Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][C@H:23]([C:31]3[N:35](CCC#N)[N:34]=[N:33][N:32]=3)[C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1CCN2C(=NCCC2)CC1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][C@H:23]([C:31]3[NH:35][N:34]=[N:33][N:32]=3)[C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(C[C@@H](c3cccc(C)c3)c3nnnn3CCC#N)cc2-c2ccc(Cl)c(Cl)c2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(-n2nc(C[C@@H](c3cccc(C)c3)c3nnn[nH]3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.3 %

Procedure:
To a solution of 3-(5-{(S)-2-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-tetrazol-1-yl)-propionitrile (1.5 g, 2.7 mmol) in dichloromethane (25 mL) was added DBU (2.9 mL, 18.9 mmol, 7.0 equiv), and the mixture was stirred at room temperature for 48 h. Dichloromethane (200 mL) was added, and the resulting mixture was washed with 1 N HCl (2×100 mL) then water (100 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography (50% dichloromethane/ethyl acetate) to afford the title compound (1.3 grams, 95%). HPLC: Rt=5.31 (Method A). MS (ESI): mass calculated for C26H22Cl2N6O, 504.12; m/z found, 505.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.32 (d, J=8.2 Hz, 1H), 7.28-7.24 (m, 3H), 7.21 (t, J=7.7 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.08 (d, J=7.7 Hz, 1H), 6.95-6.94 (m, 3H), 6.88 (dd, J=8.5, 2.2 Hz, 1H), 6.18 (s, 1H), 4.85 (dd, J=9.0, 3.6 Hz, 1H), 3.86 (s, 3H), 3.58 (dd, J=14.8, 8.5 Hz, 1H), 3.42 (dd, J=15.4, 3.6 Hz, 1H), 2.31 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[F:31][C:32]1[CH:40]=[C:39]2[C:35]([C:36]([CH2:41][CH2:42][NH2:43])=[CH:37][NH:38]2)=[CH:34][CH:33]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:43][CH2:42][CH2:41][C:36]3[C:35]4[C:39](=[CH:40][C:32]([F:31])=[CH:33][CH:34]=4)[NH:38][CH:37]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1c[nH]c2cc(F)ccc12
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3c[nH]c4cc(F)ccc34)n2)c1

Procedure:
Intermediate 4 was coupled with 2-(6-Fluoro-1H-indol-3-yl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 497. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 7.8 (d, 1H) 7.5 (m, 4H) 7.3 (m, 1H) 6.8 (m, 2H) 4.4 (d, 2H) 3.9 (m, 1H) 3.6 (m, 2H) 3.3 (m, 2H) 3.1 (m, 1H) 2.8 (m, 5H) 1.7 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1>>[CH3:23][O:24][CH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27]1
Reactant: COC[C@H]1CCCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: COC[C@@H]1CCCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and (S)-3-(methoxymethyl)piperidine to give 223. MS: (ESI+)=425.1
Reaction SMILES: Cl.[SH:2][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[CH:10](N(C(C)C)CC)(C)C.COC(OC)N(C)C>C1(C)C=CC=CC=1>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:10])[N:8]=1
Reactant: Cc1ccnc(S)n1
Reactant: CCN(C(C)C)C(C)C
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CSc1nccc(C)n1

