Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[C@@H:9]([NH2:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:24][C:25]([F:43])([F:42])[C:26]1[CH:41]=[CH:40][C:29]([O:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[C@@H:9]([NH:22][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][C:31]([O:30][C:29]2[CH:40]=[CH:41][C:26]([C:25]([F:24])([F:42])[F:43])=[CH:27][CH:28]=2)=[CH:32][CH:33]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-[4-(trifluoromethyl)phenoxy]benzoic acid used in Example 41 (41a) to give the title compound.
Reaction SMILES: [SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:10])[O:6][C:7]=1[CH:8]=O.C(O)(=O)C>C(O)C>[CH3:10][C:5]1[O:6][C:7]2[C:3](=[CH:2][S:1][CH:8]=2)[N:4]=1
Reactant: Cc1nc(CS)c(C=O)o1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2cscc2o1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5 mmol of 4-(mercaptomethyl)-2-methyl-1,3-oxazole-5-carbaldehyde was described in 50 ml of ethanol, then 50 mmol of acetic acid was added. Stirring was continued for 1 hour at a room temperature and the temperature was heated up to 80° C. to carry out the reaction for 4 hours. The reacted liquid was cooled down to a room temperature and the solvent was evaporated out. The product was purified using column separation with the solvents of ethylacetate and hexane, obtaining 2-methylthieno[3,4-d][1,3]oxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:34]([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43](O)=[O:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([C:43](=[O:44])[C@@H:42]([NH:41][C:34](=[O:35])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:46]([CH3:48])[CH3:47])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol), (S)-2-(Boc-amino)-3-methylbutyric acid (0.28 g, 1.29 mmol) and 4-ppy (9 mg, 0.06 mmol) in DMF (2 mL) was added EDCI (234 mg, 1.23 mmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc (30 mL) and washed with water (30 mL×3). The mixture was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=3/1 to 2/1) to afford the title compound as a white solid (41 mg, 29.1%). The title compound was characterized by LC-MS as shown below:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.O=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[N:1]1[N:2]=[C:3]([NH:6][CH:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[NH:4][CH:5]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
To a solution (200 mL) of 1H-1,2,4-triazol-3-amine (11 g) and ethyl 4-oxocyclohexanecarboxylate (28 g) in acetic acid was added sodium cyanoborohydride (35 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (13 g, 40%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21]>>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:12][C:13]3=[O:21])=[CH:11][C:7]=2[CH2:8][CH2:9]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: O=C1Nc2ccccc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 2-oxindole to give 0.25 g of 3-(2,3-dihydrobenzofuran-5-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][NH:42][CH3:43])=[CH:37][CH:36]=2)[CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:42]([CH2:41][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:30]4[CH2:31][CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29]4)=[CH:40][CH:39]=3)[CH3:43])=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:25])[CH:4]=1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine (40 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3. A portion of the fraction collected was further purified using prep method D to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[N:29]=1)=[O:27]
Reactant: Cc1cc(C)nc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(C)cc(C)n2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4,6-dimethylpyridine*.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.[O:19]1[CH2:21][CH:20]1[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.C(OCC)C>C1COCC1>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:21][CH:20]([OH:19])[CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: N#Cc1ccc2c(ccn2CC2CO2)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc2c(ccn2CC(O)COc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.34 g (2.02 mmol) 4-phenyl phenol are dissolved in 5 ml absolute THF under nitrogen and mixed drop-wise with 0.1 ml (1.0 mmol) tert-butyllithium with constant stirring. The mixture is stirred at room temperature for 5 min. Thereafter, the solution of 0.20 g (1.0 mmol) 1-oxiranylmethylindole-5-carbonitrile (Example 26A) in 5 ml absolute THF is added drop-wise. The batch is heated at 100° C. for 4 hours. Having cooled down, the batch is mixed with 100 ml diethyl ether and extracted three times using water. The aqueous phase is extracted twice using ethyl acetate and the combined organic phases are dried on sodium sulfate, filtrated and the solvent is removed in vacuo. The residue is purified on silica gel by means of column chromatography (flow agent: hexane/ethyl acetate 7:3). The product is obtained as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[CH:3]=1.[Br:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Br:26][C:27]1[CH:28]=[C:29]([C:6]2[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:16]3[CH:17]=[N:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH:5]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(OS(=O)(=O)C(F)(F)F)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl-2′-yl ester (example A.5) (0.773 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.43 g, 2.1 mmol) according to the general procedure IIb. Obtained as a white solid (0.69 g, 88%). MS (ISP) 393.1 [(M+H)+] and 395.1 [(M+2+H)+].
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:27]1C=CC(N)=C(C)C=1.P(Cl)(Cl)(Cl)=O.N>O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4[CH3:27])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1cc(Br)ccc1N
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (20.0 g, 71.5 mmol, Intermediate 6, step b) and 4-bromo-2-methylaniline (13.3 g, 71.5 mmol) in phosphorus oxychloride (66.8 mL, 712 mmol) was heated at 105° C. After 5 hours, the mixture was cooled to room temperature and added to water (600 mL) with cooling so that the internal temperature did not exceed 35° C. The pH of the mixture was adjusted to 8-9 by the slow addition of saturated aqueous ammonia solution such that the internal temperature did not exceed 35° C. After 30 minutes of stirring at room temperature, the mixture was filtered and the solid material was suspended in acetonitrile (200 mL), sonicated and filtered. The solid material was collected and suspended in DCM (80 mL), sonicated and filtered and washed with ether (40 mL). The filtrate was concentrated, suspended in DCM (40 mL), sonicated and filtered to provide more of the desired product. To 5 g of the isolated solid, DCM (300 mL) and aqueous saturated NaHCO3 (100 mL) were added and the mixture was transferred to a separatory funnel, and the layers were separated. The DCM layer was further washed with brine (100 mL), dried (MgSO4), filtered and the solvents were removed under reduced pressure. The crude material was purified using flash-column chromatography on silica gel eluting with DCM to provide 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:36])([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1)[C:3]1[N:12]=[C:11]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[N:16](C(OC(C)(C)C)=O)[N:15]=2)[C:10]2[C:5](=[CH:6][C:7]([O:27][CH3:28])=[CH:8][CH:9]=2)[N:4]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:36][C:2]([F:1])([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1)[C:3]1[N:12]=[C:11]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[C:10]2[C:5](=[CH:6][C:7]([O:27][CH3:28])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc2c(Nc3cc(C)n(C(=O)OC(C)(C)C)n3)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.2 %

