy)methyl)-2-chlorophenylamino)-3-oxopropyl)(methyl)amino)-cyclohexylhydroxy-(di-2-thienyl)acetate (intermediate 48; 433 mg, 0.64 mmol) and 1M hydrochloric acid (1.9 ml; 1.9 mmol) in tetrahydrofuran (12 mL) following the experimental procedure as described for intermediate 42.
Reaction SMILES: [Cl:1][C:2]([Cl:9])=[CH:3][C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].[BH4-].[Na+]>>[Cl:1][C:2]([Cl:9])=[CH:3][CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C(=O)C=C(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)C(O)C=C(Cl)Cl

Procedure:
Surprisingly, however, it has been found that 1,1-dichloro-4-methyl-pent-1-en-3-one can be reduced with alkali metal borohydrides, preferably sodium borohydride, to give 1,1-dichloro-4-methyl-3-hydroxy-pent-1-ene in virtually quantitative yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]#N)[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@:10]1([C:16]([O:18][CH2:19][CH3:20])=C)[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([OH:26])[CH3:25]>[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([N:8]1[C@H:9]2[C@:10]([OH:15])([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:16]([O:26][CH2:24][CH3:25])([O:18][CH2:19][CH3:20])[CH2:22][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: C=C(OCC)[C@@]1(O)CCCC[C@H]1N(CC#N)Cc1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCOC1(OCC)CCN(Cc2ccccc2)[C@@H]2CCCC[C@@]21O
Reaction time: 1 h

Procedure:
To silver nitrate (125 mg, 0.735 mmol) in Ethanol (27.00 ml) at room temperature was added {Benzyl[(1R,2R)-2-(1-ethoxyethenyl)-2-hydroxycyclohexyl]amino}acetonitrile (220 mg, 0.700 mmol) in 10 ml of absolute ethanol. The reaction mixture was stirred for an addition 1 hr. Another 125 mg of Silver Nitrate was added and the reaction was stirred overnight. The reaction mixture was filtered through a pad of celite, concentrated. The residue was purified by column chromatography (dry load) on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) to give the title compound. 1H-NMR (500 MHz, CDCl3) 2-4: δ 7.20-7.36 (m, 5H), 4.07 (d, 1H), 3.74 (dt, 1H), 3.62 (dt, 1H), 3.52 (dt, 1H), 3.41 (dt, 1H), 3.28 (bs, 1H), 3.06 (d, 1H), 2.61 (m, 1H), 2.00-2.14 (m, 2H), 1.88-1.98 (m, 2H), 1.70-1.80 (m, 2H), 1.54-1.62 (m, 2H), 1.22-1.44 (m, 2H), 1.18 (t, 6H). LRMS m/z (M+H) Calcd:334.5. found: 334.5.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]1[CH2:29][CH2:28][O:27]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[CH:26]2[CH2:29][CH2:28][O:27]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: Brc1cnccc1C1CCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cnccc2C2CCO2)cc1Cl
Temperature: 100 °C
Yield: 9.2 %

Procedure:
To the solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (569 mg, 2.16 mmol), 3-bromo-4-(oxetan-2-yl)pyridine (462 mg, 2.16 mmol) and PdCl2(dppf).CH2Cl2 adduct (176 mg, 0.216 mmol) in DMF (10 mL) was added a solution of Na2CO3. (2 M, 2.70 ml, 5.40 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. Reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layer was extracted with EtOAc. The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. Purification by ISCO 12 g (0-40% EtOAc/Heptane) to give 2-chloro-4-(4-(oxetan-2-yl)pyridin-3-yl)benzonitrile (54 mg, 9%) as colorless solid; ESI-MS m/z: 271 [M+H]+, Retention time 1.42 min. 1H-NMR (MeOD, 400 MHz) δ 2.58-2.67 (m, 1H), 2.82-2.90 (m, 1H), 4.61-4.67 (m, 1H), 4.77-4.83 (m, 1H), 5.88 (t, J=7.6 Hz, 1H), 7.46 (dd, J=8.0, 1.2 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.96 (d, J=4.8 Hz, 1H), 8.47 (s, 1H), 8.74 (d, J=4.8 Hz, 1H);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].S(=O)(=O)(O)O.O[CH2:16][CH:17]([CH2:19]O)O>[N+](C1C=CC=CC=1)([O-])=O>[F:8][C:4]1[C:3]([OH:9])=[C:2]2[C:7]([CH:16]=[CH:17][CH:19]=[N:1]2)=[CH:6][CH:5]=1
Reactant: Nc1cccc(F)c1O
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1c(F)ccc2cccnc12
Temperature: 140 °C
Yield: 51.8 %