Procedure:
A 22 L round bottom flask equipped with an air stirrer, heating mantle, thermometer, and reflux condenser was charged with toluene (12 L), 2-mercapto-4-methylpyrimidine hydrochloride (1) (900 g, 5.53 mol), diisopropylethylamine (1.07 kg, 8.30 mol), and N,N-dimethylformamide dimethyl acetal (1.61 kg, 12.7 mol). The reaction mixture was heated to reflux for 3.5 hours, and then the red solution was concentrated under reduced pressure to remove toluene, methanol, and some N,N-dimethylformamide. The residue was then treated with ethyl acetate (2 L), water (2 L), and enough 10% (w/v) aqueous sodium bisulfate solution to reach a pH of 4.5. After mixing, the organic layer was siphoned into a separate container, and the aqueous layer was extracted with additional ethyl acetate (2×2 L). All organic extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure to yield ˜1 L of a red oil, which was then purified by vacuum distillation at <1 mm Hg. Fractions that distilled off are as follows: T=30°-50° C.: ˜100 mL ethyl acetate and N,N-dimethylformamide; T=60°-70° C.: 436.8 g product +14.5 g N,N-dimethylformamide; T=68°-72° C.: 267.4 g of pure product. Identity and purity of each fraction was determined by 1H NMR. Fractions 2 and 3 were combined and used in the next step without further purification. Yield of 2: 704.2 g (91%). 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.49 (s, 3H), 6.75 (d, J=5.2 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H). MS (ESI+) 141.1.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([O:11][C:12]([C:14]1([O:18]/[N:19]=[C:20](/[C:24]2[N:25]=[C:26]([NH:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[S:27][CH:28]=2)\[C:21]([OH:23])=O)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.[NH2:50][CH:51]1[C:76](=[O:77])[N:53]2[C:54]([C:60]([O:62][CH:63]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:61])=[C:55]([CH2:58][Cl:59])[CH2:56][S:57][C@H:52]12>C(Cl)Cl>[C:7]([O:11][C:12]([C:14]1([O:18]/[N:19]=[C:20](/[C:24]2[N:25]=[C:26]([NH:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[S:27][CH:28]=2)\[C:21]([NH:50][CH:51]2[C:76](=[O:77])[N:53]3[C:54]([C:60]([O:62][CH:63]([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[O:61])=[C:55]([CH2:58][Cl:59])[CH2:56][S:57][C@H:52]23)=[O:23])[CH2:15][CH2:16][CH2:17]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (1.46 g, 7 mmoles) was added to a suspension of (Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid [IV-5'] (4.09 g, 7 mmoles) in 70 mL of dry methylene chloride, and the mixture was stirred for 1 hour at room temperature. The acid chloride solution was added at -20° C. to a solution of silylated 7-ACA ester, which was prepared by adding BSA (5.6 mL, 21 mmoles) to a stirred suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride [V] (3.16 g, 7 mmoles) in dry methylene chloride (70 mL). The mixture was stirred for 20 minutes at -10° C. and then at room temperature for 40 minutes. The reaction mixture was evaporated and diluted with ethyl acetate (300 mL), and the organic layer was washed with 5% aqueous sodium bicarbonate, water and a saturated sodium chloride solution. After drying over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (Wako gel C-200, 60 g); elution with chloroform. The fractions containing the desired product were combined and evaporated to obtain 5.88 g (86%) of VI-5' as a yellow powder.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[C:2]#[CH:3].O=[C:13]([C:19]([O:21]CC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[O:21]=[C:19]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:4]1[CH2:1][C:2]#[CH:3]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: C#CCNc1ccccc1N
Solvent: Cc1ccccc1
Product: C#CCn1c(=O)c(C(=O)OCC)nc2ccccc21
Yield: 93.1 %

Procedure:
9.2 g (62.9 mmol) of N-(2-propynyl) 1,2-phenylenediamine and 12.1 g (69.2 mmol) of diethyl ketomalonate were dissolved in toluene (100 mL), and the solution was refluxed for 3 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the solid matter thus obtained was washed with diisopropyl ether, to obtain 15.0 g (yield: 93%) of ethyl 2-oxo-1-(2-propynyl)-1,2-dihydroquinoxaline-3-carboxylate as a white powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[S:14])SC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:11]([SH:14])=[N:17][N:16]=[N:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSC(=S)NCCCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Sc1nnnn1CCCc1ccccc1
Yield: 20.6 %

