Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([C:14]1([CH2:20][OH:21])[CH2:18][O:17][C:16](=[O:19])[NH:15]1)[CH3:13].Cl>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:12]([C:14]1([CH2:20][O:21][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH2:18][O:17][C:16](=[O:19])[NH:15]1)[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC1(CO)COC(=O)N1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC(=O)N1
Temperature: 0 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
Tosyl chloride (142.2 g, Aldrich) was added to an ice-chilled solution of the product from step (a) (102.7 g) dissolved in pyridine (175 ml. Aldrich). The reaction mixture was stirred at ice bath temperature for six hours, then allowed to come to room temperature. The heterogeneous mixture was added to 1500 ml of a solution of brine and 1N HCl. stirred until solids appeared, filtered and washed with diethyl ether to give 194.6 g of a beige solid as the title product. 1H NMR consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](OC)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[S:25][CH3:26]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([C:21]2[CH:22]=[CH:23][C:24]([S:25][CH3:26])=[C:19]([F:18])[CH:20]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Reactant: CSc1ccc(B(O)O)cc1F
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1F

Procedure:
2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-trifluoromethylsulfonyloxy-analog following the method of Example 8. Subsequent coupling to 3-fluoro-4-(methylthio)phenylboronic acid, according to the method of Example 9, provided 2-benzyl-4-chloro-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled in the 4-position with 4-fluorophenylboronic acid following the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-arylated with 4 fluoroiodobenzene according to the method of Example 62. The resulting sulfide was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide final product according to the method of Example 68 (yield: 500 mg, 75%). mp 222-224° C. 1H NMR (300 MHz, CDCl3) δ 5.06 (s, 2H), 7.01 (t, J=9 Hz, 2H), 7.06 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.18 (t, J=9 Hz, 2H), 7.69 (dd, J=9 Hz, 3 Hz, 2H), 7.88 (t, J=9 Hz, 1H), 7.95 (s, 1H). MS (DCI/NH3) m/z 458 (M+H)+. Anal. calc. for C22H14F3N3O3S: C, 57.76; H, 3.08; N, 9.18. Found: C, 57.5; H, 3.15; N, 8.8.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC([C:42]([N:44]3[C:50]4C=CC=C[C:49]=4[CH2:48][N:47]4C(C(O)=O)=CC=[C:46]4[CH2:45]3)=O)=CC=2)CCCCC1.C(N(CC)C(C)C)(C)C.CN1CCCNCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:47]5[CH2:48][CH2:49][CH2:50][N:44]([CH3:42])[CH2:45][CH2:46]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: CN(C)c1ccncc1
Agent: CN1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride (prepared from 2.5 g of the corresponding acid of Example 22, in the manner of Example 23) was added to a stirred mixture of N,N-diisopropylethyl amine (1.73 g), 4-(dimethylamino)pyridine (0.1 g) and N-methyl homopiperazine (1.52 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® and the eluate refluxed with the slow addition of hexane to provide the title compound as off-white crystals (0.46 g), m.p. 133–136° C.
Reaction SMILES: Cl[Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1.CCN(CC)CC.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>CCCCCC>[CH3:31][C:30]([NH:34][Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1)([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)N[Si](C)(C)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Reaction time: 24 h
Yield: 88.7 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-3-phenyl-s-indacen-1-yl)silane (10.8277 g, 0.03322 moles) was stirred in hexane (150 mL) as NEt3 (3.5123 g, 0.03471 moles) and t-butylamine (2.6074 g, 0.03565 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a thick red-yellow oil (10.6551 g, 88.7 percent).
