Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[N:21]([CH2:33][CH3:34])[C:22]3[C:27]([C:28]=2[C:29]#[N:30])=[CH:26][CH:25]=[C:24]([O:31][CH3:32])[CH:23]=3)=[CH:14][CH:13]=1.C(OC=O)(=O)C>C1COCC1>[C:29]([C:28]1[C:27]2[C:22](=[CH:23][C:24]([O:31][CH3:32])=[CH:25][CH:26]=2)[N:21]([CH2:33][CH3:34])[C:20]=1[C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:8]=[O:10])=[CH:13][CH:14]=1)#[N:30]
Reactant: O=CO
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Agent: CC(=O)OC=O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCn1c(C#Cc2ccc(NC=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) are heated at 65° C. for 1 hour. This is cooled to 0° C. 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as in example 1H, is taken up in THF (1.2 mL) and added to the formic acetic anhydride mixture. This is stirred at 0° C. for 30 minutes. The reaction mixture is then partitioned between H2O and EtOAc. The EtOAc layer is washed with saturated NaHCO3, followed by saturated brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/EtOAc) yields of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide (105 mg, 96%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[C:17]([Br:27])[CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCNc1ncccc1-c1snnc1-c1cccnc1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCNc1ncc(Br)cc1-c1snnc1-c1cccnc1Cl
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
To a solution of 4-(2-chloropyridin-3-yl)-5-(2-ethylaminopyridin-3-yl)-1, 2, 3-thiadiazole (0.324 g) in acetic acid (4 mL) containing sodium acetate (0.098 g) was added dropwise a solution of bromine (0.185 g) in acetic acid (1 mL). After 5 minutes, the mixture was diluted with ethyl acetate, washed with aqueous potassium carbonate, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane/chloroform 1/3/0.5) gave 4-(2-chloropyridin-3-yl)-5-(2-ethylamino-5-bromo-pyridin-3-yl)-1, 2, 3-thiadiazole (0.329 g).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16].[C:17](Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1C=CC=CC=1>CCCCCC>[C:17]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[CH:15][S:14][CH:13]=[C:5]12)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Reactant: CCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 7 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.6 g. (4.8 ml.) of hexanoyl chloride in 70 ml. of benzene is heated with stirring under reflux for 3 hours. The reaction mixture is stirred with cooling in an ice bath for 2 hours, 150 ml. of hexane is added and the mixture is placed in a chill room. The solvents are removed in vacuo on a steam bath. A 10 ml. portion of ether is added to the residue and the mixture is returned to the chill room. The tan crystals are collected by filtration, washed with ether and dried. The ether is concentrated giving a green oil which is triturated twice with hexane and once with a mixture of hexane and ether, giving crystals which are collected, washed with ether and dried. The two crops of crystals are combined, dissolved with warming in 75 ml. of ether and filtered. The filtrate is concentrated to 35 ml. and stored in a cold room for 4 hours. The solid is collected, washed with ether then hexane and dried, giving the desired product, mp. 76°-77° C.
Reaction SMILES: [CH:1](=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H].CN(C)C=O>[Pd].CO>[CH2:1]([CH:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCCC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 35.9 %

Procedure:
1.3 g of 10-hexylidene-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one are hydrogenated at a temperature in the region of 20° C. and at a pressure of 9.4 bar of hydrogen in the presence of 120 ml of dimethylformamide, 20 ml of methanol and 0.3 g of 10% palladium on charcoal for 17 hours. After filtration of the catalyst under inert atmosphere, the solvents are evaporated off and the crude product (1.2 g) is purified by chromatography on a column of silica (120 g partially deactivated with 2 ml of water), eluting with a mixture of dichloromethane and methanol (90/10 by volume). 0.47 g of 10-hexyl-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one is thus obtained, in the form of a beige solid melting at about 185° C. (Analysis % calculated C: 74.24, H: 6.89, N: 13.67, O: 5.20, % found C: 74.3, H: 7.0, N: 13.6).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
To a solution of 6-bromo-2-nitropyridin-3-ol (1.0 g, 4.6 mmol), in anhydrous DMF (15 mL) at 0° C. was added 60% sodium hydride in mineral oil (200 mg, 5.0 mmol). The reaction mixture was stirred at 0° C. for 5 min and at room temperature for 15 min. Benzyl bromide (0.6 mL, 5.0 mmol) was added dropwise and the resulting mixture was stirred at 60° C. for 1 hour, cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Si—PPC, Et2O:pentane, gradient 0:100 to 100:0) to give 3-Benzyloxy-6-bromo-2-nitropyridine as a yellow solid (956 mg, 67%). 1H NMR (400 MHz, CHCl3-d): δ 7.60 (d, J=8.6 Hz, 1 H); 7.41-7.35 (m, 6 H); 5.25 (s, 2 H).
