Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17](OCC)=[O:18])=[N:15][N:16]=2)[N:13]=1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([NH:38][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:36][CH:35]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Solvent: CO
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Yield: 40.6 %

Procedure:
A solution of ethyl 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (41 mg, 0.10 mmol) and (4-(trifluoromethyl)phenyl)methanamine (29 μL, 0.2 mmol) in methanol (0.5 mL) was stirred at room temperature for 16 h. Analysis by HPLC/MS indicated the staring material had been consumed. The resulting suspension was filtered, the collected solid was washed with hexanes (5 mL×2), dried in air to afford 22 mg (41%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.93 min, (M+H)+=542.2.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CO.C=O.[C:29]([BH3-])#N.[Na+]>O1CCCC1>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH:15][CH3:29])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (0.10 M in acetonitrile, 1.0 mL, 0.09 mmol), prepared using procedures similar to those described in Example 2, in 1:1 ratio of methanol and tetrahydrofuran (2.0 mL) was added formaldehyde (37% wt, 6.7 μL, 0.09 mmol) followed by sodium cyanoborohydride (11.0 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h, at which time it was quenched with saturated aqueous ammonium chloride. The solution was then purified directly by reverse phase HPLC to afford the title compound (14.9 mg). 1H NMR (400 MHz, CDCl3): 8.13 (br s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 7.09-7.04 (m, 1H), 6.84-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.46-4.33 (br m, 4H), 3.93 (br m, 1H), 2.64 (s, 3H). MS (EI) for C17H15F3IN3O: 462 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:12](=[O:14])[C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from N-(3-nitro-phenyl)-oxalamic acid and 4-benzyl-piperidine according to the method described in Example 1c. Melting Point: 138-140° C. (diethylether)
Reaction SMILES: Cl[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3].[CH3:54][NH2:55]>C1(C)C=CC=CC=1>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]2[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11][CH:10]2[O:9][CH2:8][C:7]2[CH:46]=[CH:47][C:4]([C:2](=[O:3])[NH:55][CH3:54])=[C:5]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:6]=2)=[CH:17][CH:18]=1
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl
Reactant: CN
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC
Reaction time: 0.25 h

Procedure:
The solution of 0.290 g of benzyl 3-[4-chlorocarbonyl-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 69b) in 1.0 ml of toluene is slowly added dropwise to 1.5 ml of methylamine solution (approx. 10M in ethanol, precooled to 0° C.). After 15 minutes, the reaction solution is poured onto water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.11 (2:1 EtOAc-heptane); Rt=5.72.
Reaction SMILES: [NH:1]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:2]([C:7]([NH:9][C@@H:10]([C:22]([O:24]CC1C=CC=CC=1)=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>CO.O.[Pd]>[NH:1]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C@H:2]([C:7]([NH:9][C@@H:10]([C:22]([OH:24])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)O
Yield: 98.2 %

Procedure:
Boc-L-Leu-D-Trp(CH3)-OBzl (2.40 g) in MeOH (50 ml) and water (1 ml) was hydrogenated over 10% palladium on carbon in a similar manner to that of Preparation 1-4) to give Boc-L-Leu-D-Trp(CH3)-OH (1.95 g).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[S:8])[NH:6][NH2:7])[CH:2]=[CH2:3].[Cl:9][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=1[C:12](=O)[CH2:13]Cl>>[Cl:9][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=1[C:12]1[CH2:13][S:8][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[N:6][N:7]=1
Reactant: C=CCNC(=S)NN
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Product: C=CCNC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Yield: 88.8 %

Procedure:
3.93 g (0.03 mole) of 4-allyl-thiosemicarbazide and 7.00 g (0.03 mole) of 2,4-dichlorophenacyl chloride are reacted in accordance with the conditions of Example 1. Recrystallization from methanol/methyl acetate produces 8 g of 5-(2,4-dichlorophenyl)-N-2-propenyl-6H-1,3,4-thiadiazin-2-amine. m.p. 188°-189° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[I:10][C:11]1[N:12]=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16]>>[I:10][C:11]1[N:12]=[C:13]([CH3:17])[N:14]([C:2]2[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=2)[C:15]=1[CH3:16]
Reactant: Cc1nc(I)c(C)[nH]1
Reactant: Cn1ncc(Cl)cc1=O
Product: Cc1nc(I)c(C)n1-c1cnn(C)c(=O)c1

