Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13]C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4]1>CO>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:13])[CH2:6][CH2:5][CH2:4]1
Reactant: CN1CCCc2cccc(NC(=O)OC(C)(C)C)c21
Agent: Cl
Solvent: CO
Product: CN1CCCc2cccc(N)c21
Yield: 91.3 %

Procedure:
Anhydrous HCl (gas) was bubbled through a stirred solution of 1-methyl-8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline (0.83 g, 3.16 mmol) in methanol (30 mL), at room temperature, for 10 minutes. The resultant solution was stirred at room temperature for 1 hour then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (50 mL) and aqueous NaOH (10 N, 10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated to afford 0.468 g (88%) of 1-methyl-8-amino-1,2,3,4-tetrahydroquinoline as a white solid. 1H NMR (CDCl3) δ 1.83–1.91 (m, 2H), 2.69 (s, 3H), 2.78 (t, 2H, J=6.6 Hz), 3.07–3.11 (m, 2H), 3.84 (br s, 2H, NH2), 6.52 (d, 1H, J=7.5 Hz), 6.56 (d, 1H, J=7.5 Hz), 6.81 (dd, 1H, J=7.5, 7.5 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][CH:46]([N:49]2[CH2:54][CH2:53][CH2:52][C@@H:51]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:50]2)[CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:43]3[CH2:44][CH2:45][CH:46]([N:49]4[CH2:54][CH2:53][CH2:52][C@@H:51]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:50]4)[CH2:47][CH2:48]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCOC(=O)[C@@H]1CCCN(C2CCNCC2)C1
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)C34CCC(N(CC(=O)N5C[C@@H](F)C[C@H]5C#N)C(=O)OCc5ccccc5)(CC3)CC4)CC2)C1
Yield: 96.2 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (101 mg) and ethyl (3R)-1-(piperidin-4-yl)piperidine-3-carboxylate (84.3 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[4-[(3R)-3-ethoxycarbonylpiperidin-1-yl]piperidine-1-yl]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (115 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:5][CH:4]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:5][CH:4]=1)=[N+:19]=[N-:20]
Reactant: BrCc1ccc2cnn(C3CCCCO3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2cnn(C3CCCCO3)c2c1
Temperature: 90 °C
Yield: 80.8 %

