Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(#N)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH:2]([C:4]3[NH:13][C:12](=[O:14])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH3:3])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(Br)c1nc2ccccc2c(=O)[nH]1
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccccc4c(=O)[nH]3)CC2)cc1
Yield: 449.2 %

Procedure:
In a flask containing of 2-(1-bromo-ethyl)-3H-quinazolin-4-one (500.0 mg, 0.20 mmol) in acetonitrile (20 ml) was added KI (496.0 mg, 0.30 mmol), and 1-(4-methoxy-benzenesulfonyl)-piperazine (509.6 mg, 0.20 mmol). The reaction was heated for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between water (20 ml) and dichloromethane (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and dried under reduced pressure to give 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-quinazolin-4-one (Yield 385.0 mg, 45.18%). 1H NMR (400 MHz, DMSO-6): δ 1.25 (d, 3H, J=6.82 Hz), 2.67-2.56 (m, 4H), 2.88 (s, br, 4H), 3.85 (s, 3H), 3.53 (q, 1H, J=13.89, 6.82 Hz), 7.15 (d, 2H, J=8.84), 7.34 (t, 1H, J=7.33 Hz), 7.51 (d, 1H, J=8.34 Hz), 7.68-7.61 (m, 3H), 8.00 (d, 1H, J=7.83 Hz). MS m/z calc. 428.15, found (ESI); 429.4 (M+1)+. Retention time 2.68 minutes.
Reaction SMILES: [N:1]1([C:7]2[CH:29]=[CH:28][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[C:15]([F:27])=[CH:14][N:13]=3)=[CH:9][C:8]=2[CH3:30])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:31](O)(=[O:35])[C@H:32]([CH3:34])[OH:33].C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:33][C@@H:32]([CH3:34])[C:31]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:29]=[CH:28][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[C:15]([F:27])=[CH:14][N:13]=3)=[CH:9][C:8]=2[CH3:30])[CH2:2][CH2:3]1)=[O:35]
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1cc(Nc2ncc(F)c(-c3cnc(C)n3C(C)C)n2)ccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2ncc(F)c(-c3cnc(C)n3C(C)C)n2)ccc1N1CCN(C(=O)[C@H](C)O)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 2-[4-(piperazin-1-yl)3-methylanilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidine (Example 122; 490.8 mg, 1.20 mmol), L-lactic acid (129.7 mg, 1.44 mmol), HOBt.H2O (220.5 mg, 1.44 mmol) and DIPEA (0.24 ml, 1.44 mmol) in DMF (5 ml) was cooled to 0° C., followed by addition of EDAC (230.05 mg, 1.44 mmol) in portions. The mixture was then stirred at ambient temperature for 3.5 hours. The solution was concentrated in vacuo, then the residue was partitioned between DCM and water+sat. sodium hydrogen carbonate. The organic extract was washed with water (3 times), brine, dried and concentrated. To a solution of crude product in MeOH (5 ml) was added 1 pellet of KOH and the mixture was stirred at ambient temperature for 20 min. The residue obtained on evaporation was purified by chromatography on silica gel with MeOH:DCM (1:99 to 5:95) to yield the title compound, after trituration with ether, as a solid which was dried in vac oven overnight at 50° C. (415 mg, 72%). NMR: (500 MHz at 373K) 1.27 (d, 3H), 1.40 (d, 6H), 2.28 (s, 3H), 2.48 (s, 3H, under DMSO signal), 2.82 (m, 4H), 3.65 (m, 4H), 4.47 (m, 2H), 5.38 (septet, 1H), 7.00 (d, 1H), 7.35 (m, 2H), 7.40 (dd, 1H), 8.40 (d, 1H), 8.80 (s, 1H); 19F NMR (400 MHz) −149.33 (t, 1F); m/z 482.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
A mixture of (3-hydroxy-propyl)-carbamic acid tert-butyl ester (3.0 g, 0.017 mol), N,N-diisopropylethylamine (7.31 mL, 0.042 mol), and dimethyl sulfoxide (1.84 mL, 0.026 mol) in dichloromethane (100 mL) was cooled to 0° C. and flushed with nitrogen. Sulfur trioxide-pyridine complex (6.68 g, 0.042 mol) was added under a stream of nitrogen and the reaction mixture was stirred for 2.5 h. The reaction mixture was quenched using 0.1 N HCl. The aqueous layer was discarded. The organic extract was washed with additional 0.1N HCl (2×) and brine(2×), dried with Na2SO4, filtered, and concentrated to dryness to provide the title compound (2.8 g) as a clear oil which was used without further purification. 1H NMR (DMSO, 400 mHz) δ (ppm): 9.57 (s, 1H), 6.81 (bs, 1H), 3.19-3.14 (m, 2H), 2.49-2.44 (m, 2H), 1.3 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2.86 g of methyl 3-hydroxyisoxazole-5-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and 4.25 g of methyl iodide and 4.15 g of potassium carbonate were then added under ice-cooling. The mixture was stirred at room temperature overnight. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.23 g of methyl 3-methoxyisoxazole-5-carboxylate.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](I)=[C:9]([F:14])[CH:8]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])=[C:9]([F:14])[CH:8]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1cc(Cl)ccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 67h (3.9 mmol, 1.0 g) at −78° C. under N2. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 67i.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8]CC)=[O:7])C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][NH:21]2.P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>O.C(O)C>[Cl:16][C:17]1[C:18]2[CH2:19][CH2:20][N:21]3[C:22]=2[C:23]([C:11](=[O:13])[C:5]([C:6]([OH:8])=[O:7])=[CH:4]3)=[CH:24][CH:25]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Clc1cccc2c1CCN2
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(c(Cl)ccc3c1=O)CC2
Temperature: 60 °C
Yield: 71.8 %

