Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](O)=[O:24]>>[CH3:31][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:21]([O:20][CH3:19])[C:22]=1[C:23]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:24]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: COc1cccc(OC)c1C(=O)O
Product: COc1cccc(OC)c1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. for C23H24N4O3, 404.47; m/z found, 405.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.[OH-].[Na+]>>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:18]1[O:20][CH2:19]1
Reactant: ClCC1CO1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
1 g of 4-hydroxy benzophenone and 4.668 g of epichlorohydrin (0.025 mol) were dissolved, 20.5 mg of sodium hydroxide was added, and the reaction system was heated to 100° C. and then cooled to 95° C. Furthermore 201.4 mg of sodium hydroxide was added, and additional heating and agitation was carried out for 3 hours. The system was cooled to the room temperature, and salt was removed by filtering. The obtained filtrate was condensed under reduced pressure condition, and purified according to the silica gel chromatography to obtain 1.0 g of solid state 4-glycidyloxy benzophenone (Yield: 83%).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)=O>>[CH3:24][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: Cc1cccc(C(=O)CBr)c1
Product: COC(=S)c1cc(-c2nc(-c3cccc(C)c3)cs2)c(C)s1
Yield: 63 %

Procedure:
Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate, 106 mg (0.428 mmol) (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-3′methylacetophenone (0.428 mmol, 91 mg) in a manner similar to Example 22, step (a) to afford 98 mg (63% yield) of methyl 4-[4-(3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.ClCCl.B(Br)(Br)[Br:32].O>CCOC(C)=O>[Br:32][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cccc(CNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Into a 1-neck round-bottom flask were added 2-[3-({5-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]ethanol (0.20 g, 0.52 mmol) and dichloromethane (“DCM”, 5 mL). To the reaction mixture was added a solution of boron tribromide in methylene chloride (1.6 mL, 1.6 mmol, 1.0 M) at 0° C. The resulting mixture was allowed to warm up to rt and stirred overnight. The resulted mixture was cooled in a dry ice bath when water (10 mL) was added. The mixture was allowed to warm up to rt and EtOAc was added. The aqueous layer was extracted with EtOAc twice. The organic layers were combined and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product as a light brown powder (34 mg, 20%). LCMS for C19H19BrClN4O (M+H)+: m/z=371.1, 373.1. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 9.11 (s, 1H), 7.95 (s, 1H), 7.74 (t, J=6.1 Hz, 1H), 7.42 (m, 1H), 7.08 (t, J=7.9 Hz, 1H), 7.03 (dd, J=8.7, 7.6 Hz, 1H), 6.71 (dd, J=11.5, 7.6 Hz, 1H), 6.69 (s, 1H), 6.58 (dd, J=8.0, 2.3 Hz, 1H), 4.56 (m, 2H), 3.50 (m, 2H), 2.56 (t, J=7.1 Hz, 2H).
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[CH2:29][CH2:28][CH2:27][C:26](=[O:31])[C:25]=2[CH:24]=[N:23]1>C(O)(=O)C>[Br:1][CH:27]1[CH2:28][CH2:29][C:30]2[NH:22][N:23]=[CH:24][C:25]=2[C:26]1=[O:31]
Reactant: [Br-]
Reactant: O=C1CCCc2[nH]ncc21
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C1c2cn[nH]c2CCC1Br
Yield: 90.7 %

Procedure:
According to Scheme 1 Step 3: Pyridinium tribromide (25.7 mmol, 8.22 g) was added to a solution of 6,7-dihydro-1H-indazol-4(5H)-one (25.7 mmol, 3.50 g) in acetic acid (60 mL) and the reaction mixture was stirred under reflux for 2 hours. After evaporation of the solvent, the crude residue was partitioned between DCM and a saturated solution of Na2S2O3. The organic phase was washed with a saturated solution of Na2CO3 and with water, was dried over Na2SO4 and concentrated to yield 5-bromo-6,7-dihydro-1H-indazol-4(5H)-one (23.3 mmol, 5.00 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:11]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)C(OC(C)(C)C)=O)=[CH:23][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C1C(CC(O)=O)CC2C=CC(OCCCN(C3C=CC=CN=3)C(OC(C)(C)C)=O)=CC=2CN1CC1C=CC(C(F)(F)F)=CC=1.C(C(O)=O)(F)(F)F>O>[CH2:1]([N:8]1[C:14](=[O:15])[CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:11]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:23][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccccc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Agent: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(Cc2ccccc2)C1=O
Yield: 40 %