Procedure:
To tert-Butyl 3-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4-ylamino)-5-methyl-1H-pyrazole-1-carboxylate (100 mg, 0.20 mmol) was added 20% TFA/DCM, and the mixture was stirred at rt for 2.5 h. The mixture was concentrated and the residue was purified by preparative reverse-phase HPLC (TFA as a modifier). The fractions containing the desired product were neutralized with saturated aq NaHCO3 and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as an off-white solid (33 mg, 41%). 1H NMR (250 MHz, DMSO-d6) δ 12.10 (s, 1H), 10.54 (s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.59 (d, J=8.16 Hz, 1H), 7.97-8.06 (m, 2H), 7.22-7.28 (m, 2H), 5.97 (s, 1H), 3.93 (s, 3H), 2.17 (s, 3H). LCMS (ESI) m/z 401 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH3:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[CH2:8]Br>O.C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[CH:10]=[C:11]([CH3:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1
Reactant: COc1ccc(Oc2c(C)cc(CBr)cc2C)cc1C(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2c(C)cc(CC#N)cc2C)cc1C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of sodium cyanide (0.23 g, 4.69 mmol) in H2O (2 mL) at room temperature was added a solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide (0.85 g, 2.34 mmol) in ethanol (5 mL). The reaction mixture was heated at 80° C. for 2 h, cooled to room temperature, and poured into ice water (100 mL). The mixture was stirred for 1 h and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:4) to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetonitrile as a brown solid (0.64 g, 85%, m.p.: 56-58° C.): 1H NMR (300 MHz, CDCl3): δ 7.07 (s, 2 H), 6.78 (d, J=3.3 Hz, 1 H), 6.68 (d, J=9.0 Hz, 1 H), 6.35 (dd, J=3.0, 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.73 (s, 2 H), 3.40-3.25 (m, 1 H), 2.16 (s, 6 H), 1.19 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:4); Rf=0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[OH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15]2.C(=O)([O-])[O-].[Cs+].[Cs+].CC(=O)OCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc2ccc(Oc3ccnc(Cl)c3)cc2c1
Temperature: 150 °C

Procedure:
A mixture of 2-chloro-4-nitropyridine (0.228 g, 1.44 mmol), 6-hydroxyquinoline-3-carboxylic acid (Int-15, 0.3 g, 1.58 mmol), and cesium carbonate (1.41 g, 4.32 mol) in N,N-dimethylformamide (3 mL) was heated at 150° C. for 2 h in a microwave reactor. The reaction was cooled to room temperature and filtered to remove solids. The filtrate was acidified with hydrochloric acid (1 M in water) until pH 1.5. The product precipitated cleanly and was isolated by suction filtration. LC-MS: (FA) EA+ 301; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.31 (d, J=2.1 Hz, 1H), 8.98 (d, J=2.0 Hz, 1 H), 8.34 (d, J=5.7 Hz, 1H), 8.21 (d, J=9.1 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.79 (dd, J=9.1, 2.8 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.09 (dd, J=5.7, 2.3 Hz, 1H).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH:8]([CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)=[O:7]
Reactant: O=C1CCC=C1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CCC1=CCCC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chromium trioxide (0.6 mol) is added to a stirring solution of (1.2 mol) of anhydrous pyridine in 1500 ml. of anhydrous methylene chloride cooled in an ice bath. The deep red suspension is stirred for 15 minutes at 0° C. and 45 minutes at ambient temperature. A solution of 01.5 mol of 2-(2-hydroxyethyl)-cyclopent-2-en-1-one (Example 897) in 50 ml. of methylene chloride is added, all at once, to the suspension. A black terry deposit is formed immediately. After stirring the mixture for 25 minutes at ambient temperature, the methylene chloride is decanted from the tarry precipitate which is then triturated several times with ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH:16]([C:19]1([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH2:21][CH2:20]1)[CH:17]=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:16]([C:19]4([C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[N:28]=[CH:27][CH:26]=[CH:25]6)[CH2:21][CH2:20]4)=[CH:17][N:14]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2ccc(Br)cc2)nn1
Product: Brc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1

