Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[OH:43][CH2:44][C@@H:45]1[C@@H:49]([OH:50])[CH2:48][CH2:47][NH:46]1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:46]3[CH2:47][CH2:48][C@H:49]([OH:50])[C@H:45]3[CH2:44][OH:43])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC[C@H]1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](O)[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 68 h
Yield: 67.1 %

Procedure:
A mixture of 11.0 g (20.6 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 14.3 g (103 mmol) potassium carbonate and 12.2 g (75.7 mmol) (2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine in 110 ml dimethyl sulfoxide was stirred at 130° C. for 68 h. The reaction mixture was diluted with 800 ml ethyl acetate and washed with 800 ml saturated sodium carbonate solution, 500 ml water and 750 ml brine. The combined aqueous layers were extracted with two 800-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography gave 8.48 g (67%) of the title compound as a light yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[NH:20][C:11]3=[N:12][C:13]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[N:9]=[C:10]3[N:21]=2)=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2F)nc1N
Solvent: c1ccncc1
Solvent: O
Product: Fc1ccc(-c2nc3nc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
A mixture of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine (Example 153, 0.100 g, 0.35 mmol) and 4-fluorobenzoyl chloride (0.074 g, 0.46 mmol) in pyridine (1 mL) was stirred and heated to 120° C. in a sealed tube for 24 hours. Water was added and the filtered solid was purified by silica gel chromatography eluting with CH2Cl2/MeOH (98:1 to 95:5) to give the title compound (0.045 g, 33%) as an off-white solid.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.ClCCl.CO.N>>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:1](=[O:5])[C:2]#[CH:3])=[CH:9][CH:8]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: C#CC(=O)Nc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 1.1.b. from propynoic acid and 4-chloroaniline. Yield: 0.56 g (31.2% of theory); C9H6ClNO (M=179.60); calc.: molecular ion peak (M−H)−: 178/180; found: molecular ion peak (M−H)−: 178/180; Rf value: 0.53 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.Cl.[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[NH:19].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:19]=[C:15]2[CH2:16][CH2:17][CH2:18][N:14]2[CH:2]=1
Reactant: N=C1CCCN1
Reactant: O=C(CBr)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cn3c(n2)CCC3)c(F)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)ethanone (150 g, 640 mmol, Example #8, Step A), pyrrolidin-2-imine hydrochloride (108 g, 894 mmol) and Na2CO3 (134 mL, 3190 mmol) in DMF (650 mL) was stirred and heated at about 80° C. in a 3 L 3 necked flask for about 24 h. The mixture was cooled to ambient temperature and poured into water (about 5 L). The product was partitioned between EtOAc (800 mL) and the basic aqueous phase. The aqueous layer was extracted with additional EtOAc (3×800 mL). The combined organic extracts were washed with water (4×800 mL), dried over MgSO4 and filtered through a pad of Florisil® (2″ depth×3″ diameter). The pad was washed with EtOAc (4×250 mL) and the filtrate was concentrated to dryness under reduced pressure to yield the title compound as a solid (98.6 g, 70%): LC/MS (Table 1, Method a) Rt=2.72 min; MS m/z: 221.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1

Procedure:
Two grams of 4,6-dichloro-2-phenylpyrimidine is added in small portions to 10 ml. of N-methylpiperazine with slight warming and stirring. The resulting mixture is heated on a steam bath for several minutes, then poured into 250 ml. of water. The product (2.4 g., m.p. 81°-87°C.) is then recrystallized from n-pentane to afford 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine, m.p. 91°-92.5°C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)C=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P([O-])([O-])([O-])=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH:10]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7]
Reactant: CCOC(=O)CC(=O)C(OC)OC
Reactant: OCC=Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(OC)C(=O)CC(=O)OCC=Cc1ccccc1

Procedure:
2.68 g (14.1 mmol) of ethyl 4,4-dimethoxy-3-oxobutyrate, 5.14 ml (40.0 mmol) of cinnamyl alcohol and 244 mg (2.0 mmol) of 4-dimethylaminopyridine were heated under reflux in 40 ml of toluene for two nights. A phosphate buffer solution was added to the reaction liquid. After the extraction with ethyl acetate, the organic layer was washed with a saturated aqueous salt solution and then dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13])([CH3:10])[CH3:9].C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:13][C:12]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[C:17]([CH3:19])[C:11]=1[CH:8]([CH3:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2ccccc2c(O)c1C(C)C
Yield: 21 %