Procedure:
The title compound, light yellow cristalline solid, MS: m/e=331.0 (M+H+), was prepared in accordance with the general method of example 23b from 5-chloro-2-methyl-2H-pyridazin-3-one and 4-iodo-2,5-dimethyl-1H-imidazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:10]1[CH:11]=[C:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c(C)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (5.5 g, 22.26 mmol) in DMF (12 mL) was added to a mixture of 60% NaH (1.1 g, 33.39 mmol) in dry DMF (20 mL) at 0° C. under a N2 atmosphere and the mixture was stirred for 15 min. Benzyl bromide (2.9 mL, 24.49 mmol) was added and it was stirred at 80° C. for 12 h. The reaction mixture was cooled to 0° C., quenched with brine (20 mL), diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the desired product (6.5 g, 87%) as brown color solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C@@:18]([OH:25])([CH2:23][CH3:24])[C:19]([F:22])([F:21])[F:20])[N:15]=[N:14]3)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:26]([NH2:28])=[O:27])[CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[OH:25][C@@:18]([C:16]1[N:15]=[N:14][N:13]([CH2:12][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:29])=[CH:3][C:4]([C:26]([NH2:28])=[O:27])=[N:5]3)=[CH:10][CH:9]=2)[CH:17]=1)([C:19]([F:22])([F:21])[F:20])[CH2:23][CH3:24]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(Cl)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
Reactant: Cc1ccccc1B(O)O
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: [Na+]
Solvent: C1COCCO1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccccc4C)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
Temperature: 100 °C

Procedure:
4-chloro-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide (3-14, 8 mg, 0.02 mmol, 1.0 equiv.), (2-methylphenyl)boronic acid (5 mg, 0.04 mmol, 2 equiv.), Pd(PPh3)4 (0.7 mg, 0.0006 mmol, 0.03 equiv.) and 2M aqueous Na2CO3 (0.02 mL, 0.05 mmol, 2.5 equiv.) were suspended in Dioxane (0.4 mL) and the reaction mixture was heated overnight at 100° C. The crude mixture was filtered, concentrated and purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 7-({4-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-4-(2-methylphenyl)quinoline-2-carboxamide (3-15). LRMS m/z (M+H)+ 470.1 found, 470.2 required.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11]([N:5]1[CH2:6][CH2:7][C:8](=[O:9])[CH:3]([CH3:2])[CH2:4]1)=[O:12]
Reactant: CC1CNCCC1=O
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CCC(=O)C(C)C1

Procedure:
Racemic 3-methyl-4-oxo-piperidine-1-carboxylic acid methyl ester was prepared in the same manner from racemic 3-methyl-piperidin-4-one hydrochloride and methyl chloroformate.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH3:9][N:10]1[CH2:30][CH2:29][C:14]2=[C:15]([N:22]3[CH2:25][CH:24]([C:26](O)=[O:27])[CH2:23]3)[N:16]3[C:20]([N:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[N:17]3.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:15]2([N:22]3[CH2:25][CH:24]([CH:26]=[O:27])[CH2:23]3)[C:14]3[CH2:29][CH2:30][N:10]([CH3:9])[CH2:11][CH2:12][C:13]=3[N:21]=[C:20]3[N:16]2[N:17]=[CH:18][CH2:19]3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: CN1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(C2(N3CC(C=O)C3)C3=C(CCN(C)CC3)N=C3CC=NN32)CC1
Reaction time: 2 h

Procedure:
To 11.4 mg (0.10 mmol) N-ethylpiperazine was added a solution of 43 mg (0.10 mmol) 1-(7-Methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid and 0.026 mL (0.15 mmol) DIPEA in 0.5 mL DMF at room temperature. 35.3 mg (0.11 mmol) TBTU was dissolved in 0.5 mL DMF and the solution was added to the reaction mixture. Stirring was continued for 2 h and the reaction mixture was allowed to stand for overnight. The mixture was filtered over basic alumina followed by two washing cycles with 1.5 mL DMF. The solvent was removed and the residue was purified by column chromatography to yield the desired compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([CH3:30])=[CH:20][CH:21]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccc(C)cc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-p-tolyl-acrylic acid.
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17]#[N:18].N(OCCC(C)C)=O.[ClH:27]>O1CCCC1.[Cu](Cl)Cl>[Cl:27][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17]#[N:18]
Reactant: Cl
Reactant: N#Cc1c(N)nc2c(c1-c1ccccc1)CCC2
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nc2c(c1-c1ccccc1)CCC2

Procedure:
Under argon, 500 mg (2.12 mmol) of the compound from Example 16A, 0.57 ml (4.25 mmol) of isopentyl nitrite and 571 mg (4.25 mmol) of copper(II) chloride in 21 ml of tetrahydrofuran were heated under reflux for 6 h. After cooling, 1 N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 104.4 %

