Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([NH:20][CH:21]=[O:22])[CH:6](O)[C:7](=[CH2:18])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].S(Br)([Br:26])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([NH:20][CH:21]=[O:22])[CH:6]=[C:7]([CH2:18][Br:26])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCOCc1ccccc1)C(O)C(NC=O)C(=O)OCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)CCOCc1ccccc1)NC=O
Reaction time: 2 h

Procedure:
7.0 g (21.8 mmol) of 6-benzyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 70 ml of dichloromethane, and 2.0 ml (26.1 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours, 40 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, N-KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 6-benzyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil which can be reacted further without purification.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:2]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:16][CH:17]=2)([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:14]=1)[CH3:21]
Reactant: CCOC(OCC)c1ccc(CBr)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(Cc2ccc(C(OCC)OCC)cc2)(C(=O)OC)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 116.2 %

Procedure:
A solution of dimethyl malonate (0.66 g), 1-(bromomethyl)-4-(diethoxymethyl)benzene (2.73 g) in DMF (30 mL) was treated with NaH (0.4 g, 60% in mineral oil). The mixture was stirred for 3 h at room temperature and 1 h at 50° C., and then quenched with 100 mL of saturated NH4Cl. The product was extracted with 200 mL of 1:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated to give the title compound (3 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:15](=[O:16])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Br)cc1N
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(Br)cc2[nH]1
Yield: 128 %

Procedure:
The mixture of 4-bromobenzene-1,2-diamine (200 mg, 1.1 mmol), CDI (174 mg, 1.1 mmol) in dioxane was reacted at 50° C. for 16 hours. The mixture was concentrated and the residue was dissolved in DCM and extracted with water with the combined organic phases dried by Na2SO4 and concentrated to give 300 mg of crude product which was used without further purification. LCMS (m/z): 213.1/214.1 [M+H]+/[M+2H]+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[N:13]([O-])=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>O>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][N:13]=[C:4]2[OH:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1n[nH]c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (50 g) in water (200 mL) was added HCl (46 mL). To the mixture was added aqueous NaNO2 solution (17.7 g/37 mL) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. To the reaction solution was added dropwise aqueous Na2SO3 solution (79.3 g/200 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. To the mixture was added HCl (70 mL), and the mixture was stirred at room temperature for 18 hours and then at 80° C. for 4 hours. The precipitated solid was dissolved by basifying the reaction solution, and then the solution was acidified to precipitate a solid. The solid was collected by filtration and dried under reduced pressure to give Compound Q2 (36 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:32][O:33][CH2:34]/[CH:35]=[CH:36]/[C:37](O)=[O:38]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][N:27]3[C:37](=[O:38])/[CH:36]=[CH:35]/[CH2:34][O:33][CH3:32])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC/C=C/C(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: COC/C=C/C(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 54.3 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 21) and (E)-4-methoxybut-2-enoic acid (intermediate 3), to afford the title compound (21.1 mg, 54.3%). Data: LCMS (B) Rt: 2.22 min; m/z 512.3 (M+H)+.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3](N)[N:2]=1.N([O-])=[O:13].[Na+]>O.S(=O)(=O)(O)O>[N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]([OH:13])[N:2]=1
Reactant: O=N[O-]
Reactant: Nc1nnc2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1nnc2ccccc2n1
Yield: 53.4 %

Procedure:
To a solution of 2.0 g (14 mmol) 1,2,4-benzotriazine-3-amine in 30 ml water and 3 ml conc. sulphuric acid one adds dropwise at 10° C. a solution of 1 g sodium nitrite in 10 ml water. One stirs for 4 b at room temp., filters off the residue and dries. One obtains 1.1 g of title compound (55% of theory) of the m.p. 204-206° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:19]OC(OC)(C)C>CO.Cl.O1CCOCC1>[CH3:19][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=2)[CH2:9]1)=[O:16]
Reactant: O=C(O)[C@H]1CCC[C@H](C(=O)c2ccc(Br)cc2)C1
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C1CCCC(C(=O)c2ccc(Br)cc2)C1
Temperature: 50 °C
Yield: 95.5 %

Procedure:
To a solution of trans-3-(4-bromobenzoyl)cyclohexane-1-carboxylic acid (500 mg, 1.61 mmol, obtained from Rieke Metals Inc., Lincoln, Nebr., USA) and 2,2-dimethoxypropane (669 mg, 6.43 mmol) in methanol (20 mL), 5 drops of 4 M HCl in dioxane was added, and this reaction mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation to give the product 3-(4-bromo-benzoyl)-cyclohexanecarboxylic acid methyl ester as a brown oil (500 mg, yield 95.7%). 1H NMR (300 MHz, DMSO) δ 7.80 (d, 2H), 7.60 (d, 2H), 3.70 (s, 3H), 3.25 (m, 1H), 2.50 (m, 1H), 2.20-1.90 (m, 4H), 1.70-1.50 (m, 4H); LC-MS ret. time 3.30 min, m/z 324.9 (MH+).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCCC(Br)c1ccccc1

