Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:4].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:27][N:28]1[CH2:41][CH2:40][C:39]2[C:38]3[CH:37]=[C:36]([CH3:42])[CH:35]=[CH:34][C:33]=3[NH:32][C:31]=2[CH2:30][CH2:29]1>CN(C=O)C.[Cu]I.O>[CH3:27][N:28]1[CH2:41][CH2:40][C:39]2[C:38]3[CH:37]=[C:36]([CH3:42])[CH:35]=[CH:34][C:33]=3[N:32](/[CH:2]=[C:3](/[C:5]3[CH:10]=[CH:9][N:8]=[CH:7][N:6]=3)\[CH3:4])[C:31]=2[CH2:30][CH2:29]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(=CBr)c1ccncn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccncn1
Reaction time: 8 h

Procedure:
4-(1-bromoprop-1-en-2-yl)pyrimidine (236 mg, 1.2 mmol) was dissolved in DMF (5 mL) and was added K3PO4 (424 mg, 2 mmol) followed by the addition of Copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (214 mg, 1 mmol) was added and purged nitrogen for 2 min. Reaction mass was stirred at 85 degree C. for overnight. Water was added and filtered the solid mass under vacuum. Crude was purified on silica gel (100-200 mesh) using 0-10% methanol: dichloromethane as eluent. Yield: 72 mg. 1H NMR (CDCl3, Oxalate salt) δ (ppm): 9.20 (s, 1H), 8.76 (s, 1H), 8.0 (s, 1H), 7.44 (d, 1H), 7.30 (s, 1H), 7.0 (s, 2H), 2.99 (m, 4H), 2.84 (m, 4H), 2.50 (s, 3H), 2.42 (s, 3H), 2.04 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:20][CH2:19]1)[C:12](O)=[O:13])=[O:7].C(N(CC)CC)C.[C:38]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[C:38]1([CH2:44][CH2:45][CH2:46][NH:47][C:12]([C:11]2[CH:15]=[CH:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH2:19]3)=[C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH:10]=2)=[O:13])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCCCc1ccccc1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2NC(=O)c2ccco2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCc3ccccc3)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a suspension of 3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (0.1 g, 0.246 mmol) in methylene dichloride (5 ml), triethylamine (0.074 g, 0.74 mmol), (3-phenylpropyl)amine (0.044 g, 0.370 mmol) and 1-propane phosphonic cyclic anhydride (0.23 g, 0.74 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and extracted with dichloromethane (10 ml×1). The organic layer was washed with water (10 ml×2) and dried over anhydrous sodium sulfate. The organic layer was concentrated and the crude product obtained was purified by flash chromatography using silica gel column to get (0.070 g, 67.9%) of the titled compound as a brown solid.
Reaction SMILES: NC1C=NC=CC=1.[NH2:8][C:9]1[C:14](C)=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:16][C:17]1C=NC=CC=1.COC1C=NC=CC=1.[NH2-].[Na+]>C1(C)C(C)=CC=CC=1>[NH2:8][C:9]1[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Oc1cccnc1
Reactant: Cc1cccnc1N
Agent: COc1cccnc1
Agent: Nc1cccnc1
Agent: [NH2-]
Solvent: Cc1ccccc1C
Product: COc1cccnc1N
Yield: 40.3 %

Procedure:
A mixture of 28.1 g (0.72 mole) of sodamide, 400 cc of toluene containing 0.1 cc of oleic acid, and 65.5 g (0.60 mole) of 3-methoxypyridine was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 340 psig. Cooling water was turned on the reflux condenser. The mixture was heated with stirring to 120° C. and kept heating (maximum temperature 136° C.) for about 4.5 hours until noncondensable gases stopped passing through the pressure relief valve. The autoclave was cooled the 25° C., vented to atmospheric pressure, and hydrolyzed with 150 cc of water. The oil phase was separated. The aqueous phase was extracted twice with 50 cc of an equal volume solution of 4-picoline and toluene. The oil layer and extracts were combined and distilled under vacuum to give 0.14 mole of recovered 3-methypyridine, 0.05 moles of 2-aminopyridine. 0.02 moles of 3-aminopyridine, 0.02 moles of 2-amino-3-methylpyridine, and 0.18 moles of 3-hydroxypyridine. When 3-methoxypyridine was aminated with sodamide in refluxing xylene at atmospheric pressure, a 40.3% yield of 2-amino-3-methoxypyridine (m.p. 79°-80° C.) was obtained. Both 2-amino-3-methylpyridine and 2-amino-3-methoxypyridine are valuable as starting materials for preparing herbicides as shown in Suzuki et al., Ger. Offen. 2,831,578 (1979). The 3-hydroxypyridine is a valuable starting material for the preparation of the drugs pirbuterol (cardiostimulant and oral brochodialator) and pyridostigmine (cholinergic).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(N(CC)CC)C.[N-:20]=[N+:21]=[N-:22].[Na+].Cl>CN1CCCC1=O>[N+:9]([C:5]1[CH:4]=[C:3]([C:1]2[NH:22][N:21]=[N:20][N:2]=2)[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Temperature: 160 °C
Yield: 85.6 %

