Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]1[CH2:17][C:18](O)=[O:19].[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH2:27])[S:25][CH:26]=1>>[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH:27][C:18](=[O:19])[CH2:17][N:3]2[C:4]3[C:9](=[CH:8][C:7]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:26]=1
Reactant: O=C(O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid (40 mg, 0.14 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (28 mg, 0.11 mmol) according to protocol A. Retention time (min)=6.06, method [7], MS(ESI) 514.0 (M+H); 1H NMR (300 MHz, CD3Cl) δ 7.85 (d, J=9.35 Hz, 1H), 7.73 (s, 1H), 7.50 (s, 1H), 7.44-7.41 (m, 1H), 7.35-7.33 (m, 1H), 6.97 (d, J=9.9 Hz, 1H), 6.95 (s, 1H), 5.31 (s, 2H).
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][N:2]=1.[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>S(Cl)(Cl)=O.N1C=CC=CC=1>[C:1]1([C:14]([O:16][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:12])=[CH:3][N:2]=1
Reactant: O=C(O)c1cnc(C(=O)O)c2ccccc12
Reactant: CCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)c1cnc(C(=O)OCCCCCCCCCCCCCCCC)c2ccccc12
Reaction time: 19 h

Procedure:
Isoquinoline-1,4-dicarboxylic acid (1.8 g, 5 mmol) is refluxed in 10 ml of thionyl chloride for 2 h. The solution is evaporated to dryness and the residue dissolved in 20 ml of dichloromethane. The latter solution is added dropwise to a mixture of 1-hexadecanol (2.90 g, 12 mmol) in 1 ml of pyridine. After 19 h at room temperature, the precipitate is filtered off and the filtrate is evaporated to dryness. The resulting residue is crystallized in toluene/ethanol. The crystals obtained are purified by silica gel flash-column chromatography (dichloromethane). Thus the title compound, m.p. 80.7°-81.4°, is obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][CH2:11][C:10]1=[O:27].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][C:10]1=[O:27]
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC(=O)N(C)c2ccc(Cl)cc2C1c1ccccc1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
2.8 ml. (0.02 moles) of triethylamine are added to a solution of 5.73 g. (0.02 moles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 30 ml. of chloroform, and a solution of 2 ml. of ethyl chloroformate in 10 ml. of chloroform is added to the stirred mixture at room temperature. After 3 hours of stirring 1.4 ml. (0.01 moles) of triethylamine and a solution of 1 ml. of ethyl chloroformate in 5 ml. of chloroform are added to the reaction mixture. The reaction mixture is stirred for an additional 2 hours and then evaporated to dryness under reduced pressure. The residue is crystallized from ethanol. 6.7 g. (92.5%) of crystalline 1-methyl-4-ethoxycarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 173°-174° C., Rf1 = 0.5.
Reaction SMILES: [Cl-].[CH3:2][NH2+:3][CH3:4].[CH:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[Na]>C1(C)C=CC=CC=1>[CH3:2][N:3]([CH:5]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCOC(=O)CC=O
Reactant: C[NH2+]C
Agent: [Cl-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CN(C)C

Procedure:
120 ml of a toluene suspension of 50.40 g (0.62 mol) of dimethylammonium chloride were introduced with good stirring in the course of half an hour into 274.5 g of a toluene suspension which originated from the preparation of sodium ethyl formylacetate and which contained 71.2 g (0.515 mol) of sodium ethyl formylacetate. The reddish orange-coloured, mobile suspension was freed on a rotary evaporator in a slight vacuum (about 300 mbar) from low-boiling components and from about 80 to 90% of the toluene including the water passing over azeotropically. The solids were filtered off with suction and washed with 50 ml of toluene, and the combined filtrates were distilled in vacuo without a column. After a forerun of toluene, 85.8 g of colourless ethyl N,N-dimethyl-β-aminoacrylate passed over at 0.6 mbar and a head temperature of 94° to 95° C.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To 400 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 160 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 92 mg of the title compound as a colorless powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:28]=[C:27]1[CH:26]([N:25]2[C:21](=[O:23])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:15]2=[O:17])[CH2:32][CH2:31][C:30](=[O:33])[NH:29]1
Reactant: O=C(O)c1cccc(Nc2ccc3ccccc3c2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(Nc4ccc5ccccc5c4)c3C2=O)C(=O)N1
Yield: 92 %

