Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][CH:11]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][N:33]([CH2:35][C@H:36]3[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]3)[CH:34]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:23]3[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[N:32][N:33]([CH2:35][C@H:36]5[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]5)[CH:34]=4)[N:24]=3)[CH2:16][CH2:17]2)=[N:10][CH:11]=1
Reactant: Fc1ccccc1Oc1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(Oc6ccccc6F)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(2-fluorophenoxy)-2-(piperazin-1-yl)pyrimidine HCl salt (27 mg, 0.1 mmol), (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)-morpholine-4-carboxylate (40 mg, 0.1 mmol) and diisopropylethylamine (25 mg, 2.0 mmol) in dioxane (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was directly evaporated and used in the next step.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>C1(C)C=CC=CC=1>[O:20]=[C:16]([CH3:15])[CH2:17][C:18]([O:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[O:19]
Reactant: C=C1CC(=O)O1
Reactant: COC(=O)[C@@H](C)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)OC(=O)CC(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl (2R)-2-hydroxypropanoate (5.0 g, 48 mmol) and triethylamine (49 mg, 0.48 mmol) are dissolved in toluene (40 ml). At 90° C., diketene (5.2 g, 62.4 mmol) is added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling to room temperature, the mixture is poured into ice-water. The phases are separated and the aqueous phase is extracted with toluene two times. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[N:25]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:28]4[CH2:29][CH2:30][N:25]([C:31]([NH2:33])=[O:32])[CH2:26][CH2:27]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: NC(=O)N1CCNCC1
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C(N)=O)CC3)nn12

Procedure:
The title compound was prepared in analogy to Example 3 using 6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B) and piperazine-1-carboxamide instead of piperazin-2-one (tR 3.17 min (conditions 1), MH+=438, 1H-NMR in DMSO-d6: 8.95 (d, 1H); 8.46 (d, 1H); 7.80 (d, 1H); 7.65 (d, 1H); 7.61 (s, 1H); 7.60 (m, 1H); 7.08 (d, 1H); 6.07 (s, 2H); 4.98 (m, 1H); 3.15-3.40 (m, 8H); 1.88 (d, 3H)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=1.C(Cl)(=O)C(Cl)=O.[CH:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:31])[CH3:30]>C(Cl)Cl.CN(C=O)C>[CH2:33]([N:32]([CH:29]([CH3:31])[CH3:30])[C:14]([C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:11][CH:12]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Reactant: CC(C)NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(Cc1ccccc1)C(=O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (4.321 g, 14.25 mmol) in CH2Cl2 (100 mL) and DMF (2 drops) was added oxalyl chloride (1.5 mL, 2.21 g, 17.5 mmol) dropwise. Most solids dissolved at first, later a precipitate formed. The suspension was stirred for 1 hour at 0° C., and then allowed to warm to room temperature (all solids dissolved). The solution was concentrated to a dark oil, which crystallized upon standing. The crude acid chloride was taken up in toluene (50 mL, distilled, dried over Na2SO4) and cooled in ice. N-Isopropylbenzylamine (9.5 mL, 8.5 g, 56.8 mmol) was added. The resulting suspension was stirred at room temperature for 90 minutes, washed with water and a saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (400 mL silica, EtOAc/heptanes 1:1). All fractions containing the product were combined and concentrated. Some of the excess amine eluted with the product. A solution of the mixture in CH2Cl2 (50 mL) was washed with a 10% aqueous citric acid solution (2×25 mL), water (25 mL), and saturated aqueous NaCl solution (25 mL), dried over Na2SO4, and concentrated to give pure 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide as a yellowish foam (5.685 g, 13.08 mmol, 92%).