Procedure:
Methyl N-(3-phenylpropyl)dithiocarbamate (0.044 mol) and sodium azide (0.062 mol) were reacted substantially as described in Example 1C above to obtain 2.0 g (21%) colorless crystals: mp 75°-76° (pet. ether).
Reaction SMILES: C(O)CO.[CH2:5]([OH:10])[CH2:6][CH2:7][CH2:8][OH:9].[C:11](O)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17]>CN(C)C=O>[CH2:5]([OH:10])[CH2:6][CH2:7][CH2:8][OH:9].[CH2:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: O=C(O)CCCCC(=O)O
Solvent: OCCCCO
Solvent: CN(C)C=O
Solvent: OCCO
Product: OCCCCCCO

Procedure:
Top coat solution D1 is a 25% solution of a polyester urethane in dimethylformamide (DMF)/methyl ethyl ketone (MEK) (1:1) with a viscosity of 10,000 cP/25° C. The polyester urethane elastomer is obtained from 2000 g (1.0 mol) of a copolyester of ethylene glycol/butane-1,4-diol and adipic acid (molecular weight 2000), 108.0 g (1.20 mol) of butane-1,4-diol, 141.6 g (1.20 mol) of hexane-1,6-diol and the equivalent quantity of 4,4'-diphenylmethane diisocyanate (850 g) by a one-shot process. The molar ratio of chain-lengthening agents is therefore 1:1.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[C:4]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[OH:27][C:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(O)C>[ClH:1].[OH:27][C:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][N:31]([CH2:2][CH:3]2[CH2:7][NH:6][C:5](=[O:8])[C:4]2([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:30][CH2:29]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C1NCC(CCl)C1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cl
Product: O=C1NCC(CN2CCC(O)(c3ccccc3)CC2)C1(c1ccccc1)c1ccccc1
Temperature: 200 °C

Procedure:
To 10.0 g. (0.035 mole) of 4-(chloromethyl)-3,3-diphenyl-2-pyrrolidinone in 150 ml. of ethanol in a steel bomb was added 15.0 g. (0.11 mole) of potassium carbonate (finely ground) and 6.2 g. (0.035 mole) of 4-hydroxyl-4-phenylpiperidine. The mixture was heated to 200° C. for 48 hours and rotated slowly to effect mild stirring. After concentrating in vacuo, the residue was partitioned between dilute hydrochloric acid solution and ethyl acetate. The acid solution was made basic with sodium hydroxide and extracted with chloroform. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in isopropanol and treated with oxalic acid, and the oxalate salt of the starting piperidine compound precipitated out. The filtrate was concentrated in vacuo and the residue was partitioned between dilute sodium hydroxide and chloroform. The chloroform solution was dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and a solid formed which was filtered off. The filtrate was treated with ethereal hydrogen chloride and the hydrochloride salt was recrystallized in isopropanol-methanol. The salt (2.6 g., 17%) melted above 250° C.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[Cl:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11].C(N(CC)CC)C.[CH:24]([N:27]1[C:31](=[CH2:32])[C:30]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[O:29][C:28]1=[O:38])([CH3:26])[CH3:25]>ClCCCl>[Cl:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:12][C:2]([N:35]1[CH2:36][CH2:37][C:30]2([O:29][C:28](=[O:38])[N:27]([CH:24]([CH3:26])[CH3:25])[C:31]2=[CH2:32])[CH2:33][CH2:34]1)=[O:3])=[O:11]
Reactant: NC(=O)c1cccnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C1N(C(C)C)C(=O)OC12CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=C1N(C(C)C)C(=O)OC12CCN(C(=O)NC(=O)c1cccnc1Cl)CC2
Temperature: 85 °C
Yield: 54 %