Procedure:
A mixture of 3-(naphthalen-2-ylamino)phthalic acid (0.62 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.33 g, 2.0 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 95:5 methylene chloride-methanol, eluting 0.74 g of the product, in 92% yield: mp 235-237° C.; 1H NMR (DMSO-d6) δ 2.06-2.11 (m, 1H), 2.54-2.64 (m, 2H), 2.85-3.00 (m, 1H), 3.77 (s, 3H), 5.15 (dd, J=12.7 Hz, J=5.3 Hz, 1H), 7.29 (d, J=6.3 Hz, 1H), 7.39-7.52 (m, 3H), 7.57-7.69 (m, 2H), 7.80-7.95 (m, 4H), 8.66 (s, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.8, 112.5, 113.8, 117.0, 120.0, 122.1, 124.8, 126.6, 127.0, 127.6, 129.2, 130.0, 132.5, 133.7, 136.2, 137.3, 142.5, 167.0, 168.2, 170.0, 172.8; Anal. calcd for C23H17N3O4.0.1H2O: C, 68.86; H, 4.32; N, 10.47. Found: C, 68.73; H, 4.01; N, 10.36.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[C:20]([C:19]1[CH:22]=[C:23]([CH3:24])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)#[N:21]
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)nc2)CC1
Yield: 82.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (200 mg) described in Preparation Example 131 and oxazolidin-2-one (68 mg), the title compound (167 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:25]([CH3:26])[C:40]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:41])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:14][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2cccc3[nH]ccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1CCCCC1)[C@H](CC1CCCCC1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.6 g (1.69 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.25 g (1.69 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and converted to the hydrochloride.0.3 hydrate salt of the title compound with ethereal HCl yield 0.68 g (87%) as a white solid; mp=>260° C.; MS (+) ESI m/z=465 (M+H)+.
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.[NH2:7][C:8]1[C:9](Br)=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1.[C-]#N.[Na+].O>C1C=CC=CC=1>[C:2]([C:9]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=[CH:13][C:8]=1[NH2:7])#[N:1]
Reactant: Nc1cccc(C(F)(F)F)c1Br
Reactant: c1ccncc1
Agent: [C-]#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1c(N)cccc1C(F)(F)F

Procedure:
To 21 g. of dry pyridine is added slowly with stirring 23 g. (0.26 mol.) of cuprous cyanide. The mixture rapidly solidifies and is then heated to 125°. Excess pyridine is boiled off and the temperature is decreased to 110°. 3-Amino-2-bromobenzotrifluoride (48 g., 0.20 mol.) is added with stirring and the reaction mixture is heated to 165°-170° for 75 minutes. The mixture is then cooled to 90° and a solution of 75 g. (1.05 mol.) of sodium cyanide in 75 ml. of water is added followed by 250 ml. of benzene. The resulting mixture is stirred for one hour, the layers are separated and the benzene layer is washed with water, dried and evaporated to give 2-cyano-3-trifluoromethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][Mg]Cl.CCOCC.[C:16](#[N:18])[CH3:17].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][CH:16]([NH2:18])[CH3:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CC#N
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(N)Cc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
To a solution of 3-chlorobenzylmagnesium chloride (0.1 mol) in anhydrous ether (100 mL) (prepared from 3-chlorobenzyl chloride (16.1 g, 0.1 mol) and magnesium turnings (2.4 g, 0.1 mol) in anhydrous ether (100 mL)) was added anhydrous acetonitrile (4.1 g, 0.1 mol) dropwise at room temperature. When the reaction mixture was stirred at 60° C. for 3 hours, it was cooled to 0° C. followed by addition of THF (50 mL). Lithium aluminum hydride (4.2 g, 0.1 mol) was then added cautiously into the above reaction mixture and it was heated to reflux temperature for 3 hours. Ice-water was added to quench the reaction. After partitioning between ether and H2O, the separated organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. Flash column chromatography separation (silica gel, 180 g, 5% methanol in DCM) then yielded the title compound as yellowish oil (1.9 g, 11%). MS: 170.1 (M+H+).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=O.N>>[Br:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: N
Product: Brc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 3-bromobenzoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.71 (m, 2H), 7.98 (ddd, J=8.1, 2.0, 1.0 Hz, 1H), 8.22 (ddd, J=7.4, 1.6, 1.3 Hz, 1H), 8.35 (t, J=1.8 Hz, 1H), 8.46 (dt, J=7.9, 2.0 Hz, 1H), 8.83 (dd, J=4.8, 1.6 Hz, 1H), 9.27 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 302 (M+H)+, 304 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([CH2:2][CH2:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)CCOCc1ccco1
Reaction time: 1.5 h