Procedure:
To a solution of 6-(bromomethyl)-1-(2-tetrahydropyranyl)indazole (4.0 g, 14 mmol) (100) in DMF (30 mL) was added sodium azide (6 g, 92 mmol) in one portion. The suspension was heated at 90° C. for 30 minutes and a yellow solution was formed. After cooling down to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ether (2×150 mL). Combined organic layers were washed with brine then dried (MgSO4). Evaporation of solvent gave an yellow oil which was purified by column chromatography to yield title compound (2.91 g, 83%). TLC Rf 0.31 (70:30 of hexane-ethyl acetate); MS (electrospray) 258 (M+1); 1H NMR (CDCl3) δ1.75 (m, 3H), 2.10 (m, 2H), 2.55 (m, 1H), 3.72 (m, 1H), 4.01 (m, 1H), 4.48 (s, 2H), 5.73 (dd, 1H, J=8.2, 2.8 Hz), 7.12 (dd, 1H, J=8.2, 0.8 Hz), 7.55 (s, 1H), 7.71 (d, 1H, J=8.2 Hz), 8.02 (s, 1H).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18].C(N(CC)CC)C.[BH4-].[Na+]>CO>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N+:17]([O-:19])=[O:18])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:21])[CH:12]=2)[C:4](=[O:22])[O:3]1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[CH2:26]([O:21][C:13]1[CH:12]=[C:11]([NH:10][CH:9]=[C:5]2[C:4](=[O:22])[O:3][C:2]([CH3:23])([CH3:1])[O:7][C:6]2=[O:8])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
After suspending methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-hydroxybenzoate (13.975 g, 43.5 mmol) in dimethylformamide (140 ml) at room temperature under a nitrogen atmosphere, sodium hydride (1.87 g, 46.8 mmol) was gradually added. After 1.5 hours, benzyl bromide 5.7 ml, 47.9 mmol) was added dropwise and the mixture was stirred for 2 days. The reaction solution was diluted with water (700 ml) and stirred overnight, and the precipitated crystals were filtered, washed with diethyl ether and dried at 70° C. to obtain the title compound (15.477 g, 37.6 mmol, 86.5%) as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH:9]=[CH:10][N:11]=1.[Li]CCCC.[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([C:9]2[O:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:11][CH:10]=2)[OH:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(-c2ncco2)nc1
Reactant: O=CCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(CCCCCCc1ccccc1)c1cnc(-c2ccccn2)o1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
A solution of 2-(pyridin-2-yl)-oxazole (S1, 54 mg, 0.369 mmol) in THF (2 mL) was cooled to −78° C. before it was treated dropwise with 2.5 M n-BuLi (0.177 mL, 0.443 mmol). The reaction mixture was stirred at −78° C. for 20 min before 7-phenylheptanal (77 mg, 0.405 mmol) in THF (1 mL) was added dropwise. The solution was stirred for an additional 10 min at −78° C. before being warmed to room temperature. The reaction mixture was quenched with the addition of saturated aqueous NaHCO3, diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 20-70% EtOAc-hexanes) yielded the title compound (35 mg, 28%) as a colorless oil: 1H NMR (CDCl3, 500 MHz) δ 8.77 (s, 1H), 8.17 (d, 1H, J=8.0 Hz), 7.86 (t, 1H, J=8.0 Hz), 7.41 (m, 1H), 7.35-7.32 (m, 2H), 7.23 (m, 3H), 7.18 (s, 1H), 4.93 (t, 1H, J=6.5 Hz), 3.22 (br s, 1H), 2.65 (t, 2H, J=6.5 Hz), 2.01-1.98 (m, 2H), 1.68-1.66 (m, 2H), 1.44-1.42 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ 160.3, 156.1, 150.2, 146.4, 143.1, 137.5, 128.8, 128.6, 126.0, 125.1, 124.9, 122.5, 66.5, 36.3, 35.8, 31.8, 29.6 (2C), 25.8.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10]
Reactant: COC(=O)c1ccc(NC(CC(C)C)c2oc3ccccc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)O)cc2)oc2ccccc12
Yield: 80 %

Procedure:
To a mixture of methyl 4-{[3-methyl-1-(3-methyl-1-benzofuran-2-yl)butyl]amino}benzoate (1.38 g) synthesized above, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred with heating under reflux overnight. In addition, 1N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (1.06 g, 80%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=1)[CH:22]=[O:23].O>ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[C:21]([C:20]([N+:25]([O-:27])=[O:26])=[CH:19][CH:18]=1)[CH:22]=[O:23]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(C=O)c3)c2cc1OC
Temperature: 25 °C
Yield: 66.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (200 mg) and 5-hydroxy-2-nitrobenzaldehyde (299 mg) were suspended in chlorobenzene (2 ml), and the suspension was heated under reflux for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give 3-[(6,7-dimethoxy-4-quinolyl)oxy]-6-nitrobenzaldehyde (210 mg, yield 66%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:18]([Cl:29])[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[CH3:38][NH:39][CH2:40][CH2:41][OH:42].O>CN(C)C=O>[Cl:29][C:18]1[CH:17]=[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:39]([CH2:40][CH2:41][OH:42])[CH3:38])=[C:6]([O:30][CH3:31])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1Cl
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCN(C)CCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 106 %