Procedure:
4.56 ml (50 mmol) of aniline and 10.7 ml (60 mmol) of ethyl 2-isopropylacetoacetate were mixed with 50 ml of chloroform. 0.48 g (2.5 mmol) of para-toluenesulfonic acid was added, and the reaction mixture was refluxed with continuous removal of the water produced in the reaction. After 2 d chloroform was removed in vacuum, and the residue was refluxed in 10 ml of phenyl ether. After cooling, the precipitate was filtered and washed with diethyl ether to give 4-hydroxy-3-isopropyl-2-methylquinoline (21%). Following the procedure of Step 3 in Example 1, but substituting 4-hydroxy-3-isopropyl-2-methylquinoline for 9-(10H)acridone, 4-chloro-3-isopropyl-2-methylquinoline (100%) was obtained, which was reacted with 4-(4-methylpiperazin-1-yl)aniline (following the procedure of Step 4 in Example 1), to afford the title compound with 61% yield (overall yield 13%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(NS(C)(=O)=O)cc1
Yield: 22.2 %

Procedure:
A solution of 22.63 g (0.25 mol) of acryloyl chloride in 250 ml of methylene chloride was added over a period of 35 minutes to a mixture of 46.81 g (0.25 mol) of N-(4-hydroxyphenyl)methanesulfonamide, 25.30 g (0.25 mol) of triethylamine and 750 ml of methylene chloride at 0° C. The resultant solution was stirred at reduced temperature for 2.17 hours, washed three times with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene and drying gave 13.4 g (22.2 percent yield) of N-(4-acryloyloxyphenyl)methanesulfonamide; m.p.=136.5° to 139.5° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([I:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH:26]([C:28](O)=[O:29])[CH3:27])[CH:21]=[CH:22][C:23]=1[Cl:24].N[C@H](C(O)=O)C>>[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([I:15])[CH:9]=1)[NH:6][C:28](=[O:29])[CH:26]([CH3:27])[NH:25][C:20]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(I)c1
Agent: C[C@H](N)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(O)c(I)c1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using 3-iodo-L-tyrosine methyl ester hydrochloride (prepared following General Procedure K and using 3-iodo-L-tyrosine (Aldrich)) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers about alanine. The reaction was monitored by tlc (Rf=0.29 in 10% MeOH/CH2Cl2) and purification was by flash chromatography (10% methanol/methylene chloride).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH3:47])=[CH:45][N:44]=[C:43]([CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH3:47])=[CH:45][N:44]=[C:43]([CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)c(C)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K17) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (300 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Clc1cc(Br)c2cn[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(Br)cc(Cl)cc32)ccc1OCc1ccccc1
Yield: 53.4 %

Procedure:
4-Bromo-6-chloro-1H-indazole (413 mg, 1.78 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (876 mg, 3.56 mmol), copper (II) acetate (483 mg, 2.67 mmol) and pyridine (0.29 mL, 3.56 mmol) in DCM (30 mL) were stirred in the presence of molecular sieves (4A, 790 mg) in air. After 40 hours the mixture was filtered through a pad of celite and concentrated to afford 1.24 g of crude material. This was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of Et2O (0 to 30%) in hexane to afford 410 mg of desired compound (D10) containing a small amount of the N2-aryl regioisomer.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)=[C:2]=[S:3].[H-].[Na+].[NH2:18][C:19]1[C:20](=[O:41])[N:21]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[O:39][CH3:40])[CH:22]=[CH:23][C:24]=1[C:25](OCC)=[O:26].Cl>CN(C)C=O>[CH3:40][O:39][C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[CH2:30][N:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:26])[N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=3)[C:2](=[S:3])[NH:18][C:19]=2[C:20]1=[O:41]
Reactant: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1N
Reactant: FC(F)(F)COc1ccc(N=C=S)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3c(=O)n(-c4ccc(OCC(F)(F)F)cc4)c(=S)[nH]c3c2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To a solution of 1-isothiocyanato-4-(2,2,2-trifluoroethoxy)benzene (375 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 193 mg) under ice-cooling, and the mixture was cooled to 0° C. A solution of ethyl 3-amino-1-(2,4-dimethoxybenzyl)-2-oxo-1,2-dihydropyridine-4-carboxylate (535 mg) in N,N-dimethylformamide (5 ml) was added dropwise thereto, and the mixture was stirred at 0° C. for 15 min. The reaction mixture was poured into 0.3M hydrochloric acid (15 ml), and the precipitate was collected by filtration. The obtained solid was suspended in toluene, and the suspension was concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (527 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N)CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
±(1S*,2R*,4R*)-[4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (from example 55d), (100 mg) was dissolved in MeOH (1 ml) prior to the addition of 5% Pd/BaSO4 (120 mg). A hydrogen balloon was added and the solution was stirred for 1.5 h. The palladium was filtered off and the solution was concentrated to give ±(1S*,2R*,4R*)-[4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (94 mg). MS found: (M+H)+=415.2
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[O:26][CH:39]=[N:38][CH:37]=2)[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(-c3cnco3)c2)cc1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of 1-trityl-1H-imidazole-4-carbaldehyde (25.0 g, 73.9 mmol), TosMIC (14.42 g, 73.9 mmol) and K2CO3 (10.21 g, 73.9 mmol) in MeOH (750 mL) was heated to reflux for 3 h. The mixture was then allowed to cool to RT, diluted with H2O, and extracted with AcOEt. The combined org. layers were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane/AcOEt 100:0 to 0:100) gave the title compound (14.6 g). UPLC (2 min) rt 1.415 min.
Reaction SMILES: C([O:3][C:4]1[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:6]([CH3:22])=[C:7]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:8]=1)C.Br[CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38].[OH-].[Na+]>C(#N)C.O>[CH3:22][C:6]1[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:4](=[O:3])[N:8]([CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:7]=1[C:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CCOc1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(CCCS(C)(=O)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 12.6 %