Procedure:
To a solution of 2-amino-6-fluorophenol (4.0 g, 31.6 mmol) and nitrobenzene (20 mL) in a sealable reaction vessel was added in portions sulfuric acid (4.0 mL). Glycerol (12.0 g, 126 mmol) was added in one portion, and the solution turned to dark brown. The vessel was flushed with nitrogen, sealed and heated to 140° C. for 6 h. The reaction mixture was cooled to rt, diluted with 30 mL ice/water mixture, and washed 3 times with methyl t-butyl ether (removes most of the nitrobenzene). The aqueous phase was neutralized to pH=6-7 by slow addition of 6N NaOH. The resulting black precipitate was collected and the water solution was extracted with ethyl acetate 3 times. The organic extracts were combined with the black precipitate, concentrated in vacuo, and purified on silica gel column with 0-10% MeOH/DCM to give 2.67 g (51.7%) of 7-fluoro-8-quinolinol as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)glycine (4.0 g, 23 mmol), N,O-dimethylhydroxylamine hydrochloride (3.0 g, 31 mmol) and N,N-dimethylpyridin-4-amine (300 mg, 2.5 mmol) in dry CH2Cl2 (100 mL) was added N-(3-dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (5.2 g, 27 mmol) followed by triethylamine (5.4 mL, 39 mmol) at 0° C. The mixture was stirred at that temperature 30 minutes and then at room temperature over 3 days. The suspension was washed with aqueous HCl (1 M, 2×40 mL) followed by a saturated aqueous solution of NaHCO3 (2×40 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate as a white solid (4.5 g, yield 90%). 1H-NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 3.20 (s, 3H), 3.71 (s, 3H), 4.08 (br s, 2H), 5.26 (br s, 2H).
Reaction SMILES: [S:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=O)[C:9](=[O:14])[NH:8]3)[N:3]=[CH:2]1.Cl.[F:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1>C(O)C>[F:16][C:17]1[CH:18]=[C:19]([NH:23][N:24]=[C:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]4[N:3]=[CH:2][S:1][C:12]4=3)[NH:8][C:9]2=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: NNc1cccc(F)c1
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Agent: Cl
Solvent: CCO
Product: O=C1Nc2ccc3ncsc3c2C1=NNc1cccc(F)c1
Temperature: 70 °C
Yield: 60.2 %

Procedure:
6H-1-Thia-3,6-diaza-as-indacen-7,8-dione (Procedure A, 50 mg, 0.25 mmol) was combined with 3-fluorophenylhydrazine hydrochloride (50 mg, 0.3 mmol) in 2 ml of ethanol and heated at 70° C. for 6 hrs. The product was collected by filtration of the hot solution, washing with ethanol and diethyl ether, to give 47 mg (60%) of the title compound as a brown solid. 1H NMR (DMSO-d6): δ 6.82 (t, J=8.7 Hz, 1H); 7.10 (d, J=8.6 Hz, 1H); 7.37 (m, 2H); 7.41 (dd, 1H); 7.97 (d, J=8.6 Hz, 1H); 9.25 (s, 1H); 11.2 (s, 1H). ES-MS m/z 311 (M−1)−.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11].S(OC)(O[CH3:16])(=O)=O>O>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH3:16]
Reactant: Cc1cccc(C)c1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cccc1C
Temperature: 60 °C
Yield: 57.3 %