Procedure:
A starting compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 50 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 53 mg (yield 106%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]=[C:24]=[O:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:15][C:24]([NH:23][CH3:22])=[O:25])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1Br
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (200 mg, 0.53 mmol) and methyl isocyanate (61 mg, 1.07 mmol) in toluene (1 mL) was heated under reflux for 24 h. The reaction mixture turned very cloudy with the forming of a white precipitate. The reaction mixture was allowed to cool to 25° C. and then treated with hexanes. The reaction mixture was placed in the freezer for 1 h then filtered. The white solid was washed with cold hexanes to afford 1-[2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (100 mg, 44%) as a white solid: mp 259-260° C.; FAB-HRMS m/e calcd for C17H23BrN2O4S (M+H)+431.0641, found 431.0646.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8][CH2:9][CH3:10])=[CH2:7])CCC.Br[C:20]1[S:24][C:23]([C:25]2[S:26][C:27](Br)=[CH:28][N:29]=2)=[N:22][CH:21]=1.[F-].[K+]>CN(C)C=O.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([O:8][C:6]([C:20]1[S:24][C:23]([C:25]2[S:26][C:27]([C:6]([O:8][CH2:9][CH3:10])=[CH2:7])=[CH:28][N:29]=2)=[N:22][CH:21]=1)=[CH2:7])[CH3:10]
Reactant: Brc1cnc(-c2ncc(Br)s2)s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cnc(-c2ncc(C(=C)OCC)s2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Tributyl(1-ethoxyvinyl)tin (0.425 mL, 1.26 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (21.5 mg, 0.031 mmol) were added to a stirred solution of 5,5′-dibromo-2,2′-bithiazole (200 mg, 0.613 mmol) in dimethylformamide (4 mL) under nitrogen. The reaction mixture was heated at 100° C. for 2 h. The reaction was cooled, diluted with ether and aqueous potassium fluoride (0.5 g in 5 mL of water). The mixture was vigorously stirred for 1 h at room temperature, both phases were filtered through CELITE® and then separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0 to 30% ethyl acetate in hexanes) to yield 5,5′-bis(1-ethoxyvinyl)-2,2′-bithiazole (181 mg, 0.587 mmol, 96% yield) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[CH:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)=[N:15][CH:16]=1)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)=[N:15][CH:16]=1
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cn2)cc1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cn2)cc1
Yield: 28.7 %

Procedure:
Using a method similar to Example 455, step 3, using 2-thiophen-2-yl-ethylamine (0.027 mL, 0.227 mmol) and 4-(5-formyl-pyridin-2-yloxy)-benzamide (58 mg, 0.239 mmol) from step 1 (above) gives the title compound (23 mg, 27%). Mass spectrum (ion spray): m/z=353.9 (M+1); 1H NMR (DMSO-d6): 8.08 (d, J=2.1 Hz, 1H), 7.93 (bs, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.82 (dd, J=2.3 Hz, 8.3 Hz, 1H), 7.31 (bs, 1H), 7.27 (dd, J=1.0 Hz, 5.2 Hz, 1H), 7.12 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.90 (dd, J=3.5 Hz, 5.2 Hz, 1H), 6.84 (d, J=3.3 Hz, 1H), 3.68 (S, 2H), 2.91 (t, J=7.1 Hz, 2H) 2.72 (t, J=7.1 Hz, 2H), 2.25 (bs, N—H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>O.CN(C)C=O>[CH:40]1([NH:41][C:18](=[O:19])[CH2:17][CH:14]2[S:13][C:12]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[CH:6][C:5]([O:21][C:22]3[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=3)=[CH:4][C:3]=4[O:2][CH3:1])=[N:16][CH2:15]2)[CH2:38][CH2:39]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC4CC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min, and then cyclopropylamine (50 mg) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (150 mg, 68%) as colorless prisms. MS 501 (MH+). mp 248-249° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][O:11][CH2:12]3)[CH:5]=[C:4]([Cl:16])[N:3]=1.[I-:17].[Na+].I>C(Cl)(Cl)Cl.O>[Cl:16][C:4]1[N:3]=[C:2]([I:17])[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][O:11][CH2:12]3)[CH:5]=1
Reactant: [I-]
Reactant: Clc1cc(N2C3CCC2COC3)nc(Cl)n1
Agent: I
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1cc(N2C3CCC2COC3)nc(I)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
In a 250 mL round-bottomed flask was placed 8-(2,6-dichloropyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (34, 980 mg, 3.77 mmol) in chloroform (4 ml) to give a very light yellow solution. Sodium iodide (941 mg, 6.28 mmol) was added to give a suspension. The mixture was cooled to 0° C. and an aqueous solution (57% w/w) of hydrogen iodide (4.97 ml, 37.7 mmol) was added, resulting in a yellow precipitate. The mixture was slowly warmed to room temperature and stirred at room temperature for 4 h. The mixture was diluted with water and quenched with NaOH (5M) to pH˜8. Aqueous sodium thiosulfate was added to decolorize. The mixture was extracted with dichloromethane, dried over MgSO4 and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (10-40%). Collected fractions were concentrated to give the title compound (516 mg) as a white solid. LCMS analysis revealed that the product contained ˜20% starting material. The mixture was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:12]/[C:13]([OH:15])=[O:14])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(F)ccc1C=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1/C=C/C(=O)O
Temperature: 70 °C
Yield: 68.9 %

