Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: N#Cc1ccc(CBr)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccc(C#N)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A mixture of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.267 g, 1.00 mmol), 4-bromomethyl-2-fluoro-benzonitrile (0.321 g, 0.1.50 mmol), DIPEA (0.259 g, 2.00 mmol) and KI (0.017 g, 0.10 mmol) in dry CH3CN (10 mL) was stirred at 60° C. for 16 h. After that period of time the CH3CN was removed by evaporation under vacuum, and saturated aqueous NaHCO3 (20 mL) was added. The aqueous mixture was extracted with CH2Cl2 (3×30 mL, and the extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on a silica gel column (1000:30:1, CH2Cl2/CH3OH/NH4OH), affording 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-fluoro-benzonitrile as a white foam (0.400 g, 100%). 1H NMR (CDCl3) δ 1.65-1.80 (m, 3H), 2.09-2.14 (m, 1H), 2.20-2.38 (m, 2H), 2.44 (s, 6), 3.58 (s, 2H), 4.16 (s, 1H), 4.20 (s, 1H), 6.37-6.43 (m, 2H), 6.93-7.03 (m, 3H), 7.23 (d, 2H, J=7.5 Hz), 8.35 (dd, 2H, J=0.9, 4.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[NH2:24][C:25]1[C:29]([NH2:30])=[CH:28][S:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CC#N>[NH2:30][C:29]1[C:25]([NH:24][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:21][CH:20]=2)=[CH:26][S:27][CH:28]=1
Reactant: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Reactant: Nc1cscc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(NCc2ccc(C(=O)Nc3cscc3N)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
Acid 424a (1040 mg; 3.62 mmol); 3,4-diaminothiophene dihydrochloride (1017 mg; 5.44 mmol; 1.50 eq.) and BOP (1770 mg; 4.0 mmol; 1.1 eq.) were suspended in MeCN, treated with triethylamine (4 mL; 29 mmol) and stirred for 18 h at room temperature; concentrated and purified by chromatographic column on silica gel (elution 50% EtOAc in DCM) to render 527 mg (1.37 mmol; 38% yield) of compound 424c which was 90% pure. 1H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 8.56 (s, 1H), 7.78 (d, J=7.9 Hz, 2H), 7.43 (d, J=3.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 2H), 6.73 (d, J=8.8 Hz, 1H), 6.33 (d, J=3.5 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 6.13 (dd, J=2.6, 8.3 Hz, 1H), 4.33 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). LRMS: calc: 383.4642; found: 384.2 (M+H); 406.2 (M+Na) and 192.6 (M+2H)/2.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.Cl.O.[NH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:5]1([CH2:4][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCN(CC2CC2)CC1
Temperature: 85 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
To a suspension of (bromomethyl)cyclopropane (500 mg, 4 mmol, 1.0 eq.) and 4-piperidone hydrate hydrochloride (579 mg, 4 mmol, 1.0 eq.) in acetonitrile (30 mL) was added sodium carbonate (1.148 g, 11 mmol, 3. eq.). The reaction mixture was stirred 16 h at 85° C. The resulting suspension was filtered and the solid was washed with acetonitrile. The filtrate was concentrated in vacuo and purified by column chromatography on silica eluting with DCM/2N NH3 in methanol 97:3 to yield 339 mg (62%) of the tide compound as yellow oil. MS (m/e): 154.2 (MH+, 100%).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:15][CH:14]=1)=[S:11])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)[CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:17][CH:18]=1)=[S:11])[CH2:28][CH3:29]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCNC(=S)Nc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCNC(=S)Nc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
The compound (93.8 mg) obtained in Example 35-2 was dissolved in anhydrous methanol (3.8 ml) and added with 1-methyl-2-imidazole carboxaldehyde (38.5 mg) and sodium cyanoborohydride (43.4 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 13.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (86.6 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][NH:28][C:29](=[O:35])[CH2:30][S:31][CH2:32][CH2:33][OH:34])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][NH:28][C:29](=[O:35])[CH2:30][S:31][CH2:32][CH2:33][O:34][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Solvent: c1ccncc1
Product: O=C(CSCCOC(=O)c1ccccc1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
0.24 ml of benzoyl chloride was added, whilst ice-cooling, to a mixture of 0.40 g of N-[4-(4-piperidinomethyl -2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 1.02 ml of pyridine, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the mixture was concentrated by evaporation under reduced pressure. The concentrate was diluted with water and made alkaline by the addition of an aqueous ammonia solution, after which it was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:40 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.31 g of the title compound in a 61% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[CH2:9]([Br:12])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1.CCOCC>[BrH:12].[CH2:11]([N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]1=[NH:8])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: Cc1nc(N)sc1C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Br
Product: C=CCn1c(C)c(C)sc1=N
Temperature: 85 °C

Procedure:
A mixture of 4,5-dimethyl-1,3-thiazol-2-amine (1 g) and allylbromide (0.95 g) in toluene (5 mL) was heated to 85° C. for 12 hours, cooled, diluted with ether, filtered and the solvent was evaporated to afford crude product that was taken on to the next step without further characterization.