Procedure:
Sodium hydroxide (20 g, 500 mmol) was dissolved in distilled water (200 mL) and placed in a round-bottom flask fitted with a reflux condenser. To the solution were added sequentially 2,6-dimethylphenol (1, 61 g, 500 mmol) and dimethyl sulfate (48 mL, 500 mmol). The mixture was heated at 60° C. for about 17 h, cooled, and transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with benzene. The combined organic layers were washed sequentially with 10% aq. sodium hydroxide and brine, and dried (MgSO4). Concentration of the solution gave 2,6-dimethylanisole (2, 39 g, 57% yield), bp 179°-182° C./750 torr (lit.: Burton, G. W.; Joyce, A.; Ingold, K. U. Arch. Biochem. Biophys., 1982, 221, 281; 181° C.), as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[C:5]([NH2:18])[CH:4]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:19][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([NH:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH:6]=[C:7]([B:9]2[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:15])[O:13]2)[CH:8]=1
Reactant: CN(C)c1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)c1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
N1,N1-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-diamine (324 mg, 1.24 mol) was dissolved in 11 mL pyridine. The mixture was submitted to three vacuum-argon cycles and was cooled at 0° C. with an ice bath. Methanesulfonyl chloride (110 μl, 1.42 mol) was added dropwise and the reaction mixture was stirred overnight. The solvent was concentrated and the residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. The semi-solid was crystallized in hexane to obtain a solid that was filtered off and dried in the oven to give 365 mg (87% yield) of the final compound as a mixture of boronic acid and boronate ester. Purity 100%.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[F:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[F:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:26])[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=1[CH2:9][OH:8]
Reactant: CCOC(=O)C(Cc1ccc(F)c(CO[Si](C)(C)C(C)(C)C)c1)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(F)c(CO)c1)OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.8 %

Procedure:
1.2 g of Ethyl 3-[3-(t-butyldimethylsilanyloxymethyl)-4-fluorophenyl]-2-isopropoxypropionate was dissolved in 15 ml of tetrahydrofuran, and 3.3 ml of 1.0M tetrabutyl ammonium fluoride in tetrahydrofuran was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (30% ethyl acetate-hexane), to give 1.0 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([F:15])[C:9]([OH:14])=[C:10]([F:13])[CH:11]=2)[O:6][C:5](=[O:16])[CH:4]=1.S(=O)(=O)(O)[OH:18]>[OH-].[Na+]>[F:13][C:10]1[C:9]([OH:14])=[C:8]([F:15])[C:7]2[O:6][CH:2]=[C:3]([CH2:4][C:5]([OH:16])=[O:18])[C:12]=2[CH:11]=1
Reactant: O=c1cc(CCl)c2cc(F)c(O)c(F)c2o1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1coc2c(F)c(O)c(F)cc12

Procedure:
4-Chloromethyl-6,8-difluoro-7-hydroxy-2-chromenone (0.2 g, 0.81 mmol) obtained in Step A was dissolved in 1N NaOH aqueous solution (8 mL), and the mixture was stirred under reflux for 2 hours. The reactant was acidified by the addition of sulfuric acid, and then extracted with EtOAc. The organic layer was dried with MgSO4, and distilled under reduced pressure to obtain the title compound (0.16 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH:11]=[CH:10][CH:9]=1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>COCCOC.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:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Reactant: OB(O)c1ccc(-c2ccccc2)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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3)C2=N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (32.9 mg) was added to a mixture of 2M aqueous sodium carbonate solution (0.428 mL), 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) and biphenyl-4-ylboronic acid (135 mg) in 1,2-dimethoxyethane (5.701 ml). The reaction mixture was stirred under a nitrogen atmosphere at 100° C. overnight, added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, then ethyl acetate/methanol) to give the title compound (44.5 mg) as a pale-brown solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)=[O:15].CS(C)=O>C(#N)C>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)=[O:15]
Reactant: CNCCO
Reactant: NC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Solvent: CS(C)=O
Solvent: CC#N
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(N)=O)cc1
Temperature: 25 °C