Procedure:
According to the procedure of Example 25(a) except substituting (±)-2-benzyl-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid for the (±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, the title compound (0.014 g, 40%) was prepared: MS (ES) m/e 460.4 (M+H)+. Anal. Calcd for C27H29N3O4.CF3CO2H.2 H2O: C, 57.14; H, 5.62; N, 6.89. Found: C, 57.44; H, 5.32; N, 6.87.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)Oc1ccccc1C(=O)O
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccccc2OS(C)(=O)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-methanesulfonyloxybenzoic acid (0.30 g, 1.4 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) in thionyl chloride (10 mL) was heated at 40° C. for 45 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (120 mg, 0.49 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.47 mmol) and triethylarmine (98 μL, 0.72 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 110 mg (55%) of the title compound as white crystals: mp 144-145° C.; [α]21D −7.1° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 443 (10, M+).
Reaction SMILES: [OH-:1].[Ni+2:2].[OH-].[Ni].O.[C:6]([OH:9])(=[O:8])[CH3:7]>>[OH2:8].[OH2:1].[OH2:8].[OH2:8].[C:6]([O-:9])(=[O:8])[CH3:7].[Ni+2:2].[C:6]([O-:9])(=[O:8])[CH3:7]
Reactant: [OH-]
Reactant: CC(=O)O
Agent: [Ni+2]
Agent: [Ni]
Solvent: O
Product: CC(=O)[O-]

Procedure:
The nickel hydroxide (line 144) is transferred to the nickel re-slurry tank 147 where water (line 145) and 100 wt % acetic acid (146) are added to produce the final product, nickel acetate tetrahydrate (line 148). The reaction is shown below 2H2O+Ni(OH)2+2CH3COOH→Ni(CH3COO)2.4H2O
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].Cl.Cl.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:28]([OH:31])=[CH:29][CH:30]=1>>[CH2:34]([N:33]([CH2:32][C:27]1[CH:26]=[C:25]([NH:24][C:9](=[O:10])[C:8]([C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:30]=[CH:29][C:28]=1[OH:31])[CH2:36][CH3:37])[CH3:35]
Reactant: CCN(CC)Cc1cc(N)ccc1O
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Agent: Cl
Product: CCN(CC)Cc1cc(NC(=O)C(=C2C(=O)Nc3ccccc32)c2[nH]c(C)cc2C)ccc1O
Yield: 17.1 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with 4-amino-alpha-diethylamino-o-cresol dihydrochloride (110 mg) using method B to give 25 mg (17%) of the title compound.
Reaction SMILES: C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[Li].Cl[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([CH:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1.[F:39][C:40]([F:44])=[C:41](F)[F:42].Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:36]([CH:33]1[CH2:34][CH2:35][CH:30]([CH:27]2[CH2:26][CH2:25][CH:24]([CH2:23][C:41]([F:42])=[C:40]([F:44])[F:39])[CH2:29][CH2:28]2)[CH2:31][CH2:32]1)[CH2:37][CH3:38]
Reactant: FC(F)=C(F)F
Reactant: CCCC1CCC(C2CCC(CCl)CC2)CC1
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(CC(F)=C(F)F)CC2)CC1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a reaction vessel under an argon atmosphere, 41.5 g of 4,4′-di-t-butyl-biphenyl and 500 ml of THF were added, and the resultant solution was cooled to 0° C. Thereto, 2.16 g of metal lithium was added a little at a time, and stirring was carried out for 3 hours. Next, a THF 100 ml solution of 20.0 g of 4-chloromethyl-4′-propylbicyclohexane was slowly added dropwise, and stirring was carried out for another 3 hours. Then 9.00 g of tetrafluoroethylene was added to allow reaction for 30 minutes while returning to room temperature. The resultant reaction mixture was poured into 500 ml of 1N hydrochloric acid, and mixing was carried out. Then, 500 ml of toluene was added to separate layers to an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with 1N hydrochloric acid and water, and the resultant solution was dried over anhydrous magnesium sulfate. The resultant solution was concentrated under reduced pressure, a residue was purified by fractionation by means of column chromatography (silica gel; heptane), and thus 21.9 g of 4-propyl-4′-(2,3,3-trifluoroallyl)-1,1′-bicyclohexane (T-2) was obtained. Yield from compound (T-1) was 93%.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[C:18]1([S:24]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[CH:32]=O)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:32][C:28]3[N:27]([S:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:26])=[O:25])[CH:31]=[CH:30][CH:29]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccn1S(=O)(=O)c1ccccc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cccn1S(=O)(=O)c1ccccc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 1-(phenylsulfonyl)-1H-pyrrole-2-carbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[Cl:6][C:7]1[CH:15]=[C:14](F)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>C1COCC1>[Cl:6][C:7]1[CH:15]=[C:14]([NH:4][CH2:3][CH:2]([F:5])[F:1])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: NCC(F)F
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 30 h