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Na+].[Na+].C([O:29][CH2:30][CH3:31])(=O)C.[CH3:32]CCCCC>O1CCCC1>[OH:29][CH2:30][CH:31]1[CH2:32][C@:11]1([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:12]#[N:13]
Reactant: CCCCCC
Reactant: CCOC(C)=O
Reactant: N#CCc1cccc2ccccc12
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C[C@@]1(c2cccc3ccccc23)CC1CO
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
1-Naphthylacetonitrile (30 g, 180 mmole) was dissolved in dry tetrahydrofuran (THF, 300 mL) under nitrogen atmosphere, cooled to −15° C. and sodium-bis (trimethylsilylamide) in 1M tetrahydrofuran (180 mL) was added dropwise. The resulting brown mixture was stirred for 45 min at −10° C. to 0° C., cooled to −15° C. and added a solution of R-(+) epichlorohydrin (16.6 g, 180 mmol) in tetrahydrofuran (20 mL) was added dropwise at −15° C. and stirred for 30 min. Sodiumbis (trimethylsilylamide) in 1M tetrahydrofuran (180 mL) is added drop wise at −15° C. and the mixture was stirred for 45 min. The temperature of the reaction mass was then gradually raised to room temperature and maintained at room temperature for 30 min. The reaction is monitored by TLC (ethyl acetate/hexane (1:1)). The reaction mass was quenched with water (80 mL). The aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organic layer was washed with brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 55 g of crude oil. The oil was purified by column chromatography (silica gel, ethyl acetate/hexane (10:90) to yield 25 g (62%) of product. The 1H NMR shows mixture of diasteromers (2:1 cis/trans). 1H NMR δ(300 MHz,CDCl3, partial assignment): 1.55-1.59 (2H,m), 1.94-2.04 (1H,m), 2.42 (1H,m) 3.08 (1H,br,s), 3.32 (1H,m),7.42-7.68 (4H,m),7.72-7.93 (2H,m),8.37-8.40 (1H,d,J=8.4 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:23][N:24](C)C=O>O.Cl>[OH:16][C:15]1[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]#[N:24])=[CH:3][CH:4]=2)=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(Br)cc1)c1ncccc1O
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)c2ncccc2O)cc1
Temperature: 90 °C
Yield: 45 %

Procedure:
10 g (35.96 mM) of (4-bromophenyl)(3-hydroxy-2-pyridinyl)methanone are mixed with 6.44 g (71.92 mM) of cuprous cyanide in 90 ml of dimethylformamide. The mixture is refluxed for 21 h. A solution of 19.25 g of ferric chloride in 42.5 ml of water and 6.7 ml of concentrated hydrochloric acid is prepared and added to the cooled reaction medium and the resulting mixture is then heated at 90° C. for 30 minutes. After cooling, ethyl acetate and water are added and the mixture is filtered on Celite. The product is then extracted with ethyl acetate and the organic phase is washed with saturated sodium chloride solution. The solvent is evaporated off under reduced pressure to give the desired product in the form of a yellow solid with a yield of 45%.
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:16][C:17]([CH2:20][Si](C)(C)C)=[C:18]=[CH2:19])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:20]=[C:17]1[C:18](=[CH2:19])[C:10]23[O:15][CH:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16]1
Reactant: C=C=C(CC(O)CC1CCCCC1=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: C=C1CC2CC3CCCCC3(O2)C1=C
Temperature: -78 °C
Yield: 77.4 %

Procedure:
1.5 mL of diethyl ether was added to 2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cyclohexanone (100 mg, 0.36 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (64.5 μL, 0.36 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/6) to obtain 53 mg of the product (78%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccccc2)nc1C
Reaction time: 8 h
Yield: 71 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (5.1 g) synthesized in Example 1(3) was dissolved in dimethylformamide (50 mL), potassium carbonate (5.3 g) and benzylbromide (4.6 mL) were added to at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (5.9 g, 71%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]O)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:24]([CH3:25])[CH3:23])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1
