Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: COC1(Cc2ccccc2C)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC1(Cc2ccccc2C)CCC(=O)CC1
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of EXAMPLE 15B (0.51 g, 1.80 mmol) in acetone (10 mL) was treated with water (5 mL) and p-toluenesulfonic acid monohydrate (0.20 g), heated to reflux, stirred overnight, and concentrated to remove the acetone. The remaining aqueous solution was extracted with ethyl acetate (3×100 mL) and the combined extracts were washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (0.42 g, 100%). MS (ESI) m/e 233 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1cccc(CBr)c1F
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(F)c1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,3-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:21])[C:7]3[C:8]([CH:19]=[CH:20][C:4]=2[CH:3]=1)=[N:9][CH:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:12]=3.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:21]=[C:6]1[C:7]2[C:8](=[N:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=2)[CH:19]=[CH:20][C:4]2[CH:3]=[C:2]([NH:1][C:25](=[O:26])[O:27][CH2:28][CH3:29])[CH:23]=[CH:22][C:5]1=2
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(=O)c3cc(-c4ccccc4)cnc3ccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(=O)c3cc(-c4ccccc4)cnc3ccc2c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a 0° C. solution of 8-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.4 mg, 0.021 mmol) in pyridine (0.3 mL) was added a catalytic amount of 4-dimethylaminopyridine (tip of the spatula) and ethyl chloroformate (0.1 mL, 0.31 M in CH2Cl2) The mixture was then stirred at room temperature. After 7 hours, more ethyl chloroformate (3 μL, 0.032 mmol) was added. After stirring for 14 hours, a new addition of ethyl chloroformate (6 μL, 0.064 mmol) was followed by stirring for 2 more hours.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH2:15][CH2:16][CH3:17]>C(#N)C>[CH2:14]([N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: OCC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCCC1CO

Procedure:
To 10.1 g (0.1 mol) of 2-pyrrolidinemethanol and 13.8 g (0.1 mol) of potassium carbonate in 200 mL of acetonitrile add 13.7 g (0.1 mol) of butyl bromide. Heat the reaction mixture at reflux with stirring under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction remove the solvent in vacuo then dissolve the residue in water. Make the aqueous mixture acidic (pH=1) with concentrated hydrochloric acid. Extract the aqueous acid solution with 3×50 mL of hexanes. Make the aqueous solution basic (pH=12) with 20% sodium hydroxide solution and extract with 3×100 mL of methylene chloride. Dry the combined methylene chloride extracts over anhydrous sodium sulfate. Filter the drying agent and evaporate the filtrate in vacuo to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+].O>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=[C:7]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:6]=2[CH:18]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C=C(N1CCN(C)CC1)c1cc(F)ccc1S2

Procedure:
18 g of 8-fluoro-2-methyl-dibenzo[b,f]thiepin-10(11H)-one in 140 ml of absolute benzene are together with 33.2 ml of N methylpiperazine within 1/2 hour at 20°-25° treated with a solution of 5.8 ml of titanium tetrachloride in 40 ml of absolute benzene. The reaction mixture is subsequently heated for 20 hours under reflux conditions. The reaction mixture is poured, with vigorous stirring, into a mixture of 40 ml of saturated aqueous sodium bicarbonate solution and 120 ml of water, subsequently filtered and extracted with chloroform. The organic phase is dried and evaporated. One obtains 1-(8-fluoro-2-methyl-dibenzo[b,f]thiepin-10-yl)-4-methyl-piperazine, which is converted into the corresponding maleate by treatment with maleic acid. The maleate melts at 244° with decomposition.
Reaction SMILES: I[CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1.[CH2:14]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[N:29]1[S:33](=[O:35])(=[O:34])[N:32]([CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:31](=[O:42])[CH2:30]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][C:31](=[O:42])[N:32]([CH2:36][CH2:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[S:33]1(=[O:34])=[O:35])[CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1N[C@H](CI)Cc2ccccc21
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3Cc4ccccc4C(=O)N3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from (S)-3-iodomethyl-3,4-dihydro-2H-isoquinolin-1-one and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to the method used in Example 57, step B.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([N:18]=[C:19]=[S:20])[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([N:18]2[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:19]2=[S:20])[CH:17]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: C#CCNCC(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (7.0 g), 5-chloro-2-methylphenylisothiocyanate (9.2 g), triethylamine (5.0 g), and methylene chloride (100 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1N HCl (50 mL), then with water. The organic layer was dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid was collected by filtration. Recrystallization from EtOAc afforded the title compound (5.1 g) as a yellow solid, m.p. 131°-134° C. Anal. Calcd. for. C13H11N2O Cl S: C, 56.01; H, 3.98; N, 10.05. Found: C, 55.90; H, 3.77; N, 9.92. Mass spectrum (EI, M.+) m/z 278.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[C:21]([C:37]([O:39]C)=O)[C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:36])[NH:34][CH3:35])=[CH:29][CH:28]=3)=[CH:23][C:24]=2[O:25][CH3:26])[N:12]=1)(=[O:3])[NH2:2].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[C:24]([O:25][CH3:26])=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:34][CH3:35])=[O:36])=[CH:29][CH:28]=3)=[C:21]([C:37]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:39])[CH:20]=2)[N:12]=1)(=[O:3])[NH2:2]
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4C(N)=O)n3)cc2C(=O)OC)cc1
Reactant: C1CCNC1
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4C(N)=O)n3)cc2C(=O)N2CCCC2)cc1
Temperature: 100 °C