Procedure:
As in Example 115, (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid (4.79 g) and 4-nitrophenol (2.5 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.1 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 6.9 g of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester as a pale yellow oil homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:11][C:4]1[O:3][C:2]([CH3:1])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccoc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)oc1C
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a solution of methyl 2-methyl-3-furoate (7.0 g) in N,N-dimethylformamide (50 mL) was added N-bromosuccinimide (10.7 g) over 45 min under ice-cooling, and the mixture was stirred under ice-cooling for 30 min and at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (7.9 g, 72%) as an oil.
Reaction SMILES: NC1(C[O:8]C2C=CC(C#N)=CC=2)CCCC1.[C:17]([O:21][C:22](=[O:39])[NH:23][C:24]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#N)=[CH:33][CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:39])[NH:23][C:24]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]=[O:8])=[CH:33][CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: N#Cc1ccc(OCC2(N)CCCC2)cc1
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C#N)cc2)CCCC1
Product: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1

Procedure:
Synthesized from 4-(1-aminocyclopentylmethoxy)benzonitrile according to an analogous synthetic method to Preparation Example 19, tert-butyl[1-(4-cyanophenoxymethyl)cyclopentyl]carbamate (1.0 g) was used according to an analogous synthetic method to Preparation Example 20 to provide the title compound (688 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].[CH3:14][O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1>>[CH3:14][O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[CH2:12][OH:13])[C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (2-bromo-5-trifluoromethyl-phenyl)-methanol and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:6][CH:3]2[CH2:4][CH2:5][S:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCSC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCSC2)cc1
Temperature: 16 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a chilled solution of 1.12 g (0.0098 mole) of tetrahydrothiophene-3-ol in 15 mL of pyridine was added 1.91 g (0.01 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred in the cold, about 16° C., for 1 hour then placed in a cold refrigerator for 16 hours. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. An additional 0.3 g (0.0016 mole) of 4-methylphenylsulfonyl chloride was added, and the reaction mixture was stirred at room temperature for 64 hours. The reaction mixture was poured into water, and the whole was extracted with methylene chloride. The methylene chloride solution was dried and concentrated to give 1.28 g of product as an oil.
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH3:11][C:5]1[CH:6]=[CH:7][C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:9][CH:10]=1
Reactant: O=S(=O)=O
Reactant: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 28 %

Procedure:
Sulfur trioxide (0.6 g, 7.5 mmol, stabilized, 99% from Aldrich, Milwaukee, Wis.) was weighed into a 100-ml round-bottom flask in the dry box. Toluene (50 g) was added to the sulfur trioxide via syringe under an inert atmosphere. The solution was stirred at 50° C. for 22 hours under a nitrogen atmosphere before it was cooled to room temperature. A dark colored oil formed at the bottom of the solution. The toluene and oil layer was extracted with three 10-cc portions of distilled water. The analysis by HPLC showed 28% yield of p-TSA and 5.5% o-TSA (ratio p/o=5.1) for a total yield of 33.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:12][CH:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])=[CH:9][C:10]#[N:11].[CH:18]1([CH2:21][C:22](Cl)=[O:23])C[CH2:19]1.N1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:12][CH:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])=[C:9]([C:22](=[O:23])[CH2:21][CH2:18][CH3:19])[C:10]#[N:11]
Reactant: CC(C)C(C)NC(=CC#N)c1ccccc1Cl
Reactant: O=C(Cl)CC1CC1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCCC(=O)C(C#N)=C(NC(C)C(C)C)c1ccccc1Cl
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of 3-(2-chlorophenyl)-3-[(3-methylbutan-2-yl)amino]acrylonitrile (1 g, 4.02 mmol, 1 eq.) in 1,2-dichloroethane (2 ml) were added cyclopropylacetyl chloride (1.71 g, 16.08 mmol, 4 eq.) and pyridine (1.58 g, 20.1 mmol, Seq.) and the solution was heated to 80° C. for 8 h. The reaction was quenched with 1N aq. HCl (20 ml) and extracted with ethylacetate. The organic layers were combined and washed with 1N aq. NaOH (20 ml), dired over MgSO4 and concentration under vacuum. The residual oil was subjected to column chromatography to give 2-{(2-chlorophenyl)[(3-methylbutan-2-yl)amino]methylene}-3-oxohexanenitrile (1.012 g, 75% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[N:32]1[CH:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[N:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:38]([C:36]4[CH:37]=[N:32][CH:33]=[N:34][CH:35]=4)=[O:39])[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(O)c1cncnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6cncnc6)cn5n4)c3)c2)CC1
Yield: 26 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (140 mg, 0.313 mmol), pyrimidine-5-carboxylic acid (58 mg, 0.471 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (90 mg, 0.471 mmol), 1-hydroxybenzotriazole (63 mg, 0.471 mmol), triethylamine (60 μL, 0.471 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 380, the title compound (42 mg, 26%) was obtained as a pale-yellow powder.