Procedure:
A suspension of tert-butyldimethyl(3-phenylpropoxy)silane (2.22 g, 8.86 mmol), N-bromosuccinimide (1.58 g, 8.86 mmol) and benzoyl peroxide (66.4 mg, 266 μmol) in carbon tetrachloride (17.8 mL) was heated to reflux for 3 hours. The reaction was filtered, the precipitate washed with carbon tetrachloride and the solvent was evaporated. Water was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a light yellow oil (1.63 g, 55%) after column chromatography on silica gel using heptane/ethyl acetate 19:1 (v/v) as eluent. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.42-7.26 (m, 5H), 5.42 (dd, 1H), 3.76 (m, 1H), 3.68 (m, 1H), 2.48 (m, 1H), 2.28 (m, 1H), 0.90 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[NH:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:38]Br>C(O)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15]([Br:38])=[CH:14][N:13]=[C:12]([N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:11]=2[NH:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: O=c1[nH]c2c(N(Cc3ccccc3)Cc3ccccc3)nccc2n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2c(N(Cc3ccccc3)Cc3ccccc3)ncc(Br)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.6 %

Procedure:
1-benzyl-4-dibenzylamino-1,3-dihydro-imidazo[4,5,c]pyridine-2-one (1 g, 2.4 mmol) was suspended in 20 mL of acetic acid then sodium acetate (195 mg, 2.4 mmol) was added followed by bromine (456 mg, 2.85 mmol) dropwise. The mixture was stirred at room temperature for 15 minutes. A heavy precipitate was formed. The mixture was diluted in water (50 mL) and the solid was filtered and washed with water. It was then diluted in ethyl acetate (20 mL), dried over magnesium sulfate and the solvent was removed in vacuo to give 1.29 g of the title compound as a light orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=O.C(OP([CH2:35][C:36]#[N:37])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[CH:35][C:36]#[N:37]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(C(=O)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(=CC#N)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Yield: 76 %

Procedure:
(2,3,4-trimethoxyphenyl)-(3,4,5-trimethoxyphenyl)methanone (2.87 g, 7.92 mmol), cyanomethylphosphonic acid diethyl ester (2.50 ml, 15.84 mmol) in anhydrous THF (15 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 15.84 ml, 15.84 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give 3-(2,3,4-trimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile as an off-white solid (2.32 g, 76%); mp, 125-127° C.: 1HNMR (DMSO-d6) δ 7.01-6.85 (m, 2H, Ar), 6.63-6.61 (m, 2H, Ar), 5.95 (s, 1H, double bond proton), 3.87-3.32 (multiple singlets, 18H, 6OCH3); 13C NMR (CDCl3) δ 160.6, 160.2, 155.5, 153.3, 153.1, 152.4, 151.8, 142.6, 139.5, 134.7, 133.8, 126.2, 125.8, 125.4, 118.4, 118.0, 107.2, 107.1, 106.4, 106.1, 104.8, 95.9, 61.2, 61.1, 61.0, 61.0, 56.4, 56.4, 56.2; Anal. Calcd. For C21H23NO6 (+0.05H2O): C, 65.29; H, 6.03; N, 3.63. Found: C, 64.90; H, 5.94; N, 3.55.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14](/[CH:18]=N/NS(C3C=CC(C)=CC=3)(=O)=O)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.[CH2:32](B(CC)CC)[CH3:33].[OH-].[Na+].O>C1COCC1>[F:31][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:32][CH3:33])[CH:13]=2)=[CH:8][CH:9]=1
Reactant: CCB(CC)CC
Reactant: Cc1ccc(S(=O)(=O)N/N=C/c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 88.7 %

