Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13](OC)=[O:14]>O1CCCC1>[CH3:13][CH2:12][CH2:11][CH:10]([CH3:19])[CH3:9].[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][OH:7])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(CCO)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(C)C
Product: OCCc1cccc(CO)c1
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (1M in diethyl ether, 5.55 mL) was added dropwise over 5 min to a stirred solution of methyl 3-(2-hydroxyethyl)benzoate (1.0 g) in tetrahydrofuran (15 mL) cooled in an ice bath. After 1 h, the reaction mixture was quenched with methanol and evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate:isohexane, 2:1, then ethyl acetate to give the subtitled compound as a gum. Yield 0.5 g.
Reaction SMILES: CS(Cl)(=O)=O.[O:6]1[CH2:10][CH2:9][C@@H:8](O)[CH2:7]1.CCN(CC)CC.[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:32])[C:25]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(Cl)Cl.O>[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:32])[C:25]=1[N:26]1[CH2:31][CH2:30][N:29]([C@H:8]2[CH2:9][CH2:10][O:6][CH2:7]2)[CH2:28][CH2:27]1
Reactant: Fc1cncc(Cl)c1N1CCNCC1
Reactant: O[C@@H]1CCOC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Fc1cncc(Cl)c1N1CCN([C@H]2CCOC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
MsCl (393.3 mg, 265.7 μL, 3.433 mmol) was added to a solution of (3R)-tetrahydrofuran-3-ol (275 mg, 3.121 mmol) and Et3N (379.0 mg, 522.0 μL, 3.745 mmol) in DCM (5 mL) at 0° C. and the resulting solution stirred at RT overnight. The reaction mixture was diluted with water (5 mL) and DCM (5 mL) and the layers separated. The aqueous layer was extracted further with DCM (2×5 mL) and the combined organic extracts washed with saturated aqueous sodium hydrogen carbonate solution (1×5 mL), dried over MgSO4 and concentrated in vacuo. The residue was taken up in n-BuOH (5 mL) and 1-(3-chloro-5-fluoro-4-pyridyl)piperazine (1.010 g, 4.682 mmol) was added and the reaction mixture heated at 118° C. overnight. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by column chromatography on silica (24 g column, 0-100% EtOAc/petroleum ether). Product fractions were combined and concentrated in vacuo to leave (S)-1-(3-chloro-5-fluoropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine as an off white solid. MS (ES+) 288.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10]CC)=[O:9].[C:33]1(C)C=CC=CC=1>>[CH3:33][C:4]1([CH2:13][C:8]([OH:10])=[O:9])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: CC1(CC(=O)O)CCOCC1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a solution of dihydro-2H-pyran-4(3H)-one (X9) (3.13 g, from Aldrich) in toluene was added (carbethoxymethylene)-triphenylphosphorane (12.0 g, Aldrich). The solution was stirred at 110° C. for 3 days. The resulting dark solution was concentrated in vacuo and the residue directly purified by column over silica gel to yield compound X10 (4.54 g) as a clear liquid. 1H-NMR (CDCl3, 500 MHz): 5.66 (s, 1H), 4.16 (q, 2H), 3.98 (s, 4H), 3.00 (t, 2H), 2.38 (m, 2H), 1.77 (m, 4H), 1.27 (t, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccc(C(F)(F)F)cc2)C1
Yield: 88.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 4-trifluoromethylphenylboronic acid (173 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (210 mg, 83.7%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42].CCN(CC)CC.O>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([NH:46][CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:47])[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc(-c2ccccc2)n1
Temperature: 40 °C

Procedure:
4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (40 mg), glycine ethyl ester hydrochloride (23.8 mg) and NEt3 (20 l) were dissolved in THF (0.5 ml). The mixture was stirred at 40° C. until reaction completion. Water was added to the reaction mixture which was extracted with EA. The org. layers were dried (Na2SO4) and evaporated off to give 41 mg of the desired pure compound.
Reaction SMILES: CO.[OH-].[K+].[Cl:5][C:6](Cl)([Cl:22])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl>O>[Cl:5][C:6]([Cl:22])=[C:7]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: Oc1ccc(C(c2ccc(O)cc2)C(Cl)(Cl)Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1ccc(C(=C(Cl)Cl)c2ccc(O)cc2)cc1
Temperature: 20 °C

Procedure:
A 4-necked 5-liter flask, equipped with a mechanical stirrer, a thermometer, and a condenser, is charged with methanol (800 g). Potassium hydroxide (440 g) is added in portions to the methanol solution. After the addition, the solution is cooled to 20° C. To this stirring solution, 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane (420 g) is added in portions. The reaction temperature is kept below 40° C. After the addition, the temperature is raised to 50° C. and maintained for 2.5 hours. The reaction mixture is cooled to 20° C. and neutralized with 25% HCl solution. After the neutralization, the mixture is heated to reflux and water (480 g) is added. The mixture is allowed to cool to the room temperature. The precipitates are filtered and dried to afford 1,1-dichloro-2,2-bis(4-hydroxyphenyl)ethene as white solids with slight tan color.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:14][O:12][CH3:13]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CON
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(Cl)c(Cl)c1