Procedure:
5.8 g of oxalyl chloride are portionwise added to the solution of 6.2 g of 2-chloronicotinic acid amide in 150 ml of anhydrous 1,2-dichloroethane under stirring, then the reaction mixture is heated at 85° C. for 90 minutes. After cooling the mixture to 0° to 5° C. first 12.6 ml of triethylamine and then a solution of 8.4 g of 3-isopropyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 42 ml of anhydrous 1,2-dichloroethane are portionwise added while maintaining the temperature between 20° and 30° C. The reaction mixture is stirred at room temperature for an additional 30 minutes, then extracted with 200 ml of N sodium hydroxide solution and then with 100 ml of water. After combining the aqueous extract is acidified to a pH value of 5.5 to 6 by adding acetic acid and the mixture is extracted with 1,2-dichloroethane. The organic solution is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title compound in 54% yield, m.p.: 186°-188° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:20](Cl)(=O)[CH2:21][CH2:22][CH3:23].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>N1C=CC=CC=1.C1COCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]3[S:35][C:20]([CH2:21][CH2:22][CH3:23])=[N:17][N:16]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)NN)cc2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCc1nnc(-c2ccc([C@H]3CC[C@H](CCC)CC3)cc2)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.25 mol of p-(trans-4-n-propylcyclohexyl)benzohydrazide is dissolved in 300 ml of pyridine. At room temperature, 0.25 mol of butyryl chloride is added dropwise, and the mixture is stirred for a further 11/2 hours. The mixture is then poured into 1.5 1 of ice/water, and the crystals are filtered off with suction and washed with water. The product obtained is recrystallized from toluene. 0.1 mol of this compound and 0.1 mol of Lawesson's reagent are refluxed for 10 hours in 200 ml of THF. 2/3 of the solvent are removed by distillation, the residue is poured into 500 ml of water and 50 ml of 32% sodium hydroxide solution, and the precipitate is filtered off with suction and recrystallized from ethanol/activated charcoal to give 2-[p-(trans-4-n-propylcyclohexyl)phenyl]-5-propyl-1,3,4-thiadiazole.
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11](=[O:23])[NH:12][CH2:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=1[C:21]#[N:22])([CH3:9])([CH3:8])[CH3:7].[CH3:24][O:25][C:26]1[C:35]2[O:34][CH2:33][O:32][CH2:31][C:30]=2[CH:29]=[C:28]([CH:36]=O)[CH:27]=1.C[Si]([C:42]#[N:43])(C)C>O.C(OCC)(=O)C>[C:6]([O:10][C:11](=[O:23])[NH:12][CH2:13][C:14]1[CH:19]=[C:18]([NH:20][CH:36]([C:42]#[N:43])[C:28]2[CH:27]=[C:26]([O:25][CH3:24])[C:35]3[O:34][CH2:33][O:32][CH2:31][C:30]=3[CH:29]=2)[CH:17]=[CH:16][C:15]=1[C:21]#[N:22])([CH3:9])([CH3:7])[CH3:8]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1C#N
Reactant: COc1cc(C=O)cc2c1OCOC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C#N)Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of Yb (OTf)3 (0.124 g) and THF (5 mL) there were added (5-amino-2-cyanobenzyl)carbamic acid t-butyl ester (Example (1g))(0.494 g), 8-methoxy-4H-benzo[1,3]dioxine-6-carboaldehyde (0.388 g), MS3A (0.5 g) and trimethylsilyl cyanide (0.533 mL) in that order under a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (100 mL) and water (50 mL) were added to the mixture and filtration was performed with Celite. After sufficiently shaking the filtrate, the organic layer was separated off and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (0.822 g) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5nnn[nH]5)cc34)cc2)cc1
Temperature: 180 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
(4-Benzyloxy-phenyl)-(6-cyanoquinazolin-4-yl)-amine (0.106 g) in dimethylformamide was treated with sodium azide (0.06 g) and ammonium chloride (0.05 g) and the mixture stirred at 180° C. for 18 hours. The mixture was cooled, poured onto water and extracted with ethyl acetate/THF (3:1). The organic extracts were dried and concentrated in vacuo. The residue was purified using solid phase extraction to yield the title compound (0.024 g); δ H [2H6]DMSO 10.18(1H, s), 9.25(1H, s), 8.55(1H, s), 8.40(1H, d), 7.88(1H, d), 7.74(2H, d), 7.45(6H, m), 7.07(2H, d), 5.17(1H, s); m/z (M+1)+ 396.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.BrC1C=C2C(=CC=1)[C:36](=[O:40])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:40][CH3:36].[N:23]1([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(CN2CCOCC2)cc1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Product: Nc1ccc(CN2CCOCC2)cc1