Reaction SMILES: [N:1]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[C:5]([O:7]CC)=O)=[C:2]=[S:3].[C:17]1([NH:23]N)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1>[C:17]1([N:23]2[C:5](=[O:7])[C:4]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:10])[NH:1][C:2]2=[S:3])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)(N=C=S)c1ccccc1
Reactant: NNc1ccccc1
Solvent: Cc1ccccc1C
Product: CC1(c2ccccc2)NC(=S)N(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
4.7 g (20 mmol) of ethyl 2-isothiocyanato-2-phenylpropionate are dissolved in 40 ml of xylene. 2.16 g (20 mmol) of phenylhydrazine are added and the mixture is heated for 4 hours at reflux. The mixture is cooled to room temperature and a beige solid precipitates. The precipitate is filtered, washed with 5 ml of diisopropyl ether and then dried under vacuum. 4.6 g (yield=77%) of 3,5-diphenyl-5-methyl-2-thiohydantoin are thus obtained in the form of a beige powder melting at 164° C.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:44]2[CH:49]=[CH:48][C:47]([C:50]3([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:45]=2)O1>C1(C)C=CC=CC=1>[CH2:20]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[N:6]2[C:2]=1[C:44]1[CH:45]=[CH:46][C:47]([C:50]2([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])[CH2:51][CH2:52][CH2:53]2)=[CH:48][CH:49]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Brc1c(CCc2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To a suspension of 3-bromo-2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.197 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (4 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.353 g, 2 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.054 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The aqueous phase was extracted with dichloromethane (2×100 mL) and the organic extracts were combined and washed with brine (1×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10-60% ethyl acetate in hexanes) gave tert-butyl (1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.042 g, 15%) as a yellow solid. LCMS: 584 [M+H].
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])(=O)=O)=CC=1>CN(C=O)C>[N:1]([CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:23][CH3:24])=[N+:2]=[N-:3]
Reactant: CC[Si](C#CCCOS(=O)(=O)c1ccc(C)cc1)(CC)CC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](C#CCCN=[N+]=[N-])(CC)CC
Temperature: 60 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
Sodium azide (1.80 g; 27.65 mmol) was added to a solution of 4-(triethylsilyl)but-3-ynyl 4-methylbenzenesulfonate (3.12 g; 9.22 mmol) in DMF (15 mL) and stirred at 60° C. for 3 hours. After cooling, the volatiles were removed under reduced pressure and the residue was partitioned between saturated ammonium chloride and ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford 2.0 g (quantitative yield) of the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]=[CH:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[Li+].[F-].[CH2:26]([N:33]([CH2:39]OC)[CH2:34][Si](C)(C)C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]3[CH2:34][N:33]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:39][CH:20]3[CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [F-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C1CN(Cc3ccccc3)CC1CC2
Reaction time: 6 h

Procedure:
4-Oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.92 g, 9.15 mmol), LiF (296 mg, 11.4 mmol) and benzyl-methoxymethyl-trimethylsilanylmethyl-amine are mixed together in CH3CN (10 ml). The reaction mixture is sonicated under N2. The water bath is kept under 35° C. with ice. After 6 h, solvents are removed in vacuo. The residue is put on a column (1:1 EtOAc hexanes) to afford the title compound as clear oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 1.23 (3H, t), 1.56 (9H, s), 1.88-2.00 (2H, m), 2.65 (1H, m), 2.92-3.02 (4H, m), 3.24 (1H, m), 3.50-3.59 (3H, m), 4.06 (1H, q), 4.19 (2H, q), 7.18-7.27 (5H, m), 7.62 (1H, s). MS (ES+) 453 (M+1) Step 2: 6-Benzyl4-oxo-4,4a,5,6,7,7a,8,9-octahydro-1H-1,6-diaza-cyclopenta[f]azulene-3-carboxylic acid pyridin-2-ylamide
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]=2)[N:30]=1.C(=O)(O)[O-].[Na+]>>[ClH:24].[ClH:24].[ClH:24].[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH:31]=[C:32]([C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]=4)[N:30]=3)[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: Cl
Yield: 109.4 %

Procedure:
1.31 g of 4-(diphenylmethyl)-1-piperazinepropanamine and 567 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate were stirred at 185° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.80 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration again. Ethanol was added to the residue; the crystal precipitated was collected by filtration, washed with ethanol-ethyl acetate (1:3) and dried to yield 502 mg of the title compound.