Procedure:
Reaction of 3,4-dichlorobenzaldehyde with methoxylamine hydrochloride followed by reduction with sodium cyanoborohydride as described in the preparation of Compound 44-A and 44-B gave the title hydroxylamine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s), 3.99 (2H, s), 5.74 (1H, broad s), 7.20 (1H, dd, J=2.0 Hz and J=8.1 Hz), 7.40 (1H, d, J=8.1 Hz), 7.47 (1H, d, J=2.0 Hz).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:17])(=[NH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>C1C=CC=CC=1.CCCCCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:16][C:7](=[NH:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[S:27])=[CH:21][CH:20]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCCCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 1.9 g. sodium in 200 ml. dry acetone, 16 g. nonanamidine hydrochloride, and 14.2 g. 4-chlorophenyl isothiocyanate in 100 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(nonanimidoyl)-2-thiourea, m.p. 102°-103° C. (from benzene-n-hexane); hydrochloride (16.2 g.); m.p. 172°-174° C. (from acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(Cc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=288.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and benzylbromide.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([NH:9][C:10](=[O:31])[C@@H:11]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:15][CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Na+].CO>C1COCC1.O>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:11]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:10]([NH:9][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:32])=[O:2])=[O:31])=[CH:14][CH:15]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 1 (8.45 g, 18.8 mmol) was dissolved in THF (35 mL) and sodium hydroxide (1.13 g, 28.2 mmol) pre-dissolved in water (10 mL) was added. A further 15 mL of THF and 20 mL of methanol were added to obtain a homogenous solution. The reaction mixture was stirred at rt for 18 h before being concentrated in vacuo. The residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white foam, 7.25 g, 89%.
Reaction SMILES: [C:1]([N:9]1[CH:15]=[CH:14][N:13]=[CH:12][CH2:11][N:10]1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(O)C>[C:1]([N:9]1[CH2:15][CH2:14][N:13]([CH2:25][CH2:24][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:12][CH2:11][N:10]1[C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccncc1
Reactant: O=C(c1ccccc1)N1C=CN=CCN1C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCO
Product: O=C(c1ccccc1)N1CCN(CCc2ccncc2)CCN1C(=O)c1ccccc1