Procedure:
A mixture of 4-(5-{2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (intermediate 5) (66 mg, 0.15 mmol) and 1-bromo-3-methanesulfonyl propane (201 mg, 1.0 mmol) in acetonitrile (0.20 mL) was heated at 120° C. for 6 h. The mix was cooled to RT and diluted with acetonitrile (2 mL) and water (1 mL) then treated with 1M sodium hydroxide (0.20 ml). The mixture was heated at 50° C. for 2 h. The cold mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by MDAP to afford the title compound (10 mg).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]([CH2:22][CH3:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1>O>[CH3:21][C:17]1[CH:16]=[C:15]([N:14]([CH2:12][CH3:13])[CH2:22][CH3:23])[CH:20]=[CH:19][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCN(CC)c1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: O
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1

Procedure:
A mixture of phthalic anhydride (60 g.), N,N-diethyl-m-toluidine (162.8 g.), aluminum chloride (120 g.) and chlorobenzene (360 ml.) was heated (75°-95° C.) during one and one-half hours, then diluted with water (200 ml., then more). More chlorobenzene (200 ml.) was added and the chlorobenzene layer was separated and steam distilled. Addition of sodium hydroxide solution (10%) to a solution of the residue in dilute sulfuric acid (20%, 250 ml.) afforded 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (IV: Y2 = CH3, Y'4 = (CH3CH2)2N, Z4 = Z"5 = Z"6 = Z7 = H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH:9]([CH3:11])[CH3:10].FC(F)(F)C(O)=O.[CH2:19]([O:26][C:27](=[O:55])[N:28]([CH2:53][CH3:54])[CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)[N:33]=[C:32]1[CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:19]([O:26][C:27](=[O:55])[N:28]([CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:45])([F:46])[F:44])[CH:37]=2)[N:33]=[C:32]1[CH:47]1[CH2:48][CH2:49][N:50]([C:2]2[C:3]([CH:9]([CH3:11])[CH3:10])=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)[CH2:51][CH2:52]1)[CH2:53][CH3:54])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)c1c(N)ncnc1Cl
Reactant: CCN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 6-chloro-5-isopropyl-pyrimidin-4-ylamine (40.0 mg; 0.23 mmol; 1.0 eq.), ethyl-{2-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-carbamic acid benzyl ester trifluoroacetate (2) (174.0 mg; 0.23 mmol; 1.0 eq.), and Cs2CO3 (303.7 mg; 0.93 mmol; 4.0 eq.) in DMSO (1.5 ml) was stirred at 120° C. for 48 hr. The crude was purified by prep HPLC to yield the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([OH:17])=O)[NH:12][C:9]2=[CH:10][N:11]=1.Cl.Cl.[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:22])[CH3:21].CN(C=O)C.CCN(C(C)C)C(C)C>>[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:15]([C:13]2[NH:12][C:9]3=[CH:10][N:11]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[C:8]3[CH:14]=2)=[O:17])[CH2:25][CH2:24]1)([CH3:22])[CH3:21]
Reactant: COCCOc1cc2cc(C(=O)O)[nH]c2cn1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2cc(C(=O)NC3CCN(C(C)C)CC3)[nH]c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 820 mg (3.47 mmol) of 5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid and 745 mg (3.47 mmol) 1-isopropyl-piperidin-4-ylamine dihydrochloride in 30 mL absolute DMF 1.13 g (3.47 mmol) TOTU and 1.81 mL (10.41 mmol) DIPEA were added and the mixture was stirred for 4 h at room temperature. The solvent was removed in vacuo, the residue dissolved in CH2Cl2 and the CH2Cl2 phase washed with a saturated NaHCO3 solution. The organic phase was concentrated and the residue purified by chromatography over silica gel using CH2Cl2/MeOH/HOAc/H2O=90/10/1/1 as eluent. The fractions containing the product were combined and concentrated. The residue was dissolved in CH2Cl2 and the CH2Cl2 phase was washed with a saturated NaHCO3 solution. The phases were separated and the organic phase dried over Na2SO4. After filtration the solvent was removed in vacuo. Yield: 461 mg.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I.CCCCCCC>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1COc2ccccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCCCCCC
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3 (3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCl3): δ 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.