Procedure:
A mixture of 2,2-difluoroethylamine (1.65 mL, 23 mmol) and THF (50 mL) is added to a mixture of 2-chloro-4-fluoro-5-nitro-benzoic acid (5.00 g, 22 mmol), TEA (6.33 mL, 45 mmol) and 50 mL THF. The mixture is stirred overnight at rt and 30 h at 60° C., concentrated and diluted with water. The resulting precipitate is collected by filtration, washed with water and dried. Yield: 3.3 g (61%); HPLC Rt=1.14 min (method A). MS m/z: 281 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: OCC1CCCCC1
Product: N#Cc1c(N)cccc1OCC1CCCCC1

Procedure:
Prepared as in Example 22b from cyclohexylmethanol and 2-amino-6-fluorobenzonitrile as a colorless oil (50%). 1H NMR (400 MHz, CDCl3) δ 1.07-1.09 (m, 2H), 1.28-1.32 (m, 3H), 1.75-1.90 (m, 6H), 3.79 (d, J=6.4 Hz, 2H), 4.37 (s, 2H), 6.20 (d, J=8.4 Hz, 1H), 6.28 (d, J=8.4 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H). MS 231 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][C:4]=1[S:11][CH3:12].[C-:13]#[N:14].[K+]>CS(C)=O>[CH3:12][S:11][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[S:2][CH3:1])[CH2:9][C:13]#[N:14]
Reactant: [C-]#N
Reactant: CSc1ccc(CCl)cc1SC
Agent: [K+]
Solvent: CS(C)=O
Product: CSc1ccc(CC#N)cc1SC
Temperature: 0 °C

Procedure:
42.5 g (0.194 mol) of 1,2-bis(methylthio)-4-chloromethyl-benzene and 25.3 g (0.388 mol) of potassium cyanide are stirred at ambient temperature in 200 ml of DMSO. When the starting material can no longer be detected by GC analysis, the brown solution is poured into ice/water and extracted with acetic acid acetate and the organic phase is dried over magnesium sulfate. After evaporation 34.8 g (85.7%) of 3,4-bis(methylthio)-benzyl cyanide are obtained as brown substance. The 1H-NMR-spektra data (CDCl3) are in accordance with the proposed structure of the compound: 7.24-7.06 ppm (s and d, 3 aromatic H), 3.70 ppm (s, 2H), 2.47 ppm (s, CH3S) and 2.45 ppm (2 s, CH3S).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[C:19]2[CH:25]=[C:24]([N+:26]([O-])=O)[C:22]([NH2:23])=[CH:21][C:20]=2[C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+]>O1CCOCC1.O>[C:31]1([C:30]#[C:29][C:20]2[CH:21]=[C:22]([NH2:23])[C:24]([NH2:26])=[CH:25][C:19]=2[C:10]2[CH:11]=[C:12]([NH2:16])[C:13]([NH2:15])=[CH:14][C:9]=2[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1cc(C#Cc2ccccc2)c(-c2cc([N+](=O)[O-])c(N)cc2C#Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(C#Cc2ccccc2)c(-c2cc(N)c(N)cc2C#Cc2ccccc2)cc1N
Reaction time: 0.08 h
Yield: 75.5 %