Procedure:
A mixture of 1,2-dibenzoyl-1H-1,2,5-triazepine (2.0 g), 4-vinylpyridine (1.42 g) and p-toluenesulfonic acid (1.21 g) in methanol (70 ml) was stirred and heated at 60° under a nitrogen atmosphere for 3 days. The foam, obtained after evaporation of the solvent, was mixed with dichloromethane and 10% sodium carbonate solution. The organic phase was washed with water until neutral washings were obtained and dried (Na2SO4). Evaporation of the solvent gave a foam, 2.25 g. The crude product was chromatographed on a column of silica gel; elution with ethanol-ethyl acetate-dichloromethane (1:4:5) giving a major component. A hydrochloride salt, 1/3 hydrate of the titled compound was formed in ethanol; wt. 1.2 g (38%), mp 247° dec.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:17][O:18][CH2:19][O:20][C:21]1[C:30]([CH3:31])=[C:29]2[C:24]([C:25](=[O:37])[C:26]([CH3:36])=[C:27](S(C)(=O)=O)[O:28]2)=[CH:23][CH:22]=1.C(OCC)(=O)C>CS(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:27]2[O:28][C:29]3[C:24]([C:25](=[O:37])[C:26]=2[CH3:36])=[CH:23][CH:22]=[C:21]([O:20][CH2:19][O:18][CH3:17])[C:30]=3[CH3:31])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: COCOc1ccc2c(=O)c(C)c(S(C)(=O)=O)oc2c1C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCOc1ccc2c(=O)c(C)c(N3CCN(C(C)=O)CC3)oc2c1C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
1-Acetylpiperazine (220 mg, 1.70 mmol) and triethylamine (1 mL) were added to a solution of 7-(methoxymethoxy)-3,8-dimethyl-2-(methylsulfonyl)-4H-chromen-4-one (171 mg, 0.55 mmol) obtained in Example 37-3 in dimethyl sulfoxide (5 mL), and the mixture was stirred for 5 hours under cooling with ice. Ethyl acetate was added to the reaction solution. The organic layer was washed with water and then dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=97/3→93/7) to obtain 60 mg of the title compound (yield: 30%), which was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:10](=[O:11])[C:5]=2[C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[S:21][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:20])[N:9]([C@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[C:10](=[O:11])[C:5]=2[C:4]=1[CH3:22]
Reactant: COc1sc2[nH]c(=O)n([C@@H](C)c3ccccc3)c(=O)c2c1C
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1sc2c(c1C)c(=O)n([C@@H](C)c1ccccc1)c(=O)n2Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 6-methoxy-5-methyl-3-[(1S)-1-phenylethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.43 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.67 g), potassium carbonate (0.38 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.74 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10]C.[C:18]1([C:24]#[C:25][C:26]([O:28]CC)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O.[C:40]1(C)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][C:26](=[O:28])[C:25]([CH3:40])=[C:24]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CCC(=Nc1ccccc1Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)cc1=O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
Added to 700 ml of toluene were 73.1 g (0.30 mole) of N-(2-chlorophenyl)-1-phenylpropaneimine, 34.8 g (0.20 mole) of ethyl phenylpropiolate and 40.0 g (0.30 mole) of aluminum chloride. The reaction mixture was then heated with stirring as 60° C. for 3 days. After cooling, the reaction mixture was poured into 1000 ml of 2N sulfuric acid, followed by extraction with chloroform. After washing the organic layer with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). The crystals obtained were then recrystallized from a 1:2 mixed solvent of chloroform and hexane to give 17.0 g of 1-(2-chlorophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone. 1/5HCl having a melting point of 229°-231° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]=1[CH:30]=O>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:30][C:22]1[NH:23][C:24]2[C:29]([C:21]=1[CH2:20][CH2:19][CH2:18][N:17]([CH3:32])[CH3:16])=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN(C)CCCc1c(C=O)[nH]c2ccccc12
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1CCCN(C)C)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (98 mg, 0.43 mmol) was condensed with 3-(3-dimethylaminopropyl)-1H-indole-2-carbaldehyde (100 mg) to give the title compound as an orange solid.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 37 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (37%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:13][O:14][C:15]1([C:32]([F:35])([F:34])[F:33])[CH2:18][CH:17]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([CH:30]=3)[NH2:29])[N:20]=2)[CH2:16]1.CCCP(=O)=O>C(OC(=O)C)C.C(=O)(O)[O-].[Na+]>[CH3:13][O:14][C:15]1([C:32]([F:34])([F:35])[F:33])[CH2:16][CH:17]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([NH:29][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:12])[CH:30]=3)[N:20]=2)[CH2:18]1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: COC1(C(F)(F)F)CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC1(C(F)(F)F)CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Temperature: 70 °C

Procedure:
A stirring mixture of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (10 mg, 0.064 mmol) and 5-(5-(3-methoxy-3-(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (125) (21 mg, 0.064 mmol) in ethylacetate (1 mL) was added propylphosphonic anhydride solution 50 wt. % in ethyl acetate (76 uL, 0.128 mmol). The reaction was heated at 70° C. for 3 hours. The reaction was cooled to room temperature and diluted with a solution of saturated sodium bicarbonate. The organic was separated and washed with 2× water/brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography using DCM:EtOAc:MeOH (1:1:0.1). N-(5-(5-(3-methoxy-3-(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F97). 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 9.47-9.44 (m 1H), 8.59 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 7.6 Hz, 1H), 7.80-7.78 (m, 1H), 7.55-7.50 (m, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.20-7.16 (m, 1H), 3.76-3.68 (m, 1H), 3.38 (s, 3H), 2.88-2.85 (m, 4H), 2.36 (s, 3H) MS m/z 471.15 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([NH:9][NH2:10])[CH:8]=1.Cl.[CH3:13]/[C:14](/N)=[CH:15]\[C:16]#[N:17].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([N:9]2[C:16]([NH2:17])=[CH:15][C:14]([CH3:13])=[N:10]2)[CH:8]=1
Reactant: C/C(N)=C\C#N
Reactant: Cc1ccc(Cl)cc1NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(N)n(-c2cc(Cl)ccc2C)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (5-chloro-2-methylphenyl)hydrazine hydrochloride (1.49 g, 7.72 mmol, 1 eq) in 8 mL ethanol was added hydrogen chloride (4.0 mL of a 5 M aqueous solution, 20 mmol, 2 eq) and 3-aminocrotonitrile (0.664 g, 8.09 mmol, 1.05 eq). The reaction mixture was stirred at 80° C. for 16 hours and then brought to neutral pH with saturated aqueous sodium bicarbonate. The resulting solution was extracted twice with dichloromethane, and the combined extracts were dried over magnesium sulfate and concentrated to give 1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-amine, which was carried forward without further purification. LCMS (ESI) m+H=222.2; 1H NMR (400 MHz, DMSO-d6) δ: 7.39 (d, 1H), 7.37 (d, 1H), 7.25 (s, 1H), 5.22 (s, 1H), 5.00 (s, 2H), 2.04 (overlapping s and s, 6H).