Procedure:
2-(Methylamino)ethanol (9.5 g, 7 equivalents) is added to a stirred mixture of 4-[(8-bromooctanoyl)amino]benzamide (5.76 g, 16.9 mmol, e.g. which can be as prepared in Intermediate 53 (first or alternative preparation thereof)) and dimethyl sulfoxide (30 mL). The mixture is stirred at 25° C. until the reaction is substantially complete and is then diluted with acetonitrile (115 mL). After stirring for 1 hour the mixture is filtered, washed with ethyl acetate (15 mL) and tert-butyl methyl ether (TBME, 15 mL) before being dried in vacuo to yield the title compound, generally as a solid.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:7])=[O:6].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:3][C@@H:2]([C@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][N+:5]([O-:7])=[O:6])[CH:1]=[O:4]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCC=O
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from propionaldehyde and (E)-(2-nitrovinyl)benzene according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC withan OD-H column at 210 nm (2-propanol:hexane=10:90), 1.0 mL/min; major enantiomer tmajor=22.06 min, minor enantiomer tminor=30.05 min. [α]D20=−28.8 (c=2.2, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7]([OH:9])=O.Cl.[NH2:21][CH2:22][CH2:23][C:24]1[CH:41]=[CH:40][C:27]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7]([NH:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:40][CH:41]=1)=[O:9]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Reactant: COC(=O)c1ccccc1COc1ccc(CCN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1COc1ccc(CCNC(=O)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (50 mg, 0.174 mmol) and methyl 2-{[4-(2-aminoethyl)phenoxy]methyl}benzoate hydrochloride (59 mg, 0.183 mmol) were mixed in DMF (4 ml) and the mixture was then cooled in an ice-bath. TBTU (59 mg, 0.183 mmol) was added and followed by DIPEA (47.2 mg, 0.366 mmol). The mixture was stirred at room temperature overnight. Ethyl acetate and sodium hydrogencarbonate aqueous solution (sat.) were added. The two phases were separated. The organic phase was washed with water and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM and then MeOH/DCM (0.5:99.5) as eluant gave 59 mg the desired product, white solid, yield 61%.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[C:29]([CH:32]1[NH:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1)(=[O:31])[NH2:30]>CC#N>[CH:10]([N:8]1[CH2:9][CH:6]([N:37]2[CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:33][CH:32]2[C:29](=[O:31])[NH2:30])[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C(N)=O)C1
Yield: 54 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-yl methanesulfonate (2.69 g, 8.5 mmol), K2CO3 (1.76 g, 12.8 mmol), tert-butyl 3-carbamoylpiperazine-1-carboxylate (1.95 g, 8.5 mmol) in CH3CN (40 mL) was stirred at reflux for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product. (2.08 g, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[C:24]2[NH:23][N:22]=[CH:21][C:20]=2[C:19]2[CH2:25][N:26]([CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:27](=[O:50])[C@@H:28]([CH2:30][C:31](=[O:49])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:29][C:18]=2[CH:17]=1>>[Cl:15][C:16]1[C:24]2[NH:23][N:22]=[CH:21][C:20]=2[C:19]2[CH2:25][N:26]([CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:27](=[O:50])[C@H:28]([CH2:30][C:31]([N:12]3[CH2:11][CH2:10][CH:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[CH2:14][CH2:13]3)=[O:49])[CH2:29][C:18]=2[CH:17]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: Clc1ccc(C2CCNCC2)c(Cl)c1
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3ccc(Cl)cc3Cl)CC2)C1=O
Yield: 40 %

Procedure:
4-(2,4-Dichlorophenyl)-piperidine (32 mg, 0.0.8 mmol) and [4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid (25 mg, 0.07 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as off-white solid in 40% yield. High resolution MS m/e (M+H)+=575.1747.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.Cl.[F:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[F:25][CH2:26][C:27]([NH:30][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:29])[CH3:28]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CC(C)(N)CF
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CF)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
WSC HCl (1.15 g, 6 mmol) was added to a mixture of 2,4-difluorobenzoic acid (0.95 g, 6 mmol), 2-fluoro-1,1-dimethylethylamine hydrochloride (J. Med. Chem., 34, 29-37(1991): 0.77 g, 6 mmol), HOBt (0.81 g, 6 mmol) and triethylamine (0.91 g, 9 mmol) in methylene chloride (15 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with saturated aqueous NaHCO3, 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=20/1) to give the title compound (0.61 g: 44%).
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#N.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])#[N:10]>>[C:9]([C:11](=[CH:4][CH:3]=[CH2:1])[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: C=CCOC(=O)CC#N
Product: C=CC=C(C#N)C(=O)OCC=C

Procedure:
Allyl 2-cyanopenta-2,4-dienoate was prepared by the method described in Example 1 by replacing ethyl cyanoacetate by an equivalent quantity of allyl cyanoacetate. The yield of product from this reaction was 80%. The structure of the product was confirmed by an infra-red spectrum.