Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:11][CH:12]([C:15]1[CH:32]=[CH:31][C:18]([O:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:21](O)=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[N:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[CH:20]([O:19][C:18]2[CH:31]=[CH:32][C:15]([CH:12]([CH3:11])[CH2:13][CH3:14])=[CH:16][CH:17]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Nc1cnc2ccccn12
Reactant: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)O
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)Nc1cnc2ccccn12

Procedure:
3-Aminoimidazo[1,2-a]pyridine, synthesized by reduction of the corresponding nitro compound according to Example 31, was coupled with 2-(4-(1-methylpropyl)- phenoxynonanoic acid according to the procedure of Example 25 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[NH2:13][C:14]([NH2:16])=[S:15].II>C(O)C.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1[N:13]=[C:14]([NH2:16])[S:15][C:7]=1[CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: NC(N)=S
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc2c(s1)CCc1cc(Br)ccc1-2
Temperature: 100 °C
Yield: 99.9 %

Procedure:
6-bromo-3,4-dihydronaphthalen-1(2H)-one (3.5 g, 15.55 mmol), thiourea (3.55 g, 46.6 mmol) and iodine (4.34 g, 17.10 mmol) were dissolved in 20 ml of ethanol and the solution was heated at 100° C. for 4 hr. The volume of ethanol was reduced and the solid amine hydroiodide salt was filtered and washed with ether. The solid obtained was dissolved in water and basified with 10% NaOH solution and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated to obtain the desired compound (4a) (4.37 g, 80%). m/z 280.9 (79Br) & 282.9 (81Br) (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][CH:11]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:12]([NH:14][C:15]1([C:22]#[N:23])[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:13].C(N(CC)C(C)C)(C)C>C(#N)C>[C:22]([C:15]1([NH:14][C:12](=[O:13])[CH:11]([NH:10][C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)#[N:23]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: N#Cc1ccnc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)Nc2nccc(C#N)n2)CC1
Yield: 52 %

Procedure:
2-Chloro-4-pyrimidinecarbonitrile (0.3 mmol, Daves, G. D. Jr., O'Brien, D. E., Cheng, C. C. J. Het. Chem, 1964, 1, 130) and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide (0.7 mmol) were dissolved in acetonitrile (10 mL) containing N,N-diisopropylethylamine (0.6 mmol). The solution was heated to a gentle reflux for 17 h. The volatiles were evaporated and the residue was subjected to chromatography (silica gel, eluant=EtOAc then MeOH). The methanolic fraction was concentrated to a colorless solid which was rechromatographed (10% MeOH/EtOAc) to afford the title compound as a colorless solid (52%). The material was recrystallized from dichloromethane/petroleum ether.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28]([OH:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[OH:31][C:28]([C:27]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]=2[CH:7]=1)([CH3:30])[CH3:29]
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)(O)c1ccncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(-c3cnccc3C(C)(C)O)cc21
Temperature: 100 °C
Yield: 0.5 %

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (304 mg, 1.1 mmol), 2-(3-Bromo-pyridin-4-yl)-propan-2-ol (217 mg, 1.0 mmol), Na2CO3 (2 M in water, 1.5 mL, 3.0 mmol) and PdCl2(PPh3)2 (56 mg, 0.08 mmol) in DMF (6 mL) was heated at 100° C. for 4 hrs. After concentration, the residue was diluted with DCM and saturated NH4Cl solution. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-3.5%) to give the title compound (1.4 mg, 0.5%); ESI-MS m/z: 285 [M+1]+, Retention time 0.98 min; 1H-NMR (CDCl3, 400 MHz) δ 1.51 (s, 6H), 3.43 (s, 3H), 6.95 (d, J=1.6 Hz, 1H), 7.04 (dd, J=8.4, 1.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 8.11 (d, J=6.0 Hz, 1H), 8.40 (s, 1H), 8.65 (d. J=6.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[C:11]([O:14][CH2:15][CH2:16][O:17]C)(=O)C.Cl>C1C=CC=CC=1.O>[CH3:11][O:14][CH2:15][C:16]([CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:17]
Reactant: CC1CCC(=O)CC1
Reactant: COCCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COCC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
2.5 g of 60% sodium hydride was suspended in 50 ml of benzene and a mixture of 5.6 g of 4methylcyclohexanone and 5.4 g of methoxyethyl acetate was added dropwise thereto under cooling. After stirring at room temperature for two hours, 20 ml of water was added and the pH value of the reaction mixture was adjusted to 3 with concentrated hydrochloric acid. After removing the benzene phase the aqueous phase was extracted with ether. The benzene solution and the ether solution were combined, washed with water, dried and concentrated to give 7.4 g of crude 2-methoxyacetyl4-methylcyclohexanone. This crude product was subjected to the subsequent step.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:26])[C@H:12]([CH:23]([CH3:25])[CH3:24])[NH:13][C:14](=[O:22])[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:8][CH2:7][O:6]1)(=O)C>CO.Cl>[CH3:1][O:4][C@@H:5]1[C@@H:9]([NH:10][C:11](=[O:26])[C@H:12]([CH:23]([CH3:24])[CH3:25])[NH:13][C:14](=[O:22])[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:8][CH2:7][O:6]1
Reactant: CCCC(CCC)C(=O)N[C@H](C(=O)N[C@H]1CCO[C@H]1OC(C)=O)C(C)C
Agent: Cl
Solvent: CO
Product: CCCC(CCC)C(=O)N[C@H](C(=O)N[C@H]1CCO[C@@H]1OC)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
In methanol (50 ml) was suspended (2S, 3S)-2-acetoxy-3-[[N-valproyl-(L)-valyl]amino]tetrahydrofuran (0.55 g) followed by addition of concentrated hydrochloric acid (5 drops) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain (2S,3S)-2-methoxy-3-[[N-valproyl-(L)-valyl]amino]tetrahydrofuran (chemical structure below) (0.38 g, 72%). As recrystallized from ethyl acetate, colorless crystals, m.p. 150°-156° C., optical rotation [α]D+ 18.5° (c=0.50, CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]#[N:12])[N:8]=[CH:7]1)[CH3:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH2:1]([O:3][C:4](=[O:13])[C:5]([N:6]1[CH:10]=[C:9]([C:11]#[N:12])[N:8]=[CH:7]1)=[CH:17][N:18]([CH3:20])[CH3:19])[CH3:2]
Reactant: CCOC(=O)Cn1cnc(C#N)c1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1