Reaction SMILES: [CH:1]1([CH:7]([N:10]2[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=[C:11]2[C:21]2[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][N:33]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:40]=[CH:41][C:32]([O:9][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]2[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=[C:11]2[C:21]2[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[N:33][CH:34]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(CO)C2CCCCC2)c(OC)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)nc1
Yield: 4 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate from 2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethanol and methyl 6-hydroxynicotinate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The crude product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give the desired compound as a white solid (4%). MS (Turbo Spray) m/z=553.4 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Br)c1ccccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccccc1)c1ccccc1F
Yield: 99.8 %

Procedure:
A solution of bromo-(2-fluoro-phenyl)-acetic acid methyl ester (I259) (1.47 g, 5.95 mmol), aniline (814 ul, 8.93 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.53 mL, 8.93 mmol) in acetonitrile (10 mL) is heated under microwave irradiation at 100° C. for 1 hour. The solvent is evaporated, the residue is taken up with DCM and washed with water and brine, dried over Na2SO4 and evaporated to afford intermediate I262 as a dark brown oil (1.54 g, quantitative yield).
Reaction SMILES: [CH2:1]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH2:1]([N:5]1[C:17](=[O:18])[C:16]([OH:22])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6]1(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNS(=O)(=O)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Butyl-1-phenylmethanesulfonamide (2.0 g, 8.80 mmol) was dissolved in dry DMF (13 mL) under an atmosphere of nitrogen. Diethyl oxalate (1.44 g, 9.83 mmol) was added and the reaction mixture was cooled to 0° C. using an ice-bath. Potassium tert-butoxide (1.25 g, 11.14 mmol) was added in one portion and the reaction mixture was stirred for 5 mins at 0° C., followed by 19 h at rt. The mixture was cooled in an ice-bath and HCl (2M) was carefully added to give a pH˜1 of the mixture. Most of the solvents were evaporated and the residue was partitioned between HCl (2M) and EtOAc. The combined organic layers were washed with water several times, dried over MgSO4 and evaporated to dryness. The residue was purified using preparative HPLC (ACE C8, 0.1M NH4OAc/MeCN, gradient) to give the title compound (0.96 g, 39%); 1H NMR (400 MHz, DMSO-d6): δ 7.88-7.83 (m, 2H), 7.22-7.29 (m, 3H), 7.14 (bs, 1H), 6.98-7.15 (m, 2H), 3.48 (t, 2H), 1.59-1.67 (m, 2H), 1.27-1.37 (m, 2H), 0.88 (t, 3H); 13C NMR (100 MHz, DMSO-d6): δ 163.1, 158.4, 132.3, 128.7, 124.2, 123.2, 37.8, 30.9, 20.2, 14.1; Mass Spectrum: M−H+ 280.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([SH:15])([CH3:14])[CH3:13].[OH-].[Na+]>CS(C)=O.O>[CH:12]([S:15][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:14])[CH3:13]
Reactant: CC(C)S
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Sc1ccc(N)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 96.8 %

Procedure:
To a stirred solution containing 34.5 g (0.20 mole) of 4-chloro-3-nitroaniline and 24 g (0.30 mole) of isopropyl mercaptan in 200 ml of DMSO was added dropwise at ambient temperature a solution of 8.0 g (0.20 mole) of sodium hydroxide in 10 ml of water. The addition was exothermic to 60° and the mixture became deep red in color. After three days, the reaction mixture was poured into water and extracted with methylene chloride. The combined extracts were washed with water, dried with anhydrous MgSO4, filtered and concentrated to give 41.1 g (97%) of product as a red-brown syrup.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc(OCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Temperature: 0 °C