Procedure:
To a solution of 3-cyanonitrobenzene (20 g) in 1-methyl-2-pyrrolidinone (200 ml) was added triethylamine hydrochloride (27.9 g) followed by sodium azide (26.4 g). The mixture was heated at 160° C. for 1.5 hours, then cooled to ambient temperature, poured into ice water (1000 ml) and acidified using 5M hydrochloric acid. The solid which precipitated from the mixture was filtered, washed with water and dried under vacuum at 50° C. to afford the title tetrazole (22.1 g) as a beige powder. mp 154°-156° C. 1H NMR (360 MHz, CDCl3) δ 7.59 (1H, dd, J=8 Hz), 8.19 (1H, d, J=8 Hz), 8.36 (1H, d, J=8 Hz), 8.86 (1H, s).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[C:33]([F:34])([F:36])[F:35])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: FC(F)(F)c1cc(CCl)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(C(F)(F)F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (50 mL) at room temperature. The mixture was stirred for 1 h at this temperature and 1-benzyloxy-4-chloromethyl-2-trifluoromethyl-benzene (CAB03050, 1.50 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) and water (30 mL) were added. The mixture was transferred into a separation funnel and washed with water (2×30 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (40 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.87 g (83%). 1H-NMR (400 MHz, d6-DMSO) δ=5.05 (s, 2H), 5.23 (s, 2H), 6.78 (d, J=9.0 Hz, 2H), 7.26 (d, J=8.6 Hz, 1H), 7.30-7.44 (m, 5H), 7.51 (dd, J=8.6, 2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 8.79 (s, 2H). LRMS (FAB+): 450.2 (100, [M+H]+). HRMS (FAB+): 450.15404 C24H19N5OF3 requires 450.154170
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])C(C#N)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.Cl.[OH-].[Na+].[C:33]([OH:36])(=[O:35])[CH3:34]>O>[Cl:19][C:6]1[CH:5]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:34]([C:33]([OH:36])=[O:35])=[N:21]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(=O)O
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 120 °C
Yield: 78 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (31) (136 mg, 0.312 mmol) in glacial acetic acid (3.0 mL) was treated with concentrated hydrochloric acid (0.345 mL). The reaction mixture was heated to 120° C. for 24 h. Starting material was still present by LC/MS. Additional concentrated hydrochloric acid (0.34 mL) was added. The reaction mixture was heated to 120° C. for another 24 h. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). At this time, the reaction was made basic by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ether (100 mL). The organic layer was discarded. The aqueous layer was acidified by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (32) (111 mg, 78%) as an orange solid which was used without further purification; LRMS for C17H13Cl2N5O6 (M+) m/z=454. Molecular Weight=454.2291; Exact Mass=453.0243
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH2:11][C:12]4[C:17]([C:18]=3[C:19]=2[C:20]#[N:21])=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:32]CC1>>[O:32]=[C:11]1[C:10]2[C:9]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:19]([C:20]#[N:21])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1-c1ccccc1C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C
Yield: 89 %