Procedure:
A solution of 2,2'-bis(phenylethynyl)-5,5'-dinitrobenzidine (0.474 g, 0.00100 mol) in dioxane (50 ml), freshly distilled from FeSO4 (3.65 g, 0.024 mol), was added to a boiling solution of FeSO4 (3.65 g, 0.024 mol) in water (50 ml.) which was stirred under nitrogen. After 5 minutes, ammonium hydroxide (20 ml, 30%) was added slowly followed by 20 ml. more of dioxane. The resultant dark suspension was stirred and refluxed for 30 minutes at which point additional ammonium hydroxide (20 ml) was added. Refluxing was continued for 30 minutes and then the reaction mixture was cooled and extracted three times with 100 ml. of chloroform. The combined chloroform extracts were concentrated to dryness on a rotary evaporator. The residue was dissolved in methylene chloride (20 ml.) and filtered after which the filtrate was poured with stirring into 20 ml. of hexane. The resultant precipitate was filtered, washed with hexane, and dried at 23° C in a vacuum oven at 1 mm of Hg for 24 hours to give 0.313 g (76% yield) of 2,2'-bis(phenylethynyl)-5,5'-diaminobenzidine which softened above 100° C to a viscous melt.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23]C3C=CC=CC=3)=O)=[CH:16][CH:15]=2)[N:11]=[C:10]([C:30]([O:32][CH3:33])=[O:31])[CH:9]=1.C(N(CC)CC)C.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>CN(C=O)C>[CH:41]1([NH:44][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:11]=[C:10]([C:30]([O:32][CH3:33])=[O:31])[CH:9]=[C:8]([N:3]4[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]4[CH3:1])[N:13]=3)=[CH:15][CH:16]=2)=[O:23])[CH2:43][CH2:42]1
Reactant: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Methyl 6-[(3S)-3-methylmorpholin-4-yl]-2-[4-(phenoxycarbonylamino)phenyl]pyrimidine-4-carboxylate (547 mg) was dissolved in DMF (8 mL) and triethylamine (0.59 mL) followed by cyclopropylamine (0.491 mL) added. The reaction was stirred at 40° C. for 2 hours then the mixture was vacuumed to dryness and partitioned between DCM (50 mL) and water (50 mL). The organic layer was dried over magnesium sulphate and vacuumed to dryness then chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (351 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:16]3=[O:26])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[N+:27]([O-])([OH:29])=[O:28]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:16]3=[O:26])=[C:13]([N+:27]([O-:29])=[O:28])[CH:14]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CCN1CCN(c2ccc(-c3ccc(C#N)cc3)cc2)C1=O
Reactant: O=[N+]([O-])O
Product: COC(=O)CCN1CCN(c2ccc(-c3ccc(C#N)cc3)cc2[N+](=O)[O-])C1=O

Procedure:
Prepared by reacting 1-(4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one with fuming nitric acid at 0° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([CH:36]=1)[C:34]#[N:35]>CN(C=O)C>[C:34]([C:33]1[CH:36]=[C:29]([CH:30]=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39])[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2)#[N:35]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Temperature: 75 °C
Yield: 85.7 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (50 mg, 0.183 mmol) and cesium carbonate (89 mg, 0.274 mmol) in DMF (2 mL) was added 5-(chloromethyl)-2-isopropoxybenzonitrile (46 mg, 0.22 mmol). The reaction was heated at 75° C. for 5 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (70 mg). LCMS m/z=447.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.1 Hz, 3H), 1.40 (d, J=6.1 Hz, 6H), 1.51-1.61 (m, 1H), 1.98-2.08 (m, 1H), 2.08-2.24 (m, 2H), 2.55 (dd, J=15.6, 8.6 Hz, 1H), 2.93 (dd, J=15.6, 5.4 Hz, 1H), 3.45-3.54 (m, 1H), 3.82-3.92 (m, 1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.61-4.68 (m, 1H), 5.00 (s, 2H), 6.17 (s, 1H), 6.85 (dd, J=8.8, 2.4 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([C:16](=[O:27])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1)[CH2:7][CH2:6]2.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[CH2:48][NH2:49])[CH3:42]>ClCCl.C1COCC1.CN(C=O)C>[CH2:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[CH2:48][NH:49][C:24]([C:20]1[CH:19]=[C:18]([NH:17][C:16]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([S:2][CH3:1])=[C:11]([C:12]([F:13])([F:15])[F:14])[CH:10]=3)[CH2:6][CH2:7]2)=[O:27])[CH:23]=[CH:22][CH:21]=1)=[O:25])[CH3:42]
Reactant: CCN1CCCC1CN
Reactant: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)O)c1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1cccc(NC(=O)N2CCc3cc(SC)c(C(F)(F)F)cc32)c1
Reaction time: 1 h

Procedure:
The carboxylic acid from Example 12 (0.5 g, 1.25 mol) in dichloromethane (10 ml) was treated with oxalyl chloride (6.3 ml, 3.4 mmol) and DMF (catalytic). The solution was stirred for 1 hour and evaporated to dryness. The residue in dry THF (5 ml) was added to a stirred solution of triethylamine (0.3 ml, 4 mmol) and N-Ethyl-2-aminomethyl pyrrolidine (0.57 g, 4.5 mmol). After 3 hours at room temperature the solution was partitioned (EtOAc/H2O). Drying and removal of organics followed by rexst (EtOAc/60°-80° C. petrol) afforded the title compound as a white powder, m.pt. 174°-175° C.