Procedure:
A stirred solution of 4-fluoro-2-methyl-benzaldehyde (20 g, 144.9 mmol) and malonic acid (30.1 g, 289.8 mmol) in pyridine (100 mL) was heated to 50° C. Piperidine (10 mL) was added and the reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled RT and poured into chilled aqueous 1N HCl solution (1500 mL), the resulting precipitate was filtered and washed with petroleum ether 60-80 and dried in vacuo to obtain (E)-3-(4-fluoro-2-methylphenyl)acrylic acid (18 g, 69%) as an off white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:19])([F:20])[F:18])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:33]=[N:34][CH:35]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 205.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellow wax which slowly crystallized upon drying. UPLC-MS (Condition 3) tR=1.12 min, m/z=497.3 [M+H]+, m/z=495.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.79 (m, 1H) 1.84 (qd, J=8.43, 4.33 Hz, 1H) 2.88 (d, J=11.42 Hz, 1H) 3.18-3.29 (m, 2H) 3.34-3.47 (m, 1H) 4.14-4.27 (m, 1H) 4.88 (d, J=3.39 Hz, 1H) 7.67 (dd, J=8.66, 2.01 Hz, 1H) 7.75 (t, J=8.41 Hz, 1H) 7.84 (dt, J=9.72, 2.10 Hz, 1H) 7.97 (dd, J=11.73, 2.07 Hz, 1H) 8.07 (d, J=2.38 Hz, 1H) 8.48-8.54 (m, 1H) 8.60 (d, J=2.76 Hz, 1H) 8.79 (d, J=2.26 Hz, 1H) 10.45 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:7]=2[N:6]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:7]=2[N:6]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Solvent: CC(=O)O
Product: CC(=O)NCCCc1nc2cc(C3=NNC(=O)CC3C)ccc2[nH]1
Yield: 89 %

Procedure:
##STR59## 050 g (1.75 mmol) of 6-[2-(3-aminopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone are boiled with 0.34 ml (3.50 mmol) of acetic anhydride in 20 ml of glacial acetic acid for 45 minutes. The cooled solution is extensively concentrated by evaporation under vacuum and the residue is taken up with 10 ml of water. The resulting solution is adjusted to pH 9 with 10% ammonia. After concentration of this solution by evaporation to about one-third of its volume and cooling in an ice bath, a yellowish solid crystallizes, and this solid is suction filtered and then boiled up in 30 ml of acetonitrile. The solid obtained as residue is suction filtered, washed with 10 ml of acetonitrile and dried under vacuum. 0.51 g (89%) of colourless crystals melting at 244° to 246° C. are obtained.