Procedure:
A solution of 3-(piperidin-1-yl)-1-(thiophen-2-yl)-9H-fluorene-4-carbonitrile (356 mg) in THF was added sodium hydride (38 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; yield 89%; mp 172-174° C.; ESMS 371 (M++1); IR (KBr) 1703 cm−1 (CO), 2218 (CN); 1H NMR (300 MHz, CDCl3) δ 1.66-1.75 (m, 2H, CH2), 1.81-1.90 (m, 4H, 2CH2), 3.38-3.44 (m, 4H, 2CH2), 6.88 (s, 1H, ArH), 7.18 (dd, J=8.85 Hz & J=3.75 Hz, 1H, ArH), 7.44 (t, J=7.5 Hz, 1H, ArH), 7.48 (d, J=6 Hz, 1H, CH), 7.59 (t, J=7.6 Hz, 1H, ArH), 7.68 (d, J=7.2 Hz, 1H, ArH), 7.84 (d, J=4.7 Hz, 1H, CH), 8.38 (d, J=7.5 Hz, 1H, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[N:5]=[C:4]2[NH:14][CH:15]=[N:16][C:3]=12.C(O[C@@H:21]1[O:43][C@H:42]([CH2:44][O:45]C(=O)C2C=CC=CC=2)[C@@H:32]([O:33]C(=O)C2C=CC=CC=2)[C@H:22]1[O:23]C(=O)C1C=CC=CC=1)(=O)C.FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S([O-])(=O)=O.[K+].C[Si](C)(C)N[Si](C)(C)C.C[Si](Cl)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl.CO.N>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[N:5]=[C:4]2[N:14]([C@@H:21]3[O:43][C@H:42]([CH2:44][OH:45])[C@@H:32]([OH:33])[C@H:22]3[OH:23])[CH:15]=[N:16][C:3]=12
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CCOC(=O)Nc1cc(Cl)c2nc[nH]c2n1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of 1.2 g ethyl N-(7-chloro-3H-imidazo-[4,5-b]-pyridin-5-yl)-carbamate, prepared as described by Schelling and Salemink, Receuil 93 (6), 160 (1974), 2.52 g of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose, 4.06 g potassium nonafluorobutanesulfonate and 0.56 g hexamethyldisilazane in 70 ml of acetonitrile is added 1.67 g of trimethylsilyl chloride. The mixture is heated to reflux under nitrogen for 21 hours. It is cooled, diluted with methylene chloride (100 ml) and treated with saturated aqueous sodium bicarbonate (50 ml). The organic phase is separated, and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with saturated aqueous sodium bicarbonate, then with brine, and then dried (sodium sulfate). Evaporation of the solvent in vacuo gives an oil which is dissolved in 100 ml of methanol saturated with ammonia, and the solution is stirred at room temperature for 40 hours. The clear solution is concentrated in vacuo, the residue is redissolved in water and washed twice with ether. The aqueous layer is concentrated in vacuo to give a glass. It is dissolved in hot acetonitrile, the solution is filtered, and the solvent is evaporated in vacuo to afford ethyl N-[7-chloro-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridin-5-yl]-carbamate, m.p 107°-111°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24].[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][CH2:17][N:12]1[C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCC1CCN1C(=O)COc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (0.94 g, 5.150 mmol), NaI (0.19 g, 1.287 mmol), and K2CO3 (2.13 g, 15.452 mmol) in dry DMF (10 mL) was stirred at room temperature overnight (18 hours). The reaction was diluted with water (150 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.525 g, 67%) as a yellow solid. 1H NMR (DMSO-d6) δ 1.47-1.65 (m, 4H), 1.79-2.13 (m, 4H), 2.18 (s, 3H), 2.89-2.95 (m, 1H), 3.98 (t, 2H, J=7.8 Hz), 4.79 (s, 2H), 7.40 (d, 1H, J=9.0 Hz), 7.80 (d, 1H, J=2.7 Hz), 7.98 (dd, 1H, J=2.4, 9.0 Hz); ESI-MS (m/z, %): 306 (MH+, 100).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7](Br)[N:6]=1)=[O:4].[CH:18]([OH:21])([CH3:20])[CH3:19].[H-].[Na+].[OH-].[K+]>O1CCOCC1.CN(C=O)C.C(O)=O.O>[CH:18]([O:21][C:7]1[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[N:9][C:8]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:20])[CH3:19]
Reactant: COC(=O)c1cnc(N2CCCCC2)c(Br)n1
Reactant: CC(C)O
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O=CO
Product: CC(C)Oc1nc(C(=O)O)cnc1N1CCCCC1
Temperature: 60 °C
Yield: 21.3 %

Procedure:
A mixture of 0.212 g (0.707 mmol) 6-bromo-5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester, 0.006 g (0.778 mmol) isopropanol and 0.034 g (0.778 mmol) NaH (55% dispersion in oil) in 1.7 mL dioxane was heated to 60° C. for 16 h. Water and 5N KOH was added and the mixture was heated to 50° C. for 4 h. Formic acid and DMF was added and the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product fractions were combined and evaporated to yield 0.04 g (21%) of the title compound. m/z (ES+): 266.4 (M+H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([O-:14])=O)[CH:8]=2)[NH:3][CH:2]=1.Cl.O=C1CC2C(=CC=C(/C=C/C(O)=O)C=2)N1.[CH3:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH2:41][NH:42][CH3:43])=[CH:33]1.CC1NC2C(C=1CNC)=CC=CC=2>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([N:42]([CH3:43])[CH2:41][C:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]([CH3:31])[CH:33]=3)=[O:14])[CH:8]=2)[NH:3][CH:2]=1
Reactant: O=C([O-])/C=C/c1cnc2[nH]cnc2c1
Reactant: CNCc1cn(C)c2ccccc12
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Agent: O=C(O)/C=C/c1ccc2c(c1)CC(=O)N2
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2[nH]cnc2c1
Yield: 90 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(3H-imidazo[4,5-b]pyridin-6-yl)acrylate (0.14 g, 0.74 mmole), from Preparation 6, for the (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 1-methyl-3-(methylaminomethyl)indole (0.14 g, 0.81 mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the title compound (0.23 g, 89%) was prepared as a light yellow solid: MS (ES) m/e 346 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:13]([O:15][CH3:16])=[O:14])[N:7]1C(OC(C)(C)C)=O)=[O:5].Cl>O1CCOCC1>[CH2:2]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:17][C:18]([OH:20])=[O:19])[C:13]([O:15][CH3:16])=[O:14])[NH:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)C1CCC(CN(CC(=O)OC(C)(C)C)C(=O)OC)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(CN(CC(=O)O)C(=O)OC)N1
Yield: 114.3 %