Procedure:
4.4 g of diethyl ethoxymethylenemalonate was added to 3 g of 4-chloroindoline and the mixture was heated on an oil bath at 110° to 120° C. during which time liberation of ethanol was observed. 20 g of polyphosphoric acid prepared from 10 g of phosphoric acid and 10 g of phosphorus pentoxide was added thereto and the mixture was heated on an oil bath at 130° to 140° C. for 40 minutes. After completion of the reaction, the mixture was allowed to cool to 60° C., poured into water and rendered neutral with a 10% aqueous sodium hydroxide solution. The crystals precipitated were collected by filtration and washed with water. The crystals thustreated were mixed with 50 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed on an oil bath for 1 hour. As the reaction proceeded the mixture changed to a uniform solution. The solution was treated with activated carbon while hot followed by filtration. The filtrate was rendered acidic with concentrated hydrochloric acid to obtain 3.5 g of 9-chloro-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid. Recrystallization of the product from dimethylformamide gave 3.5 g of white needles having a melting point of 307.5° C. (decomposition).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH3:37])[CH:32]=2)[CH:27]1[C:38]([OH:40])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][C:48]=1[Si:49]([CH3:52])([CH3:51])[CH3:50])[NH2:45].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:41][C:42]1[CH:43]=[C:44]([NH:45][C:38]([CH:27]2[C:28]3[C:33](=[CH:32][C:31]([O:36][CH3:37])=[CH:30][CH:29]=3)[CH2:34][CH2:35][N:26]2[C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])=[O:40])[CH:46]=[CH:47][C:48]=1[Si:49]([CH3:51])([CH3:50])[CH3:52]
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: C[Si](C)(C)c1ccc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
T3P (4.46 mL, 7.50 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1.537 g, 5 mmol), 3-fluoro-4-(trimethylsilyl)aniline (0.916 g, 5.00 mmol), DIEA (4.35 mL, 25.00 mmol) and DMAP (0.672 g, 5.50 mmol) in ethyl acetate (35 mL), and the mixture was stirred at 70° C. for 18 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2→20% ethyl acetate/hexane), and the precipitate was washed with IPE/hexane to give tert-butyl 1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.85 g, 3.91 mmol, 78%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][CH3:36])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Cl:37]CC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:20].[ClH:37].[CH2:35]([NH:34][C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:32][CH3:33])[CH:29]=2)[N:24]=1)[CH3:36]
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.01 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (290 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8) provided, after evaporation and drying, 25 mg of 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.45 mL). The reaction mixture was stirred for 5 min at RT, concentrated at 40° C. under vacuum, to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 50 as a yellow solid (30 mg, 6% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC1(C)C(C)(C)OB([C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH2:28][CH2:29][N:30]([S:36]([NH:39][C:40]2[S:44][N:43]=[CH:42][N:41]=2)(=[O:38])=[O:37])[CH2:31]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[O:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH2:28][CH2:29][N:30]([S:36]([NH:39][C:40]2[S:44][N:43]=[CH:42][N:41]=2)(=[O:37])=[O:38])[CH2:31]3)[CH2:13][CH2:14]1
Reactant: FC(F)(F)c1ccc(Br)c(N2CCOCC2)c1
Reactant: CC1(C)OB(c2cccc3c2CCN(S(=O)(=O)Nc2ncns2)C3)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2N2CCOCC2)C1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.023 g, 0.033 mmol), 4-(2-bromo-5-(trifluoromethyl)phenyl)morpholine (Intermediate G, 0.154 g, 0.497 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (Intermediate F, 0.140 g, 0.331 mmol), and potassium phosphate (0.281 g, 1.326 mmol) in 2.5 mL dioxane and 1 mL water was heated to 100° C. 2 hours. The reaction mixture was cooled to rt, diluted with EtOAc and washed with 1 N citric acid solution. The organic layers were dried over MgSO4 and concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C-18 50 g, 5 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 5-(2-morpholino-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.016 g, 0.030 mmol). [M+H]+=525.8 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.23 (s, 1H), 7.38-7.44 (m, 1H), 7.26-7.36 (m, 3H), 7.14-7.22 (m, 2H), 4.35-4.40 (m, 2H), 3.39-3.49 (m, 3H), 3.28-3.38 (m, 2H), 2.86-2.96 (m, 2H), 2.73-2.81 (m, 2H), 2.47-2.60 (m, 1H)
Reaction SMILES: [C:1]([C:4]([C:6]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:24][C:7]=1[O:8][CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[O:5])([OH:3])=[O:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:4]([C:6]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:24][C:7]=1[O:8][CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5])([OH:3])=[O:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(=O)C(=O)O)c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C(=O)C(=O)O
Yield: 83.2 %