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]2[CH2:16][C:17]([CH2:19][CH:12]1[CH2:13][CH2:14]2)=O>C(O)C>[CH3:10][N:11]1[CH:12]2[C:19]3[C:7]4[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:8][C:17]=3[CH2:16][CH:15]1[CH2:14][CH2:13]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CN1C2CCC1c1c([nH]c3ccccc13)C2
Temperature: 25 °C

Procedure:
A mixture of phenylhydrazine hydrochloride (2.89 g, 19.99 mmol; Aldrich) and tropinone (2.78 g, 19.99 mmol; Aldrich) in ethanol (15 mL) was heated at reflux for 3 hours. The resulting solution was cooled to room temperature and the volatiles were removed under vacuum. The residue was taken up in 7% (w/w) H2SO4/dioxane (42 g) and heated at 60° C. under nitrogen for 14 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in water (25 mL) and the solution was made basic (pH >9) by addition of 25% NaOH (20 mL). The resulting mixture was extracted with CH2Cl2 (2×25 mL) and the extract was concentrated to residue which was purified by flash chromatography (120 g silica eluted with CH2Cl2—CH3OH-14.8 M aqueous, 90:10:1) followed by crystallization from ethyl acetate to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.56-1.72 (m, 1H), 1.89 (t, J=9.3 Hz, 1H), 2.20-2.34 (m, 2H), 2.36 (s, 3H), 2.46 (d, J=16.7 Hz, 1H), 3.25 (dd, J=16.7, 4.8 Hz, 1H), 3.55 (t, J=5.4 Hz, 1H), 4.20 (d, J=5.2 Hz, 1H), 6.90-7.05 (m, 2H), 7.25 (d, J=7.1 Hz, 1H), 7.38 (d, J=7.1 Hz, 1H); MS (DCI) m/z 213 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8](Cl)=O.[C:17](#[N:19])C>>[F:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[CH2:8][N:3]1[CH2:2][CH2:1][N:4]([CH2:8][C:7]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:6]=2[F:5])[C:17]1=[NH:19]
Reactant: CC#N
Reactant: NCCN
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Product: N=C1N(Cc2cc(F)c(F)cc2F)CCN1Cc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared in three steps as described in Procedure D. In the first step, ethylenediamine was reacted in acetonitrile with 2,4,5-trifluorobenzoylchloride (2 eq) in the presence of TEA to give the N,N′-dibenzoylated ethylenediamine upon aqueous work-up. After the last step (reaction with cyanogen bromide, performed at 200° C. for 60 min using MW heating), the precipitated solid was filtered off and recrystallized to give the title compound as the hydrogen bromide salt. MS (ES+) m/z 374 ([M+1]+, 100); HR-MS: 374.1086 ([M+1]+, C17H14F6N3; calc. 374.10919).