Product: CN(C)CCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 19.1, 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and Dimethylamine were converted to yield {5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-dimethyl-amine as light brown semisolid, MS: 338 (MH+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[N:34]1[S:35][N:36]=[C:37]2[C:42]([NH2:43])=[CH:41][CH:40]=[CH:39][C:38]=12>>[N:34]1[S:35][N:36]=[C:37]2[C:42]([NH:43][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6]([C:31]3[CH:30]=[CH:29][C:28]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:33][CH:32]=3)=[O:7])=[O:18])=[CH:41][CH:40]=[CH:39][C:38]=12
Reactant: Nc1cccc2nsnc12
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)Nc2cccc3nsnc23)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 66% purity by LC/MS. MS(ESI+): m/z=472.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=1)=[O:4].ClCCCl.C(=O)(O)[O-].[Na+]>O>[O:14]=[C:12]1[C:8]2[NH:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[CH2:10][CH2:11]1
Reactant: COC(=O)c1cc(CCC(=O)O)c[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc2c([nH]1)C(=O)CC2
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a polyphosphoric acid (115%, 1.6 g) was added 3-(5-(methoxycarbonyl)-1H-pyrrol-3-yl)propanoic acid (174 mg, 0.88 mmol) and 1,2-dichloroethane (8 mL). The reaction mixture was heated for 1 h at 100° C. Water (20 mL) was added and the mixture was carefully poured into a 50 mL Erlenmeyer flask containing solid sodium bicarbonate and ice. The reaction was neutralized (pH 7) and was then extracted with EtOAc (5×50 mL). The combined organic extracts were washed with water, NaHCO3 and brine, dried (Na2SO4) filtered and concentrated. Purification by flash chromatography (0-40% EtOAc/Heptane) afforded methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (106 mg, 67%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.91 (s, 4H), 3.92 (s, 3H), 6.78 (d, J=1.76 Hz, 1H), 9.33 (br s, 1H); LCMS-MS (ESI+) 180.2 (M+H).
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:48][C:49]1([F:55])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:2]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:52]3[CH2:53][CH2:54][C:49]([F:55])([F:48])[CH2:50][CH2:51]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc2[nH]1
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (83%).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH:15][C:16]([NH:18][CH3:19])=[O:17].C1(C)C(O)=CC=CC=1>>[CH3:14][N:15]1[C:9](=[CH:10][C:11]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])[C:8](=[O:13])[N:18]([CH3:19])[C:16]1=[O:17]
Reactant: CNC(=O)NC
Reactant: O=C1C=CC(=O)N1c1ccccc1
Agent: Cc1ccccc1O
Product: CN1C(=O)C(=CC(=O)Nc2ccccc2)N(C)C1=O

Procedure:
A solution of 17.3 parts of N-phenyl maleic imide and 8.8 parts of N,N'-dimethyl urea in 100 parts of cresol is stirred for three hours at 190° C. The solvent is distilled off in vacuo and the residue fractionated. The oily liquid which distills at a boiling point of 220° C./0.1 Torr solidifies after a while and may be recrystallised from n-propanol (Mp. 114°-115° C.). IR and NMR-spectra confirm the assumed compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH2:8][O:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([NH2:17])[CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30]C(=O)[C:26]=12)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C[CH2:41][O:42]C1C=CC(N)=CC=1OC)(C)C>>[O:18]([C:25]1[CH:26]=[C:27]2[C:33](=[CH:34][CH:35]=1)[C:41](=[O:42])[N:17]([C:12]1[CH:11]=[C:10]3[C:15]([CH:16]=[C:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][O:9]3)=[CH:14][CH:13]=1)[C:28]2=[O:30])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(N)ccc1OCCN(C(C)C)C(C)C
Reactant: Nc1ccc2c(c1)OCC(CN1CCCC1)=C2
Reactant: O=C1OC(=O)c2c(Oc3ccccc3)cccc21
Product: O=C1c2ccc(Oc3ccccc3)cc2C(=O)N1c1ccc2c(c1)OCC(CN1CCCC1)=C2

Procedure:
3-Pyrrolidin-1-ylmethyl-2H-chromen-7-ylamine [WO 0121577 A2] was treated with 3-phenoxyphthalic anhydride in the same manner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 to give the title compound.