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.27 g (91.0% yield) of tan solid is obtained from 0.20 g (0.608 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, and 0.14 g (0.608 mmol) of 4-Morpholin-4-ylmethyl-phenylamine: mp 186-187 oC; MS (ESI) m/z 490.1 (M+H)+1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH:15]1([N:21]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)N)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:21]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:23]4[C:24]([C:10]=3[CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1)=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=4
Reactant: CCOC(=O)c1ccc(N(N)C2CCCCC2)cc1
Reactant: O=C1CCC(=O)c2ccc(Cl)cc2N1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2NC(=O)C1
Temperature: 85 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (1.18 g, 5.65 mmol) and ethyl 4-(N-cyclohexylhydrazino)benzoate (1.14 g, 4.35 mmol) in acetic acid (11 ml) was stirred at 85° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, and conc. sulfuric acid (0.55 ml) was added to the reaction mixture. The mixture was stirred at 85° C. for 3 hr. The mixture was allowed to cool, and the reaction mixture was poured into water (230 ml) and extracted with a mixed solvent of ethyl acetate (200 ml) and ethanol (30 ml). The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Water (10 ml) and ethanol (10 ml) were added to the obtained crude product and the precipitated solid was collected by filtration. The obtained solid was washed with a mixed solvent (10 ml) of water:ethanol (1:1) and dried in vacuo to give ethyl 3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (0.97 g, yield 39%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=S(Cl)[Cl:17]>>[ClH:17].[Cl:17][CH2:7][C:6]1[N:2]([CH3:1])[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(CO)cnc1-c1ccccc1
Product: Cl
Product: Cn1c(CCl)cnc1-c1ccccc1
Yield: 86 %

Procedure:
A solution of (1-methyl-2-phenyl-1H-imidazol-5-yl)methanol (0.600 g, 3.19 mmol) in dry SOCl2 (11 mL) was refluxed at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with CH2Cl2, and then triturated with diethyl ether, filtered and dried under suction to afford 5-(chloromethyl)-1-methyl-2-phenyl-1H-imidazole hydrochloride (0.67 g, yield 86%) as a white solid. 1H NMR (300 MHz, MeOD) δ 7.79-7.79 (m, 6H), 4.98 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:18]=1.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[NH2:17][C:14]1[N:15]=[N:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:18][C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc2oc(-c3ccc(N)nn3)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(-c2cc3cc(O)ccc3o2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
6-(5-Methoxy-benzofuran-2-yl)-pyridazin-3-ylamine (0.14 mmol) was mixed with CH2Cl2 (3 mL) at 0° C. under argon atmosphere. BBr3 (1M in CH2Cl2, 1.0 mL) was added dropwise and the mixture was stirred for 2 h at rt. The mixture was hydrolysed with H2O followed by NaHCO3 (sat. aq.). The resulting mixture was extracted with EtOAc and the organic extracts were dried over Na2SO4. After filtration and evaporation of the solvent, the crude material was purified by preparative HPLC to afford the title compound as a yellow solid (8 mg). 1H NMR δ ppm 9.21 (s, 1 H) 7.74 (d, 1 H) 7.40 (d, 1 H) 7.27 (s, 1 H) 6.96 (d, 1 H) 6.86 (d, 1 H) 6.76 (dd, 1 H) 6.69 (s, 2 H); MS m/z 228 (M+H).