Procedure:
The mixture of methyl 4-(4-(2-carbamoylphenylamino)-5-chloropyrimidin-2-ylamino)-5-methoxy-4′-(methylcarbamoyl)biphenyl-2-carboxylate (Step 1, 220 mg, 0.75 mmol) and 1 mL of pyrrolidine is heated at 100° C. overnight. The crude is concentrated in vacuo and applied to preparative RP-HPLC to afford 4′-(4-(2-Carbamoylphenylamino)-5-chloropyrimidin-2-ylamino)-5′-methoxy-N-methyl-2′-(pyrrolidine-1-carbonyl)biphenyl-4-carboxamide; ESMS m/z 600.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][C:6]=2[CH:15]=1.S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:21])=[O:13])=[CH:7][C:6]=2[CH:15]=1
Reactant: O=C(O)C1=Cc2cc(Br)ccc2NCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Temperature: 80 °C

Procedure:
To a suspension of 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylic acid (68.2 g) in methanol (100 ml) was added concentrated sulfuric acid (37.3 g) at 0° C., and the mixture was heated at 80° C. for 10 hours. After allowing to cool, the solvent was evaporated under reduced pressure. Ethyl acetate and water were added thereto and 1N sodium hydroxide solution was added to pH=4 at 0° C. The solution was separated, and the organic phase was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was subjected to silica gel column to remove origin components (ethyl acetate), and the resulting solid was washed with diisopropyl ether to give methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (44.0 g). The filtrate was purified with silica gel column (hexane:ethyl acetate=4:1) to give methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (3.4 g).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:43]I>C(OCC)(=O)C>[I:43][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1
Reactant: II
Reactant: CCCCCCCC(=O)c1ccc(CCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)c1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4′-(2-Hydroxy ethyl)octanophenone prepared in the step B (137 g), imidazole (53 g) and triphenyl phosphine (174 g) were dissolved in ethyl acetate (550 ml) to obtain a solution. Iodine (197 g) was added to the solution with cooling, and the solution was stirred at room temperature for 1 hour. Then the reaction solution was diluted with ethyl acetate, the solution was washed with saturated sodium sulfite solution, and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated. The concentrated residue was extracted with hexane-ethyl acetate (20:1), and extracted solution was passed through a silica gel layer. The filtrate was concentrated to obtain 4′-(2-iodoethyl)octanophenone (175 g) in the form of white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26](I)=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][OH:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]([O:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CN(C)CCO
Reactant: CNc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: CNc1ncnc2c1nc(OCCN(C)C)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(8-iodo-6-(methylamino)-purin-9-yl)phenyl]urea and 2-(dimethylamino)ethanol by the same techniques as in Example 136.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:16]=[CH:17][C:18]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[C:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:16]=[CH:17][C:18]=2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CCl)cc1
Reaction time: 1 h