Procedure:
3.8 g (21.4 mmol) of the compound from Example 33A and 7.4 ml (6.3 g, 42.8 mmol) dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For working up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1>>[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:20][CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc(I)cc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(I)cc2)o1
Yield: 62 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (1.00 g, 4.60 mmol) was converted using 4-iodobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.21 g, 62%) which was obtained as a white solid. MS: m/e=430.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12]O)[CH:7]=[CH:8][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:12][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:15])([F:14])[F:1])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cccc(OC(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1cccc(CCCBr)c1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
Compound 58-2 (3.15 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (4.13 g) and N-bromosuccinimide (2.79 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.54 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6](/[CH:7]=[N:8]/[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>ClCCl>[CH:9]([N:8]1[CH:7]([C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:32]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(/C=N/C(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C2ON2C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
(E)-N-(4-methoxybenzylidene)-1,1-diphenylmethanamine 39 (3.62 g, 12.0 mmol) was dissolved in dichloromethane (130 mL) at 0° C., followed by the portionwise addition of mCPBA (2.96 g, 13.2 mmol). The resulting solution was warmed to room temperature, and stirred for 16 h prior to being transferred to a separatory funnel, and being washed 3 times with 50 mL of saturated sodium bicarbonate solution. The organic layer was then dried with anhydrous sodium sulfate, filtered, and concentrated to afford 40 as a light yellow oil (3.52 g, 92%). LRMS (ESI): (calc.) 317.4 (found) 318.2 (MH)+.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN=[N+]=[N-])CC1
Temperature: 120 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Tertiary butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (48 g, 163.6 mmol) was dissolved in dimethylformamide (500 mL) and sodium azide (19.15 g, 295 mmol) was added thereto, followed by stirring at 120° C. for 6 hours. After the reaction was completed, the reactants were cooled to room temperature, extracted with ethyl acetate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford the title compound (35 g, 89%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:12][C:13]#[N:14]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:12][C:13]#[N:14])[CH2:7][CH2:6]1
Reactant: COCCN1CCNCC1
Reactant: N#CCBr
Product: COCCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 1-(2-Methoxy-ethyl)-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=184.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:24][CH2:25][C:26]1[C:27]([CH2:32]Cl)=[CH:28][CH:29]=[CH:30][CH:31]=1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([O:21][CH2:32][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][Cl:24])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1CCl
Reactant: Oc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCc1ccccc1COc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
To a cooled suspension of 7-chloro-2-(5-hydroxybenzofuran-2-yl)quinoline (0.71 g) in tetrahydrofuran (12 ml), sodium hydride (60% in mineral oil, 0.125 g) was added below 10° c. After being stirred for 15 minutes, α,α'-dichloro-o-xylene (1.68 g) was added to the mixture. After subsequently being stirred at ambient temperature for 1.5 hours, the mixture was refluxed for 25 hours. After the solvent was removed under reduced pressure, the residue was subjected to column chromatography on silica gel (25 g) and eluted with a mixture of chloroform and n-hexane (1:1). The fractions containing object compound were combined and concentrated under reduced pressure give 7-chloro-2-[5-(2-chloromethylbenzyloxy)benzofuran-2-yl]quinoline (0.56 g).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1
Reactant: [H][H]
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OCO1
Agent: N
Solvent: CO
Solvent: O
Product: NCC[C@@H]1C[C@H](CC(=O)O)OCO1
Temperature: 45 °C
Yield: 60.6 %