Procedure:
5-[(tert-Butoxycarbonylmethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (304 mg, 0.68 mmol) was added to a solution of hydrogen chloride in dioxane (4N, 15 mL). After 16 hours the solvent was removed under reduced pressure and the resulting residue was azeotroped with toluene to provide 5-[(carboxymethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-2-carboxylic acid ethyl ester (224 mg)—assumed 100% yield.
Reaction SMILES: [C:1]1([C@H:7]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21]CC2C=CC(OC)=CC=2)[CH:16]=[O:17])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C>[C:1]1([C@H:7]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[OH:21])[CH:16]=[O:17])[C:8]([F:11])([F:10])[F:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(COc2ccc(C=O)cc2O[C@@H](c2ccccc2)C(F)(F)F)cc1
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c(O[C@@H](c2ccccc2)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-[(S)-1-phenyl-2,2,2-trifluoroethoxy]-4-[(4-methoxyphenyl)methoxy]-benzaldehyde (2.08 g, 0.005 mol) in acetic acid (25 mL) was heated to 150□C. and stirred for 72 h. It was then cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (100 mL), and the organic solution washed with water (100 mL) and extracted with 1M sodium hydroxide (5×100 mL). The basic extracts were combined and acidified to pH 1 with concentrated HCl, then extracted with ethyl acetate (2×100 mL). The organic extracts were combined, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel and elution with petroleum ether:ethyl acetate (6:1) gave the product as a colourless oil, which later crystallised to a white powder (1.14 g, 80%). RF (dichloromethane) 0.53. 1H NMR (CDCl3) □ 9.71 (s, 1H, O═C—H), 7.09 (d, 1H, J 8.3 Hz, ArH), 6.39 (s, 1H, OH), 5.50 (q, 1H, J 6.0 Hz, CHCF3).
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[NH2:21][C:22]1[S:23][CH2:24][CH2:25][N:26]=1>CN(C=O)C.O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:26]3[C:22]([S:23][CH2:24][CH2:25]3)=[N:21][C:2]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1)#[N:11]
Reactant: NC1=NCCS1
Reactant: N#Cc1ccc(C(=O)C(Br)c2ccc(C#N)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2nc3n(c2-c2ccc(C#N)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3.8 g of 1-bromo-2-oxo-1,2-di(4-cyanophenyl)ethane, prepared as described above in part (b) and 3.8 g of 2-aminothiazoline in 70 ml of DMF was stirred at room temperature for 18 hours. The reaction mixture was diluted with cold water, and the precipitated product was filtered and dried in vacuum. The material was suspended in 200 ml of toluene, 125 mg of p-toluenesulfonic acid was added, and the mixture was refluxed for 2 hours with removal of water. After cooling, the crude product was filtered and recrystallized twice from acetic acid to afford the part (c) title compound, 1.3 g, m.p. 255°-260°; Analysis: C19H12N4S.0.5AcO; Theory; C 67.03%, H 3.91%, N 15.64%; found C: 67.03% H: 3.96%, N: 15.04%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[CH:23]=[O:24])=[CH:15][CH:14]=2)[N:10]=1>[C].[Pd].C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][CH:18]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1/C=C/c1ccc(/C=C/C=C/C=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccco2)nc1CCc1ccc(CCCCC=O)cc1
Yield: 90 %

Procedure:
A mixture of (E,E,E)-5-[4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]vinyl]phenyl]-2,4-pentadien-1-al (2.4 g), palladium-carbon (5%, 0.3 g) and ethyl acetate (100 ml) was subjected to catalytic hydrogenation at 1 atm and room temperature. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to yield 5-[4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]ethyl]phenyl]pentan-1-al (2.2 g, 92%) as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(Cc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 63.8 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(4-cyanobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 4-cyanophenylboronic acid (0.032 g; 0.216 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.046 g; 0.432 mmol), sodium iodide (0.065 g; 0.432 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.057 g (62%) of the title compound as a white solid.