Procedure:
A mixture of N′-[(1E)-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazide (0.67 mg, 1.52 mmol) in THF was treated with triethyl borane (1.0 M in THF, 1.52 mL, 1.52 mmol), stirred for 2 minutes, treated with NaOH (2.5 N, 0.61 mL, 1.52 mmol), refluxed for 2 hours, cooled to room temperature, poured into water and extracted with EtOAc. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel (ISCO) using hexanes/EtOAc (50/1) as the eluting solvents to give 1-{[4-(difluoromethoxy)phenyl]ethynyl}-3-propylbenzene as a clear oil (386 mg, 89% yield), MS m/e (M+H)+ 286; 1H NMR (400 MHz, DMSO-d6) 0.85 (t, J=7.32 Hz, 3H), 1.57 (m, 2H), 2.6 (t, J=7.32 Hz, 2H), 7.2 (m, 3H), 7.35-7.45 (m, 4H), 7.58 (d, J=8.79 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:35][CH2:36][CH:37]1[CH2:39][C:38]1([F:41])[F:40])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][C:38]1([F:41])[CH2:39][CH:37]1[CH2:36][CH2:35][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:7]3[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:3][C:2]=3[F:1])[O:9][C:10]=2[CH:16]=1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (14.1 mL) was added to a solution of hexachloroethane (7.46 g) and triphenylphosphine (9.91 g) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (5.31 g) and acetonitrile (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (10.7 g) as a mixture with impurities. A mixture of tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.28 g, a mixture with impurities), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g), potassium carbonate (0.367 g), and DMF (30 mL) was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (1.06 g) and potassium carbonate (0.733 g) were added, and the mixture was stirred at 60° C. for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.83 g) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[Cl:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([CH3:22])[C:19]([NH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:20]
Reactant: N#Cc1ccc(N)cn1
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)C(=O)Nc1ccc(C#N)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.635 g, 6.3 mmol) was added to a suspension of 5-amino-2-cyano-pyridine (0.500 g, 4.2 mmol) in dry dichloromethane (10 mL) under stirring at 0° C. To this, 2-chloropropionyl chloride (0.800 g, 6.3 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. Reaction mixture was diluted with dichloromethane (50 mL) and was washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified using column chromatography (silica gel, 30% ethyl acetate in petroleum ether as an eluent), and further crystallized from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:22]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCCc1ccccc1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CCCN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 25.2 %

Procedure:
Following the procedure of Example 3, step 4, 0.300 g (1.60 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.244 g (1.77 mmol) of anhydrous potassium carbonate and 0.243 ml (1.60 mmol) of 1-bromo-3-phenylpropane. Chromatography on flash silica, eluting with 50-100% ethyl acetate/petroleum ether and 2-10% methanol/dichloromethane, then on a Lobar column, eluting with 50% ethyl acetate/petroleum ether, gave 0.123 g (26%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate, the title product hydrochloride was obtained as a white solid, m.p. 196°-201° C. NMR δ(D2O/CD3CN) 1.54 (1H, m), 1.68 (1H, m), 1.75-1.89 (2H, m), 2.08-2.15 (2H, m), 2.61-2.77 (4H, m), 2.84 (1H, t, J=12.2 Hz), 2.92 (2H, m), 3.08-3.18 (3H, m), 3.56 (1H, m), 3.71 (1H, m), 7.19-7.26 (3H, m), 7.29-7.33 (4H, m), 7.39-7.43 (2H, m). m/z (CI+, NH3) 306 (M+H)+, 200 (M-CH2CH2Ph)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:59]1([C:63](O)=O)[CH2:62][CH2:61][CH2:60]1>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:63]([CH:59]5[CH2:60][CH2:61][CH2:62]5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: O=C(O)C1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C2CCC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (101 mg), N,N-diisopropylethylamine (0.130 ml), cyclobutanecarboxylic acid (0.024 ml) and DMF (2 ml) was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2 ml), and the mixture was stirred at 90° C. for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (22.72 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[F:35][C:36]1([F:43])[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[F:35][C:36]1([F:43])[CH2:41][CH2:40][CH:39]([O:34][C:31]2[CH:32]=[CH:33][C:28]([N:4]3[C:5](=[O:27])[C:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]3[CH2:1][CH3:2])=[CH:29][CH:30]=2)[CH2:38][CH2:37]1
Reactant: OC1CCC(F)(F)CC1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(F)(F)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (600 mg), 4,4-difluorocyclohexanol (362 mg,), diisopropyl azodicarboxylate (1.9 M in toluene, 1.4 mL), triphenylphosphine (698 mg) and tetrahydrofuran (10 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow oil (635 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH:10]=NO)=[CH:4][CH:3]=1.[OH:14]S(O)(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:9](=[O:13])[C:10]2=[O:14]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(F)cc1
Product: O=C1Nc2ccc(F)cc2C1=O
Temperature: 80 °C

Procedure:
To a hot solution of conc. H2SO4 (20 mL) at 60° C., (N-(4-Fluoro-phenyl)-2-hydroxyimino-acetamide (5 g, 27.0 mmol) was added portion wise. After completion of the addition, the temperature was increased to 80° C. and maintained for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried to obtain the title compound as brick red solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Yield: 87 %

Procedure:
Morpholine (1.2 g, 14.12 mmol) was added to a stirring solution of 3,4,5-trifluoronitro benzene (1 g, 5.65 mmol) in acetonitrile (15 mL) and the reaction mixture was refluxed for 5 h. A viscous liquid was obtained upon concentration, which was then poured into crushed ice. The solid thus obtained was filtered off and dried under reduced pressure to obtain the title compound (1.2 g, 88%).