Yield: 56.2 %

Procedure:
A solution of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoic acid (460 mg, 1.42 mmol, 1.00 equiv), EDCI (320 mg, 1.68 mmol, 1.18 equiv), HOBT (240 mg, 1.78 mmol, 1.25 equiv), pyridin-3-ylmethanamine (180 mg, 1.67 mmol, 1.17 equiv) and triethylamine (440 mg, 4.36 mmol, 3.06 equiv) in N,N-dimethylformamide (6 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of ice/water. The solid was collected by filtration and washed with 3×10 mL of hexane. The crude product was purified on a silica gel column eluted with chloroform/methanol (50:1-20:1) to give 0.33 g (56%) of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a gray solid. LC-MS: (ES, m/z): 414 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 9.16 (s, 2H), 8.56 (s, 1H), 8.46 (s, 1H), 8.00-7.95 (m, 3H), 7.75 (d, 1H), 7.34 (m, 1H), 6.86-6.81 (m, 2H), 6.68 (d, 1H), 4.50 (d, 2H), 3.78 (s, 2H), 2.50 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([N:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][C:24]([OH:26])=[O:25])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:33][C:34]([NH2:36])=[NH:35])=[N:11][CH:10]=1.Cl.NC(N)=N.[C:42](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)C1C=CC=CC=1)([CH3:45])([CH3:44])[CH3:43]>COCCOC>[C:42]([O:25][C:24](=[O:26])[CH2:23][N:22]([S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:33][C:34]([NH2:36])=[NH:35])=[CH:17][CH:16]=1)(=[O:20])=[O:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)c3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)CN(c1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CN(c1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 13.3 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-phenylglycine trifluoroacetate ##STR16## NaH (32 mg, 80% dispersion by wt in mineral oil, 1.07 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (164 mg, 1.71 mmol) in DME (5.0 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-phenylglycine t-butyl ester (200 mg, 0.43 mmol) was added and the mixture heated at 95° C. for 6 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880N3 (97:3:0.3 to 95:5:0.5) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-phenylglycine t-butyl ester (28 mg, 0.057 mmol) as a yellow resin.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]1)=[O:11].Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:46]([C:47]2[NH:48][CH:49]=[CH:50][N:51]=2)=[CH:45][N:44]=[C:43]([NH:52][CH2:53][CH2:54][NH:55]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:42]=1>>[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:46]([C:47]2[NH:51][CH:50]=[CH:49][N:48]=2)=[CH:45][N:44]=[C:43]([NH:52][CH2:53][CH2:54][NH:55][C:24]2[N:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=2)[N:42]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(=O)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
1-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}-ethyl)amino]-3-pyridyl}ethan-1-one was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-yl]ethylamine and 1-(6-chloro-3-pyridyl)-ethanone (prepared as described in Tetrahedron 48:9233 (1992)) in accordance to the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[CH2:15]([N:22]1[CH2:31][CH2:30][CH:29]2[C:24](=[N:25][C:26]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:27][C:28]2=O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:15]([N:22]1[CH2:31][CH2:30][C:29]2[C:28]([Cl:12])=[N:27][C:26]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:25][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1N=C(CN2CCOCC2)N=C2CN(Cc3ccccc3)CCC12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)c1ccccc1
Product: Clc1nc(CN2CCOCC2)nc2c1CCN(Cc1ccccc1)C2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