Procedure:
A stirred solution of ethyl (RS)-4-(2-carboxycarbonyl-5-(3-thienylmethoxy)phenoxy)-4-(2-methylphenyl)butanoate (0.37 g) and 1 N sodium hydroxide (2.7 mL) in dioxan (6.6 mL) is heated at 60° C. for 1.5 hours. The reaction mixture is evaporated and the residue dissolved in water (5 mL). The pH of the solution is adjusted to 1 by addition of 1 N hydrochloric acid and the mixture extracted with ethyl acetate (20 mL). The organic phase is dried over magnesium sulphate and evaporated. The residual yellow oil is triturated with ether to give (RS)-4-(2-Carboxycarbonyl-5-(3-thienylmethoxy)phenoxy)-4-(2-methylphenyl)butanoic acid as a yellow solid (0.29 g), m.p. 173-175° C. [Elemental analysis:- C,63.2; H,5.07%. Calculated:- C,63.4; H,4.88%].
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]#[N:12])[CH:3]=1.[F:13][CH2:14][CH2:15][OH:16].[H-].[Na+]>>[CH:8]1([C:7]2[C:2]([O:16][CH2:15][CH2:14][F:13])=[CH:3][C:4]([C:11]#[N:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: N#Cc1cc(Cl)c(C2CC2)cn1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(OCCF)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-cyclopropyl-pyridine-2-carbonitrile (example 145b), 2-Fluoro-ethanol (CAN 371-62-0) as starting materials and sodium hydride as reagent. The title compound was isolated (267 mg, 68%) as a yellow solid; MS (ESI, m/z): 207.1 (M+H+).
Reaction SMILES: [Si](Cl)(C(C)(C)C)(C)C.C(O[C:12]1[CH:13]=[CH:14][C:15]2[N:20](CC)[C:19]3[CH:23]=[CH:24][C:25](OCC)=[CH:26][C:18]=3[O:17][C:16]=2[C:30]=1CO)C.N1C=CN=C1.O>CN(C)C=O.CCCCCC.C(OCC)C>[CH:23]1[C:19]2[NH:20][C:15]3[CH:14]=[CH:13][CH:12]=[CH:30][C:16]=3[O:17][C:18]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CCOc1ccc2c(c1)Oc1c(ccc(OCC)c1CO)N2CC
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc2c(c1)Nc1ccccc1O2
Reaction time: 0.5 h