Procedure:
4-(chloromethyl)benzoyl chloride (12 g, 63.5 mmol) was dissolved in THF (120 mL) and a solution of 1,1-dimethylethyl (3-aminobiphenyl-4-yl)carbamate (19.86 g, 69.8 mmol) and DIPEA (12.2 mL, 69.8 mmol) in THF (300 mL) was added dropwise at room temperature. After stirring for 1 hour, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated in Et2O to give 1,1-dimethylethyl [3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 9.92 (s, 1H), 8.75 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.83 (s, 1H), 7.63 (m, 3H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (dd, J=8.4 and 1.8 Hz, 1H), 7.44 (t, J=7.2 Hz, 2H), 7.33 (t, J=7.2 Hz, 1H), 4.84 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=O.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>O>[Cl:18][C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2cn[nH]c(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)c2cnnc(Cl)c2c1
Temperature: 25 °C
Yield: 91 %

Procedure:
1 g (4.9 mmol) of 5,7-dimethoxy-2H-phthalazin-1-one and 10 mL of phosphoryl chloride are heated at 80° C. for 2 hours. After cooling to room temperature, the reaction medium is poured dropwise into 50 mL of water and the mixture is then basified with 6N sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water and with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. 1 g of a beige-coloured solid is obtained (91% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[CH:13][CH:14]=4)=[C:4]2[CH:3]=1.[C:24](#[N:27])[CH:25]=[CH2:26]>>[CH3:23][N:16]1[C:15]2[C:10]3[C:11](=[C:4]4[C:5](=[N:8][C:9]=3[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1=3)[CH:6]=[CH:7][C:2](/[CH:26]=[CH:25]/[C:24]#[N:27])=[CH:3]4)[CH:12]=[CH:13][CH:14]=2
Reactant: C=CC#N
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cccc1c23
Product: CN1c2ccccc2-c2nc3ccc(/C=C/C#N)cc3c3cccc1c23
Yield: 62 %

Procedure:
The general procedure (Method M) applied to 3-chloro-8-methyl-8H-quino[4,3,2-kl]acridine, 28 (300 mg, 0.94 mol) and acrylonitrile (0.144 mL, 2 eq) gave the title compound (193 mg, 0.58 mmol, 62%).
Reaction SMILES: Cl[C:2]1[C:11]([F:12])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1>N.[Ni].CO>[F:12][C:11]1[CH:2]=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2
Reactant: COc1ccc2nc(Cl)c(F)c(Cl)c2c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc2ncc(F)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
To a suspension of 2,4-dichloro-3-fluoro-6-methoxyquinoline (0.9 g, 3.66 mmol) in ammonia in methanol (10 mL, 462 mmol) was added carefully the slurry of Raney Nickel (5 g, 3.66 mmol) in Methanol (10 mL). The resulting reaction mixture was hydrogenated at 150 psi pressure, stirred at room temperature for 24 h. Filtered the catalyst, washed with methanol, evaporated the filtrate under reduced pressure to afford crude mass, purified by silica gel chromatography eluting with 10%-50% ethyl acetate in pet-ether to afford 3-Fluoro-6-methoxy quinoline (0.27 g, 41%) as pink solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.65 (d, J=2.9 Hz, 1H), 8.01-7.98 (d, J=9 Hz, 1H) 7.67-7.64 (dd, J=9 Hz, J=2.9 Hz 1H), 7.33-7.30 (dd, J=9.0 Hz, J=2.9 Hz, 1H), 7.03 (d, J=2.9 Hz 1H), 3.93 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([OH:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([O:15][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
To a solution containing 300 mg (1.15 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide produced in Example 2 and pyridine (0.9 mL), 328.4 mg (1.72 mmol) of 4-methylbenzenesulfonyl chloride was added at 0° C. After stirring at 0° C. for 5 hours and at room temperature for further 5 hours, water (5 mL) was added and the resultant was stirred at room temperature for 2 hours. Extraction was carried out with ethyl acetate and after the organic layer was washed with saturated brine, the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and purifying was carried out on silica gel column chromatography to obtain (S)-N-[4-(trifluoromethyl)phenyl]-3-(4-methylphenyl)sulfonyloxypentanoic acid amide as a white solid (455.1 mg, isolated yield: 49%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.86 (3H, t), 1.75-1.82 (2H, m), 2.38 (3H, s), 2.72-2.83 (2H, m), 4.87-4.93 (1H, m), 7.23-7.26 (2H, m), 7.54-7.59 (4H, m), 7.74-7.78 (3H, m)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(Cl)Cl.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:22][N:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CSc1nncc(-c2ccc(F)c(Br)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnnc(-c3ccccn3)n2)cc1-c1ccccn1
Temperature: 60 °C
Yield: 15.9 %