Procedure:
This compound was prepared from the condensation of 6-(4-bromophenyl)-1,2,4-triazin-3-amine and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde using a procedure analogous to that described for the synthesis of Example 7, Step 8. LCMS: (M+H)=442.3/444.2.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:22]([CH3:27])([CH3:26])[C:23]2=[O:24])=[CH:11][CH:10]=1
Reactant: CC(C)(C(=O)O)c1cccnc1Nc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(Cl)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add trifluoroacetic acid (5 mL) to 2-[(4-chlorophenyl)amino-a,a-dimethyl-3-pyridineacetic acid (S) (3.00 g, 0.010 mole) in dichloromethane (40 mL). Stir for 16 hours at room temperature. Rotoevaporate to remove the solvent. Add saturated organic solution with MgSO4, filter, and rotoevaporate. Dissolve the oil in dichloromethane, and chromatograph on silica gel, eluting with dichloromethane. Combine the appropriate fractions, and concentrate under reduced pressure to give a solid. Recrystallize with diethyl ether-isopropyl ether to give the title compound AB as a white solid.
Reaction SMILES: C([O:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[CH2:11](I)[CH3:12]>>[CH2:11]([CH:9]1[CH2:8][CH2:7][C:6](=[O:10])[CH2:5][C:4]1=[O:3])[CH3:12]
Reactant: CCI
Reactant: CCOC1=CC(=O)CCC1
Product: CCC1CCC(=O)CC1=O

Procedure:
The title compound (D12) was prepared from 3-ethoxy-2-cyclohexen-1-one and ethyl iodide using a procedure similar to that described in Description 11. Product was used in the preparation of D14 without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a suspension of 1-(4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (189 g, 630 mmol) in DME (700 ml) at −3° C. was added methanesulfonyl chloride (50.5 ml, 650 mmol) and the mixture stirred for 15 minutes. Triethylamine (182 ml, 1.31 mol) in DME (74 ml) was then added dropwise over 15 min. After the addition was complete, the reaction was then warmed to 35° C. for 45 minutes. It was then cooled and filtered, washing with DME (180 ml). To the filtrate was added iron (II) chloride (0.87 g) and the mixture was then heated to 75° C. for 2.5 hour then allowed to cool. Water (700 ml) was added, the resulting solid removed by filtration, washed with water and dried. This solid was dissolved in dichloromethane (1.5 l) and purified in two portions by Biotage chromatography eluting with hexane-ethyl acetate (3:1). Combination and concentration of the appropriate fractions gave 148.3 g (84%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:41]([C:40]3[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)=[O:42])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)c1ccc(OC)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 4-methoxybenzoyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H39N2O3Cl2 [(M+H)+] 629.2332, observed 629.2337.
Reaction SMILES: C([NH:9][CH:10]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[C:17]([O:26]C)[CH:16]=1)[C:11]([O:13]C)=[O:12])(=O)C1C=CC=CC=1>Cl>[C:22]([C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([CH:10]([C:11]([OH:13])=[O:12])[NH2:9])=[CH:16][C:17]=1[OH:26])([OH:24])=[O:23]
Reactant: COC(=O)c1cc(C)c(C(NC(=O)c2ccccc2)C(=O)OC)cc1OC
Agent: Cl
Product: Cc1cc(C(=O)O)c(O)cc1C(N)C(=O)O

Procedure:
A stirred suspension of methyl 2-benzamido-2-(4-methoxycarbonyl-3-methoxy-6-methylphenyl)acetate (120 mg, 0.32 mmol) in aqueous hydrochloric acid (5M, 3 ml) was heated to 110° C. for 7 days in a PTFE lined stainless steel sealed reaction vessel. The contents were periodically cooled, evaporated and topped up with an equivalent amount of fresh aqueous hydrochloric acid. The contents were cooled and chromatographed on ion exchange resin following the procedure described in Example 1 (iii) to give the title compound as an off-white solid, m.p. >250° C.