N,N-Dimethylaniline (1.2 g, 10 mmol) and phosphorus oxychloride (12.2 g, 80 mmol) were added to the solution of 7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4(4aH)-one (˜10 mmol) in 1,2-dichloroethane (30 mL, anhydrous) and were stirred in a preheated oil bath at 90° C. for 30 min. Reaction mixture was poured into ice, neutralized by solid sodium bicarbonate, extracted by ethyl acetate and dried over sodium sulfate. Solvent was removed in vacuo and brown oil residue was directly gone to next step.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=O)=[CH:6][CH:5]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[OH:31]/[N:30]=[C:12](/[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)\[CH2:11][C@H:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:28])=[CH:5][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: NO
Reactant: CNC(=O)c1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC(=O)c1ccc([C@@H](C/C(=N\O)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 132, step 6, from N-methyl-4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-benzamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=388.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[C:7](=[O:21])[CH:8](C(OC)=O)[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.CS(C)=O.O>>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:21])[CH2:8][CH:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)C1C(=O)c2sc(Br)cc2C1c1ccc(Cl)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C1CC(c2ccc(Cl)cc2)c2cc(Br)sc21
Temperature: 150 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a 500 mL round bottom flask was added a solution of methyl 2-bromo-4-(4-chlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate (3.96 g, 10.3 mmol) in dimethyl sulfoxide (88.393 mL, 1245.6 mmol). Water (4.420 mL, 245.3 mmol) was added and the reaction mixture was heated to 150° C. and allowed to stir for 3 hours. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (500 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using a ISCO (40 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (2.91 g, 82%) as a brown oil. LC/MS (AA) ES− 327, 329, 331. 1H NMR (dmso-d6, 400 MHz): δ 7.40-7.38 (m, 2H), 7.31 (s, 1H). 7.24-7.22 (m, 2H), 4.67 (dd, 1H), 3.40 (dd, 1H), 2.72 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1(S(O)(=O)=O)[C:15](S(O)(=O)=O)=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:7]([CH3:32])=[N:6]3)[NH:3]1.[Na][Na]>>[CH3:32][C:7]1[CH:8]=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[C:5](=[C:4]3[C:13](=[CH:12][CH:11]=2)[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][C:2]([CH3:1])=[N:3]3)[N:6]=1
Reactant: Cc1cc(-c2ccccc2)c2ccc3c(c2n1)NC(C)(S(=O)(=O)O)C(S(=O)(=O)O)=C3c1ccccc1
Agent: [Na][Na]
Product: Cc1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(C)nc3c2n1

Procedure:
2, 9-Dimethyl-4, 7-diphenyl-1, 10-phenanthrolinedisulfonic acid, disodium salt
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:20]3[N:19]=[N:18][C:17]([Cl:16])=[CH:22][CH:21]=3)[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1ccc(CN2CCC(Nc3ccc(Cl)nn3)CC2)cc1
Temperature: 120 °C

Procedure:
A solution of 1-(4-chlorobenzyl)-piperidin-4-yl amine (1 g, 4.45 mmol) (prepared by a procedure similar to that described in WO2001098273), 3,6-dichloropyridazine (670 mg, 4.45 mmol) and sodium carbonate (940 mg, 8.90 mmol) in dimethylacetamide (5 ml) was heated at 120° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 40 minutes. After this period, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. Purification by reverse phase HPLC (conditions as previously described) gave E16 (228 mg, 15%). C16H18Cl2N4 requires 336; Found 337 (MH+). 1H NMR (360 MHz, CDCl3) δ1.52 (qd, J=11.5, 3.5 Hz, 2H), 2.08 (d, J=12.5 Hz, 2H), 2.16 (t, J=11.3 Hz, 2H), 2.82 (d, J=11.5 Hz, 2H), 3.48 (s, 2H), 3.77-3.87 (m, 1H), 4.55 (d, J=7.8 Hz, 1H), 6.59 (d, J=9.3 Hz, 1H), 7.14 (d, J=9.3 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 7.29 (d, J=7.7 Hz, 2H)