Procedure:
To a mixture of 5-(3-bromo-4-fluorophenyl)-3-methylsulfanyl-[1,2,4]triazine (0.2 g, 0.67 mmol), cuprous 3-methylsalicylate (0.315 g, 1.5 mmol), 2-(tri-n-butylstannyl)pyridine (0.736 g, 2.2 mmol) and lithium chloride (0.085 g, 2.0 mmol) in dry 1,4-dioxane (8 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.032 mmol) and the mixture heated at 60° C. Fog 24 h. The reaction was allowed to cool to ambient temperature, diluted with DCM (20 ml) and washed with 10% ammonia solution (10 ml). The organic layer was washed with water (40 ml) and the combined organics dried over Mg2SO4, filtered and the solvent removed at reduced pressure. The crude product was purified by preparative thin-layer chromatography on silica gel, eluent 3% methanol in dichloromethane. The solid obtained was triturated with diethyl ether to give 5-[4-fluoro-3-(pyridin-2-yl)phenyl]-3-(pyridin-2-yl)-[1,2,4]triazine as a powdery orange solid (35 mg): δH (400 MHz, CDCl3) 7.39-7.48 (3H, m), 7.51 (1H, m), 7.81-8.00 (3H, m), 8.47 (1H, m), 8.71 (1H, m), 8.80 (1H, m), 8.93 (1H, m), 9.81 (1H, s); m/z (ES+) 330 (M++H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1.C([O-])(=O)C.[Na+]>ClCCl.O>[Br:1][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cnn(-c2cccc(C)c2)c(=O)c1OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cnn(-c2cccc(CBr)c2)c(=O)c1OC
Yield: 89.4 %

Procedure:
While stirring vigorously and exposing to light from a 300 watt incandescent lamp, a solution of 80.0 g of bromine in 400 ml of dichloromethane is dripped into a solution of 105 g of 1-(3'-methylphenyl)-4,5-dimethoxypyridazin-6-one and 51.6 g of sodium acetate in 1.5 liters of dichloromethane and 500 ml of water. The dichloromethane is then separated off and the remainder is washed with a sodium carbonate solution and concentrated. There is obtained 124 g of 1-(3'-bromomethylphenyl)-4,5-dimethoxypyridazin-6-one of m.p. 67°-69° C. and a purity of 90%.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(=O)[C:24]([Cl:26])=[O:25].[Cl-].[Ca+2].[Cl-]>ClCCl.O>[Cl:26][C:24]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)=[O:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution containing the product of example 1B (2.46 g, 10.0 mmol) and AlCl3 (2.66 g, 20.0 mmol) in 30 mL of dichloromethane at 0° C. was added oxalyl chloride (5 mL, 2 M solution in dichloromethane, 10 mmol). The mixture was stirred at room temperature for 30 minutes. After this time the reaction mixture was poured into an ice-cold solution containing calcium chloride (3 g) in 100 mL of water. The reaction mixture was stirred for 2 h and was extracted with dichloromethane (2×100 mL). The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure, and the resulting oil was purified by flash chromatography (ethyl acetate/hexane, 1/8) to afford the title compound as a colorless oil. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (m, 2H), 1.19 (t, J=7.06 Hz, 3H), 1.47 (m, 2H), 1.57-1.85 (m, 5H), 2.22 (d, J=6.75 Hz, 2H), 2.47 (m, 1H), 4.07 (q, J=7.06 Hz, 2H), 7.35 (d, J=8.29 Hz, 2H), 7.85 (d, J=8.29 Hz, 2H).