Reaction SMILES: C([Mg]Br)C.[CH3:5][CH:6]([O:10][CH2:11]/[CH:12]=[CH:13]/[C:14]#[CH:15])[O:7][CH2:8][CH3:9].Br[CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>O1CCCC1>[CH3:5][CH:6]([O:10][CH2:11]/[CH:12]=[CH:13]/[C:14]#[C:15][CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:7][CH2:8][CH3:9]
Reactant: C#C/C=C/COC(C)OCC
Reactant: CCCCCC#CCBr
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC#CCC#C/C=C/COC(C)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl magnesium bromide in tetrahydrofuran (47 mL, 1.17 M) was treated dropwise with a solution of (E)-4-methyl-3,5-dioxa-7-decen-9-yne (7.7 g) in tetrahydrofuran (10 mL). After complete addition, the mixture was heated at 60° for 45 min, cooled to room temperature, treated with anhydrous cuprous chloride (0.35 g, dried at 145° at 0.05 mmHg for 16 hours) and stirred for 10 min. The 1-bromo-2-octyne (7.23 g) in tetrahydrofuran (10 mL) was added dropwise to the above mixture (mild exothermic reaction) and after complete addition the resulting mixture was heated for 45 min at 60° C. After this time, the contents were cooled to room temperature, poured onto saturated aqueous ammonium chloride solution and extracted with ether. The combined ether extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by liquid chromatography (two columns, 3% by volume ethyl acetate in 97% by volume hexane) to yield the product (E)-4-methyl-3,5-dioxa-7-octadecen-9,12-diyne
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[H-].[Na+].[H][H].[CH3:14][C:15]1[CH:20]=[N:19][C:18]([CH2:21]Cl)=[CH:17][N:16]=1>CN(C)C=O.O>[CH3:14][C:15]1[CH:20]=[N:19][C:18]([CH2:21][N:6]2[CH2:7][CH2:8][NH:9][C:5]2=[CH:4][N+:1]([O-:3])=[O:2])=[CH:17][N:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: Cc1cnc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(CN2CCNC2=C[N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
2-Nitromethyleneimidazolidine (12.9 g) was dissolved in dry dimethylformamide (100 ml), and at room temperature 60% oily sodium hydride (4.4 g) was added. The mixture was stirred at room temperature until the generation of hydrogen ceased. Then, 2-methyl-5-pyrazinylmethyl chloride (14.3 g) was added at room temperature, and the mixture was stirred at 40° C. for 8 hours. After cooling to room temperature, the reaction mixture was added to 200 ml of water, and extracted with dichloromethane. On distilling off dichloromethane from the organic layer under reduced pressure, 1-(2-methyl-5-pyrazinylmethyl)-2-(nitromethylene)imidazolidine (5.4 g) was obtained as yellow crystals having a melting point of 163° to 166° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[CH:18][CH:19]=2)[C:14]([NH:29][C:30]([NH2:32])=[NH:31])=[N:13][CH:12]=1>CC(N(C)C)=O>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[CH:18][CH:19]=2)[C:14]([NH:29][C:30]([NH2:32])=[NH2+:31])=[N:13][CH:12]=1
Reactant: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Reactant: O=C(O)c1ccccc1
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(N)=[NH2+])c3c2)c1
Product: O=C([O-])c1ccccc1
Temperature: 40 °C
Yield: 70 %

Procedure:
A slurry of benzoic acid (3.95 kg, 32.33 mol) and (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidine (10.2 kg, 31.69 mol) in DMA (61.2 L) was heated at 60° C. until dissolution was complete. The solution was slowly cooled to 40° C., seeded, granulated at 40° C. and then at ambient temperature. The thick slurry was cooled to 0° C., granulated, and the solid was collected by filtration, washed with DMA (5.1 L) and MeCN (10.2 L) and dried overnight in vacuo at 55° C to give (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidinium benzoate (9.85 kg, 22.19 mol, 70%) as an off white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[C:5](=[O:13])[C:4]2[N:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][C:3]1=2.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:8]([C:6]2[C:5](=[O:13])[C:4]3[N:14]=[C:15]([CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:16][C:3]=3[N:2]([CH3:1])[CH:7]=2)=[O:9])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)nc2c1=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2nc(CN3CCOCC3)sc21
Temperature: 190 °C

Procedure:
A mixture of ethyl 4-methyl-2-(morpholin-4-ylmethyl)-7-oxo-4,7-dihydro[1,3]-thiazolo[5,4-b]pyridine-6-carboxylate (Preparation 30, 105 mg) and 4-chlorobenzyl-amine (1 mL) is heated to 190° C. for 40 min. and then allowed to cool to ambient temperature. The solvent is removed in vacuo. The mixture is diluted with ether to precipitate 89 mg (66%) of the title compound as a tan solid. Physical characteristics: 1H NMR (DMSO-d6) δ 2.59, 3.64, 3.91, 4.00, 4.56, 7.33-7.36, 8.75, 10.59; IR (diffuse reflectance) 2857, 2809, 1662, 1599, 1569, 1550, 1531, 1526, 1517, 1492, 1346, 1296, 1116, 797, 732 cm−1. Anal. Found: C, 55.50; H, 4.98; N, 12.00.