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Na+].[Na+].[C:27]([O:31][C:32](=[O:47])[NH:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)=O)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:10][C:8](=[O:9])[CH:7]=[C:37]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:47])([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1ccc(C(=O)CCCNC(=O)OC(C)(C)C)cn1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC(=O)OC(C)(C)C)CCCNC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of t-butyl dimethylphosphonoacetate (6.86 g, 30.6 mmol) in tetrahydrofuran (150 mL) at −78° C. under argon was added a solution of sodium bis(trimethylsilylamide) (30.6 mL of a 1.0 M solution). After 15 min., a solution of 1-3 (3.0 g, 10.2 mmol) in tetrahydrofuran (30 mL) was added, and the reaction was warmed to ambient temperature, then heated to 40° C. for 1 h. The reaction mixture was then cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give an oil that was purified by flash column chromatography (silica gel, 15 to 25% ethyl acetate/hexanes) to give 1-4 and its 2 isomer.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])=[CH:9]2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[N:22]1([C:20]([C:10]2[N:11]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14][CH:13]=3)=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Yield: 85 %

Procedure:
A solution of 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid ethyl ester (924 mg, 2.4 mmol) and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in tetrahydrofuran (8 mL), methanol (2 mL) and water (4 mL) was refluxed for 3 h. The volatiles were removed in vacuo and the residue was dissolved in water and acidified with hydrochloric acid (1N). The precipitate was filtered, washed with water and dried in vacuo. The crude product was purified by flash chromatography on silica gel with dichloromethane: methanol (98:2 then 19:1 v/v) as eluant, to give 727 mg (85%) of the desired compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([OH:15])=[CH:12]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:15][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=2)[CH:12]=1
Reactant: COC(=O)CBr
Reactant: C=CCOc1ccc2ccc(O)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2ccc(OCC(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7.9 g of 7-(2-propenyloxy)-2-naphthalenol and 8.3 g of potassium carbonate in 50 ml of anhydrous acetone was stirred at room temperature for 1.5 hours. Methyl bromoacetate (4.7 ml) was added and stirring was continued for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield (8.4 g) of [[7-(2-propenyloxy)-2-naphthalenyl]oxy]acetic acid methyl ester, mp 69°-70° after recrystallization from ether-hexane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][N:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:7]([C:8]([NH:35][C@@H:33]([C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[N:32][CH:31]=2)[CH3:34])=[O:9])=[CH:6][C:5]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)O)c2C)cc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with 2,4′-dimethyl-5-(pyrrolidin-1-ylsulfonyl)biphenyl-3-carboxylic acid (40 mg, 0.11 mmol), (R)-1-(2-methylpyrimidin-5-yl)ethanamine (20 mg, 0.14 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (106 mg, 0.28 mmol), N,N-diisopropylethylamine (39 μL, 0.22 mmol) and N,N-dimethylformamide (1.33 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to afford the compound as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.Cl.[OH-].[Na+]>O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:2]2[CH:3]=[C:4]([CH3:14])[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Nc2cc(C)nc(-c3ccccn3)n2)cc1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a mixture of 6-chloro-4-methyl-2-(2-pyridinyl)pyrimidine (115 mg, 0.56 mmol),p-anisidine (68 mg, 0.55 mmol) in water (10 mL) was added 2 N HCl (0.3 mL). The mixture was refluxed for 6 h, cooled to room temperature, and neutralized with 2N NaOH to pH 10. The resulting mixture was then extracted with 1:1 Hexane/EtOAc (50 mL). The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (1:1 Hexane/EtOAc) to yield the product as a tan solid (72 mg, 45%). 1H NMR (CDCl3): 8.80 (d, J=4.5 Hz, 1H), 8.45 (d, J=8.1 Hz, 1H), 7.81 (m, 1H), 7.35 (m, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.12 (s, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.41 (s, 1H), 3.83 (s, 3H), 2.45 (s, 3H).