Procedure:
Combine fur-2-ylmethyl 2-hydroxyethyl ether (10 mmol), and N,N-diisopropylethylamine (4.0 mL, 23 mmol), and dichloromethane (20 mL). Cool in an ice-bath. Add dropwise, methanesulfonyl chloride (1.0 mL, 13 mmol). After 1.5 hours, extract the reaction mixture with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain fur-2-ylmethyl 2-methanesulfonylethyl ether.
Reaction SMILES: Br[C:2](Br)([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].[NH2:11][NH:12][C:13]([NH:15][NH2:16])=[S:14].CO>O>[NH2:16][N:15]1[C:3](=[O:4])[C:2]([C:6]([CH3:9])([CH3:8])[CH3:7])=[N:11][N:12]=[C:13]1[SH:14]
Reactant: CC(C)(C)C(Br)(Br)C(=O)O
Reactant: NNC(=S)NN
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Temperature: 0 °C

Procedure:
A mixture of 2,2-dibromo-3,3-dimethylbutyric acid, 55 parts, and thiocarbohydrazide, 22 parts, in 500 parts of (1:1) methanol and water was heated to reflux for five hours. Upon cooling the reaction mixture to 0° C., a solid formed and was collected. The solid, 4-amino-6-t-butyl-3-mercapto-1,2,4-triazin-5-one, was obtained in 78% of theory (29 parts).
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24](=[O:25])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=2[CH3:44])=[CH:15][CH:14]=1>CN(C)C=O.C(OCC)(=O)C>[CH:2]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:24](=[O:25])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=2[CH3:44])=[CH:17][CH:18]=1)([CH2:4][CH3:5])[CH3:3]
Reactant: CCC(C)Br
Reactant: CCCc1nc(C)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of 2-bromobutane (0.19 mL), cesium carbonate (1.7 g) and 4′-{[5-(4-hydroxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) in N,N-dimethylformamide (5 mL) was stirred for 2 hr at 80° C. The mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (0.5 g, 89%).
Reaction SMILES: [N:1]1[C:13]2[C:12](=[O:14])[N:11]3[C:6](=[N:7][CH2:8][CH2:9][CH2:10]3)[C:5]=2[N:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:6]1[C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:13]=2[C:12](=[O:14])[NH:17][N:16]=1
Reactant: O=C1c2nccnc2C2=NCCCN12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NCCCNc1n[nH]c(=O)c2nccnc12

Procedure:
7,8-Dihydro-6H-1,4,5,8a-tetraaza-fluoren-9-one (0.53 mmol) was treated with hydrazine hydrate (3.0 mmol) in ethanol (3 mL) for 20 h at RT. Ethanol was removed under vacuum and the crude produce was purified by flash chromatography (MeOH/DCM/Et3N) to yield 8-(3-amino-propylamino)-6H-pyrazino[2,3-d]pyridazin-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)cc1
Yield: 14 %