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>COCCOC>[C:13]1([NH:12][C:10](=[O:11])[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:7]([OH:9])=[O:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Solvent: COCCOC
Product: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
Cis-4-cyclohexene-1,2-dicarboxylic anhydride (7.6 g., 0.05 mole) was dissolved in 150 ml. 1,2-dimethoxyethane and 4.7 g. aniline (0.05 mole) was added. The reaction mixture was heated to reflux for one hour and allowed to stand overnight. The solvent was evaporated. The product then obtained was purified by pouring into 200 ml. of 10% hydrochloric acid solution. This was extracted with diethyl ether, dried over anhydrous magnesium sulfate, filtered and the solvent stripped off. There was obtained 7.3 g. of the title compound. The structure was confirmed by infrared analysis and n.m.r.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C=O)C.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20]>CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH2:19][C:18]([F:22])([F:21])[F:17])[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NCC(F)(F)F
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: FC(F)(F)CNc1nc(Cl)nc2ccoc12
Temperature: 120 °C
Yield: 71.4 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (0.80 g, 4.23 mmol, ArkPharm) and DMF (3.0 mL). 2,2,2-Trifluoroethanamine (1.05 g, 10.58 mmol, Acros) was added. The mixture was heated in a microwave at about 120° C. for about 15 min. The mixture was diluted with Et2O (100 mL). The mixture was washed with water (3×25 mL). The combined aqueous layer was extracted with Et2O (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was transferred neat and was purified by preparative TLC eluting with 3:1 hexanes/EtOAc to give 2-chloro-N-(2,2,2-trifluoroethyl)furo[3,2-d]pyrimidin-4-amine (0.76 g, 71%): LC/MS (Table 2, Method h) Rt=1.85 min; MS m/z: 252, 254 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23])=O)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[NH2:11][C@H:12]1[C@@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23]
Reactant: [H][H]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1
Yield: 77 %

Procedure:
(3S, 4R)-3-benzyloxycarbonylamino-4-phenoxy-azetidin-2-one (1.85 g. 5.9 mmole) is hydrogenated with 2 g of 10% palladium on activated carbon in THF (30 ml) and ethyl acetate (30 ml) at 50 psi hydrogen pressure at room temperature for 2 hours. After removal of catalyst by filtration, 810 mg of deprotected (3S, 4R)-3-amino-4-phenoxy-azetidin-2-one is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([OH:22])=[O:21]>CC(O)C>[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([O-:22])=[O:21]
Reactant: O=CO
Agent: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Solvent: CC(C)O
Product: O=C[O-]
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a mechanically stirred suspension of O-desmethylvenlafaxine (100.0 g, 0.380 mol) in 2-propanol (500 mL) at 70–75° C. under a nitrogen atmosphere was added dropwise a solution of 96% formic acid (20 ml, d=1.22, 23.42 g, 0.509 mol., 1.34 molar excess) over a period of 45 min. The resulting, hazy solution was kept for a further 10 min. at 70–75° C. and then filtered through a pad of Celite filter aid (20 g, prewashed with hot 2-propanol). The filter pad was washed with hot (70–75° C.) 2-propanol (2×81 mL). The filtrate and washings (temperature 44–45° C.) were warmed to 50° C., under a nitrogen atmosphere, using slow mechanical stirring. The solution was seeded with crystals of O-desmethylvenlafaxine formate and allowed to cool. After further seeding at 45° C. the solution was allowed to cool to 40–41° C. whereupon the solution became cloudy. The stirred, cloudy solution was maintained at 40–42° C. for 25 min. and then cooled quickly (using cold water) to 35° C. It was then maintained at 34–35° C. for 1.5 h. Copious crystallization occurred during this latter period. The stirred thick slurry of crystals was allowed to cool to 25° C. over a period of 50 min. and then cooled to 7° C. (using ice) over a period of 1 h. and 40 min. The slurry was chilled to −10° C. in 10 min. and kept at that temperature for 30 min. The crystals were collected on a filter and washed with chilled (−5 to −10° C.) acetone (3×200 mL). After drying in a vacuum oven at 46–47° C., for 47 h. at 80 mm Hg, under a nitrogen stream, the product, O-desmethylvenlafaxine formate, weighed 101.59 g (86% yield) and it had mp=146.5–148° C. It was characterized by DSC (sharp endotherm at 152.4° C.).