Procedure:
A solution of 1.92 g (1.3 eq.) of tert-butyldimethylsilyl chloride in 10 ml of N,N-dimethylformamide was added dropwise while cooling with ice to a mixture of 3.23 g (9.80 mmol) of 3,7-diethoxy-10-ethyl-10H-dibenzo[b,e][1,4]oxazine-4-methanol and 1.47 g (2.2 eq.) of imidazole in 30 ml of N,N-dimethylformamide. The reaction mixture was stirred at 0° for 30 minutes, brought slowly to room temperature, stirred for 1 hour and then poured into 100 ml of water, 50 ml of diethyl ether and 50 ml of hexane. The organic phase was separated, extracted twice with water, dried over magnesium sulphate and concentrated. The residue was chromatographed on 250 g of silica gel with diethyl ether/hexane (1:10), whereupon, after drying in a high vacuum, 4.30 g (98.9%) of 10-methyl-3,7-diethoxyl-4-[(tert-butyl-dimethylsilyl)oxy]methyl!-10H-dibenzo[b,e][1,4]oxazine were obtained as a colourless solid of m.p. 77.5°-78.5°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([Cl:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[Cl:23][C:24]1[C:25]([C:30](O)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1>>[Cl:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:30]([C:25]1[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:31]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3Cl)ccc21
Reactant: O=C(O)c1ncccc1Cl
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(CNC(=O)c4ncccc4Cl)c3Cl)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-(5-aminomethyl-4-chloro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 218) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as an off-white solid. MS: 441.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[CH3:10]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O>CS(C)=O.[Cl-].[Na+].O>[O:1]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]2)[CH2:10]1
Reactant: CC(C)(C)[O-]
Reactant: N#CC1CCC(=O)CC1
Agent: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1CCC2(CC1)CO2
Reaction time: 8 h

Procedure:
A solution of 4-oxocyclohexanecarbonitrile (1.90 g) in dimethylsulfoxide (8 mL) was added dropwise to a solution of potassium t-butoxide (2.60 g) and trimethylsulfoxonium iodide (5.09 g) in dimethylsulfoxide (30 mL) at room temperature. The mixture was stirred overnight, diluted with 20% brine, and extracted with 3× ethyl acetate. The combined organic layers were washed with 20% brine, dried over Na2SO4, and concentrated. The crude was purified on a 40 g column using an ISCO Companion flash system eluting with hexane/ethyl acetate (6:4 to 5:5) to give the desired product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1.CN(C=O)C>O1CCOCC1.CO>[N:33]1[CH:32]=[C:31]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[CH:36]=[N:35][CH:34]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: Brc1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)[nH]2)c1
Yield: 28.1 %

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (203.4 mg, 0.62 mmol) was added, followed by 5-bromo-pyrimidine (100 mg, 0.62 mmol). Then 1 mL of anhydrous DMF was added, the vial was capped and microwaved at 250° C. for 30 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension, the solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions containing the product were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a light-brown foamy solid (34.7 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]=[C:4]([C:16]([O:18]C)=[O:17])[C:3]=1[Cl:20].[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]=[C:4]([C:16]([OH:18])=[O:17])[C:3]=1[Cl:20]
Reactant: COC(=O)c1nc(-c2ccc(C)c(C)c2)cc(N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)cc1C
Yield: 100 %

Procedure:
Methyl 4-amino-3-chloro-6-(3,4-dimethylphenyl)pyridine-2-carboxlate (0.9 g, 0.003 mol) was heated at reflux in methanol (50 mL) and 1N sodium hydroxide (75 mL) for two hours. The reaction mixture was partially concentrated and then acidified with concentrated hydrochloric acid. The solid was collected and dried to give 4-amino-3-chloro-6-(3,4-dimethylphenyl)-pyridine-2-carboxylic acid (0.85 g, 0.003 mol), mp 192-4° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](O)=[O:14])=[CH:7][C:6]=1[NH:16][C:17](=[O:37])[CH2:18][CH:19]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[O:35][CH3:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([NH:39][CH3:38])=[O:14])=[CH:7][C:6]=1[NH:16][C:17](=[O:37])[CH2:18][CH:19]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[O:35][CH3:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(CCC(=O)O)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC
Reactant: CN
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)NC)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-[2-t-butyl-5-(2-carboxyethyl)phenyl]-3-(2,4,5-trimethoxyphenyl)octanamide (prepared as described in Preparation 84) and methylamine, the title compound was obtained as a colorless foam-like substance.