Procedure:
Using 1.00 g of (4-chlorobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 1.0 g of sodium hydride (60% in oil), and 0.93 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.21 g of 2-(4-chlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (15)).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:18])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:18])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN1CCCCCC1Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(CC2CCCCCN2C)cc1

Procedure:
Add a solution of 0.75 g of acetyl chloride in 5 ml of benzene drop by drop to a solution of 1.9 g of the title compound of Example 22 and 1 g of triethylamine in 10 ml of benzene. After an hour concentrate the resulting product, take it up with water and diethyl ether, collect the organic phase and concentrate it to obtain the title compound.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=[O:9])C=1Cl.[F:15][C:16]1[C:24]2[N:23]([CH3:25])[C:22]3[CH2:26][CH2:27][N:28]([CH2:30][C:31]4[N:32]=[CH:33][NH:34][C:35]=4[CH3:36])[CH2:29][C:21]=3[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[F:15][C:16]1[C:24]2[N:23]([CH3:25])[C:22]3[CH2:26][CH2:27][N:28]([CH2:30][C:31]4[N:32]=[CH:33][NH:34][C:35]=4[CH3:36])[C:29](=[O:9])[C:21]=3[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reaction time: 4 h
Yield: 20.5 %

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (133 mg) in THF (4 ml) was added dropwise to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1Hpyrido[4,3-b]indole (70 mg) in THF (12 ml) at -10° under nitrogen, and stirring was continued for 4 h. Water (20 ml) was then added, and the resulting solution was left to stand overnight. Excess THF was removed in vacuo, and the resultant aqueous solution was extracted with ethyl acetate (3×50 ml). The combined, dried organic extracts were adsorbed onto silica and purified by FCC eluting with System A (100:10:1) to give the title compound (15 mg), m.p. 231.5°-233°.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH:22]([OH:24])[CH3:23])[CH:21]=1)[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:17]=[C:16]2[C:33]#[N:34].[Cl:35][C:36]([Cl:40])([Cl:39])[C:37]#[N:38]>C1COCC1>[Cl:35][C:36]([Cl:40])([Cl:39])[C:37](=[NH:38])[O:24][CH:22]([C:20]1[CH:21]=[C:13]([Cl:12])[CH:14]=[C:15]2[C:19]=1[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:17]=[C:16]2[C:33]#[N:34])[CH3:23]
Reactant: CC(O)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Reaction time: 1 h
Yield: 73.4 %

Procedure:
DBU (0.020 mL, 0.130 mmol) was added to a solution of (±)-5-chloro-7-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (456 mg, 1.299 mmol) and Trichloroacetonitrile (0.391 mL, 3.90 mmol) in THF (10 mL) and the reaction was stirred for one hour. The solvent was evaporated and the reaction was purified by chromatography on SiO2 with 10:89:1 ethyl acetate/hexanes/triethylamine to give (±)-1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (472 mg, 0.953 mmol, 73.3% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J=2.0 Hz, 1H), 6.60 (q, J=6.3 Hz, 1H), 6.27 (d, J=11.3 Hz, 1H), 5.25 (d, J=11.3 Hz, 1H), 3.48 (m, 2H), 1.72 (d, J=6.3 Hz, 3H), 0.80-1.05 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)Cl>ClCCCl>[Br:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1
Reactant: CCOC(=O)c1csc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1csc(CBr)n1
Temperature: 70 °C
Yield: 8 %

Procedure:
A mixture of ethyl-2-methylthiazole 4-carboxylate (500 mg, 2.9 mmol), N-bromosuccinimide (877 mg, 4.9 mmol), and benzoyl peroxide (5-10 mg ) in 1,2-DCE (3 mL) was heated at 70° C. for 85 h. After cooling to room temperature, DCM (10 ml) was added and washed with water (3 times). The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative chromatography to yield the above-titled compound (58 mg). 1H NMR (CDCl3): 8.23 (1H, s), 4.77 (2H, s), 4.43 (2H, q), 1.42 (3H, t).