Reaction SMILES: N[CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.CCN(CC)CC>C1COCC1>[C:30]([O:29][C:27]([CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CN)c(C)nc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CC(=O)OC(C)(C)C)c(C)nc2n1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a stirred solution of ethyl 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (Example 54, Step 10, 200 mg, 0.53 mmol) in THF (5 mL) at room temperature was added (BOC)2O (1.0 M in THF, 1.05 mL, 1.05 mmol) and Et3N (0.37 mL, 2.65 mmol). After 2 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with NH4Cl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography gave ethyl 6-((tert-butoxycarbonyl)methyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (100 mg, 40%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:16][C:15]1[C:2]([OH:1])=[C:3]([CH:12]=[CH:13][CH:14]=1)[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CCC(=O)c1cccc(O)c1O
Solvent: O
Product: COC(=O)CCC(=O)c1cccc(OC(C)=O)c1O
Reaction time: 2 h

Procedure:
Methyl 3-(2,3-dihydroxybenzoyl)propionate was treated with boroacetic anhydride in acetic anhydride on a steam bath for 20 minutes and the mixture was poured into water and stirred for 2 hours to give methyl 3-(3-acetoxy-2-hydroxybenzoyl)-propionate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CCN)c(Cl)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1ccc(OC)c(OC)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To the solution of 2-(2-chloro-3,4-dimethoxyphenyl)ethanamine (2.8 g, 12.98 mmol) in dichloromethane (DCM) (40 mL) at 0° C. was added triethylamine (1.990 mL, 14.28 mmol) and ethyl chloroformate (1.371 mL, 14.28 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was washed with water, brine, dried over magnesium sulfate and chromatographed to give ethyl 2-chloro-3,4-dimethoxyphenethylcarbamate (1.7 g, 5.91 mmol, 97% yield). LCMS (M+H)+: 288.1
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]1([O-:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].O>CN(C)C=O>[O:21]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cc(-c2ccccc2)c(Br)s1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2ccccc2)c(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 5-bromo-4-phenylthiophene-2-carbaldehyde (652 mg) in N,N-dimethylformamide (10 mL) was added sodium phenolate (425 mg) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=99:1→9:1) to give the title compound as a pale-yellow solid (yield 152 mg, yield 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(#N)C.CN(C)C1C=CN=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=2)(=[O:25])=[O:24])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Br)cn1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To 2-Amino-5-bromopyridine (15, 1.50 g, 8.67 mmol) in acetonitrile (20.0 mL) were added pyridine (6.0 mL, 0.074 mol), 4-dimethylaminopyridine (0.10 g, 0.82 mmol) and 4-trifluoromethyl-benzenesulfonyl chloride (48, 2.14 g, 8.75 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated, poured into water, acidified with 1N HCl to pH=2, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was washed with ethyl acetate to give a white solid as desired compound (49, 2.80 g, 84.8%). MS (ESI) [M+H+]+=381.0, 383.0.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([Cl:25])=[CH:27][CH:28]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 12 h
Yield: 48.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazo-1-yl]butanoate (Reference Example 33; 1.00 g, 2.70 mmol) and 4-chloroaniline (1.04 g, 8.0.9 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was stirred at 150° C. for 12 hr. After cooling, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, water and brine. Organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (600 mg, 1.30 mmol, 48%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[C:16]([CH3:21])=[N:17][O:18][C:19]=2[CH3:20])=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH2:22]([O:24][C:25](OCC)(OCC)OCC)[CH3:23]>CC(O)=O>[CH3:21][C:16]1[C:15]([C:11]2[CH:10]=[C:3]([C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[C:2]3[N:1]=[C:25]([O:24][CH2:22][CH3:23])[NH:14][C:13]=3[CH:12]=2)=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: CON(C)C(=O)c1cc(-c2c(C)noc2C)cc(N)c1N
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)O