Procedure:
A solution of 1.04 g (4.88 mmol) of (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid.
Reaction SMILES: [C:1]([CH:6]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18](C(OCC)=O)[C:17]2=[O:30])=[CH:10][C:9]=1[Cl:31])([O:3]CC)=[O:2].[OH-].[Na+].Cl>CO.C(Cl)Cl>[C:1]([CH:6]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:7][C:8]1[C:9]([Cl:31])=[CH:10][C:11]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:30])=[CH:12][C:13]=1[Cl:14])([OH:3])=[O:2]
Reactant: CCOC(=O)C(Oc1c(Cl)cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc1Cl)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C(Oc1c(Cl)cc(Cn2c(=O)[nH]c3ccccc32)cc1Cl)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of 0.082 g (0.14 mmol) of the product of step C in 1.0 mL of methanol and 1.0 mL methylene chloride was added 250 gL of a 5.0 N solution of sodium hydroxide and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then adjusted to pH=5-6 with dropwise addition of 6 N hydrochloric acid, and then concentrated in vacuo. The residue was redissolved in methanol, filtered, and evaporated. The mixture was then purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH-NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.061 g (90%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[C:15]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:29])[CH:11]=1.CS(C)=O>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[C:19]2[C:14](=[C:15]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:29])[CH:11]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12
Temperature: 12 °C

Procedure:
To a solution of 3-pentanol (5.8 ml, 52.7 mmol) in dry THF (5 ml) was added sodium hydride (NaH) portionwise over a period of 10 min. A solution of 4-chloro-2-methyl-8-(2,4,6-trimethyl-phenyl)-quinoline (4.0006 g, 13.52 mmol) in dry THF (10 ml) was added. After stirring at room temperature as for 10 min, 15 ml of dry DMSO was added. The resulting mixture was heated in a 12° C. oil bath for 1.5 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried, filtered, and concentrated to give the title compound as 5.002 g of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][NH:36][CH:37]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38]1>>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:36]([CH3:35])[CH:37]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNC1CCN(C)C1
Product: CN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Methyl-(1-methyl-pyrrolidin-3-yl)-amine following General Procedure C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:22])[CH3:20])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and dimethylamine (5.6 N in EtOH, 8.7 mL, 48.8 mmol) in DMSO (35 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (2.81 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[F:39])=[O:30])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:18])[CH:13]=2)[CH:7]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[F:39])=[O:30])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCC(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl {[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetate (100 mg, 0.19 mmol) in 10 ml of MeOH was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for one hour and poured into 100 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give {[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetic acid as white solid. Yield: 95 mg, 98%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[CH3:10])=[N:7][CH:8]=1.Br[C:13]1[C:14]2[CH2:22][N:21]([C:23]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:24]=3[C:25]#[N:26])[CH2:20][CH2:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:23]([N:21]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][N:18]=[C:13]([NH:1][CH2:2][C:3]4[CH:8]=[N:7][C:6]([N:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=4)[C:14]=3[CH2:22]2)=[C:24]([CH:27]=1)[C:25]#[N:26]
Reactant: CN(C)c1ccc(CN)cn1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Br)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)c1ccc(CNc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A mixture of 5-(aminomethyl)-N,N-dimethylpyridin-2-amine (24 mg, 0.16 mmol), 2-(4-bromo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-chlorobenzonitrile (50 mg, 0.14 mmol), and N,N-diisopropylethylamine (62 μL, 0.36 mmol) in acetonitrile (1.9 mL) was subjected to microwave irradiation at 180° C. for 6 hrs. The reaction mixture was concentrated to an oil which was purified by silica gel column (0-15% MeOH/CH2Cl2) to obtain a light yellow solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(O[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:35]=[O:36])(=O)=O>CN(C)C=O>[C:42]1([CH2:41][O:40][C:39]2[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][C:32]=2[CH2:31][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Reactant: c1ccc(CCNCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(CN(CCc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of N-benzyl-N-(2-phenylethyl)amine (351 mg) and diisopropyl-ethylamine (145 mg) in dimethylformamide (1.5 ml) was added 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (355 mg). After stirring at room temperature for 3 hours, the reaction mixture was partially concentrated under reduced pressure and the residue was purified by flash chromatography column using petroleum ether:diethyl ether (1:3) as eluant. The pure fractions were combined and evaporated under reduced pressure to give 4-phenylmethoxy-3-[[N-phenylmethyl-N-(2-phenylethyl)amino]methyl]benzaldehyde (420 mg) as a gum. 1H NMR (CDCl3) δ9.89 (s, 1H, CHO); 5.20 (s, 2H); 3.88 (s, 2H); 3.85 (s, 2H); 2.92 (m, 4H, CH2CH2).