Product: CCOc1nc2c(C(=O)N(C)OC)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-N-methoxy-N-methylbenzamide (25 g, 0.086 mol) was dissolved in a 1:1 mixture (32 mL total) of tetraethylorthocarbonate and AcOH and allowed to stir under air at room temperature for 1.5 hr. The reaction mixture was concentrated in vacuo at room temperature and the crude residue was dissolved in EtOAc. The solution was washed three times with bicarb, once with water, and organic layer was concentrated in vacuo to give 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-N-methoxy-N-methyl-1H-benzo[d]imidazole-4-carboxamide as a dark oil. Crude material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][OH:21].[OH-].[K+]>>[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: OCC1CCCO1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Cl)n1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1

Procedure:
In analogy to the procedure described in Example 4 a), 6-chloro-5-(trifluoromethyl)picolinic acid (CAN 855915-21-8) was reacted with (tetrahydrofuran-2-yl)methanol (CAN 97-99-4) in the presence of potassium hydroxide to yield the title compound as yellow solid; MS (EI): m/e=290.0 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:19]([CH3:25])([CH3:24])[CH:18]([OH:26])[CH2:17][C:16]([CH3:28])([CH3:27])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:19]([CH3:24])([CH3:25])[C:18](=[O:26])[CH2:17][C:16]([CH3:28])([CH3:27])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc2c(cc1/C=C/c1ccc(C(=O)O)c(C)c1)C(C)(C)CC(O)C2(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cc1/C=C/c1ccc(C(=O)O)c(C)c1)C(C)(C)CC(=O)C2(C)C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 1.6 g (4.2 mmol) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-methyl-6-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid in 50 ml of methylene chloride at room temperature was added 1.97 g (4.65 mmol) of Dess-Martin periodinane. After 1 h, the reaction mixture was poured into brine and extracted with methylene chloride. The organic fraction was dried over sodium sulfate, adsorbed onto silica gel and purified by flash chromatography (gradient elution: hexane-8% ethyl acetate/hexane) to afford 1.45 g (92%) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-methyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid (M+=376).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH3:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:11][C:10]=1[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:11][C:10]=1[C:21]1[CH:22]=[N:23][N:24]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])[CH:25]=1
Reactant: Cc1sc(Nc2ccccn2)nc1-c1cn[nH]c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cn1cc(-c2nc(Nc3ccccn3)sc2C)cn1
Temperature: 70 °C
Yield: 32.2 %

Procedure:
According to Scheme 18 Step 1: Ethyl-2-bromoacetate (0.27 mmol, 45.4 mg) was added to a suspension of N-(5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (0.27 mmol, 70 mg) and K2CO3 (0.54 mmol, 82 mg) in DMSO (4 mL) and then the reaction mixture was heated at 70° C. for 3 hours. Water was added and the aqueous phase was extracted with AcOEt. The organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10 to 30:70) as eluent to afford ethyl 2-(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)acetate (87 μmol, 30 mg, 32%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(Cl)Cl.C1COCC1>[C:20]([C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:12]=2)[NH:16][CH:15]=1)#[N:21]
Reactant: N#Cc1c[nH]c2ccc(C(CCO)c3ccccc3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 5-(3-hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LXV (600 mg, 2.17 mmol) in THF/DCM (1/1, 12 ml) was added dropwise MsCl (168 μl, 2.17 mmol). The mixture was stirred at 0° C. for 10 min and TEA (360 μl, 2.58 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 2 hours, diluted with THF (6 ml), stirred at 0° C. for additional 2 hours, poured into an ice/water mixture, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated affording the metanesulfonic acid 3-(3-cyano-1H-indol-5-yl)-3-phenyl-propyl ester as a yellow oil. A solution of this mesylate in MeNH2 (33% in EtOH, 10 ml) was heated in a sealed tube at 100° C. for 1 hour. The mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and DCM. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) affording 5-(3-methylamino-1-pheny-propyl)-1H-indole-3-carbonitrile LXVI as a white solid (156 mg). MS (M+H)=290.