Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([N+:23]([O-:25])=[O:24])=[C:6]([C:8]([C:21]#[N:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C(OCC)=O)[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([N+:23]([O-:25])=[O:24])=[C:6]([CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]#[N:22])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccccc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(Cc1ccccc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of 2-Amino-α-cyano1,6-dihydro-5-nitro-α-(phenylmethyl)-6-oxo-4-pyrimidineacetic acid, ethyl ester as prepared above (2.0 g) in 1N NaOH (100 mL) is stirred at room temperature for 1 h and is acidified with 4N HCl (30 mL). The precipitate is collected by filtration and dried under vacuum to give 2-Amino-l,6-dihydro-5-nitro-6-oxo-α-(phenylmethyl)-4-pyrimidineacetonitrile (600 mg, 36%). ##STR12##
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[Cl:8][S:9](O)(=[O:11])=[O:10]>>[Cl:1][C:2]1([S:9]([Cl:8])(=[O:11])=[O:10])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1csc(Cl)n1
Product: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1

Procedure:
can be prepared in a process in which, in a first step, 2,4-dichloro-thiazole is reacted with chlorosulphonic acid to give 2,4-dichloro-thiazole-sulphonyl chloride, in which, in a second step, the 2,4-dichloro-thiazole-sulphonyl chloride is reacted with primary amines or with a primary and a secondary amine to give 2-amino-4-chloro-thiazolesulphonamides, and in which, in a third step, the sulphonamides mentioned are reacted with dichlorohalogenomethylsulphenyl chlorides to give the substances of the formula (I).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C:29]1[NH:30][C:31]2[C:36]([C:37]=1[CH3:38])=[CH:35][C:34]([OH:39])=[CH:33][CH:32]=2>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:39][C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29]([CH3:28])=[C:37]4[CH3:38])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.5 g, 4.99 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (2.07 g, 15 mmol) and 2,3-dimethyl-5-hydroxyindole (1.21 g, 7.5 mmol), (Arch. Pharm. 1972, 305, 159), in DMF (75 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated. The solid residue was purified by silica column chromatography, eluting with 2.5% methanol in dichoromethane to give 7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (976 mg, 46%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5](Cl)[CH:6]2[CH:10]([N:11]=1)[N:9]([CH:12]1[CH2:16][CH:15]([OH:17])[CH:14]([CH2:18][O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:13]1=[CH2:39])[CH:8]=[N:7]2.[OH-:41].[Na+]>C(#N)C>[NH2:2][C:3]1[NH:4][C:5](=[O:41])[C:6]2[N:7]=[CH:8][N:9]([CH:12]3[CH2:16][CH:15]([OH:17])[CH:14]([CH2:18][OH:19])[C:13]3=[CH2:39])[C:10]=2[N:11]=1
Reactant: C=C1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O)CC1N1C=NC2C(Cl)=NC(N)=NC21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: C=C1C(CO)C(O)CC1n1cnc2c(=O)[nH]c(N)nc21
Temperature: 82 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
Acetonitril (30 ml) and 2N aqueous hydrochloric acid (23.3 ml) were added to the compound of formula (VI) obtained in Example 1-8 (1.38 g, 2.56 mmol) and stirred at 82° C. for 12 hrs with heating. After completion of the reaction, the resulting mixture was cooled to room temperature and washed with ethyl acetate to remove tritylcarbinol. The material thus obtained was neutralized to pH 6.8 by using 3N aqueous sodium hydroxide (13.6 ml) and stirred at 90° C. for 1 hr. The solution thus obtained was stirred with cooling slowly to room temperature and further stirred at room temperature for 1 hr to obtain crystal. The resulting material was cooled to 6° C. and stirred for 1 hr to obtain the title compound (0.554 g, yield: 73.1%).
Reaction SMILES: [CH2:1]([CH:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:8][C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl>[CH2:1]([CH:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:8][C:9]1[S:13][C:12]([C:14]([Cl:28])=[O:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCC(CCCCCC)Cc1ccc(C(=O)O)s1
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)Cc1ccc(C(=O)Cl)s1
Temperature: 0 °C
Reaction time: 64 h
Yield: 88.4 %

Procedure:
5-(2-Hexyldecyl)-2-thiophenecarboxylic acid (1.00 g, 2.84 mmol., 1.00 equiv.) and CH2Cl2 (5 mL) were added to a 10 mL schlenk flask. The solution was cooled to 0° C. Oxalyl chloride (0.60 mL, 6.5 mmol, 2.3 equiv.) was then added. The ice/water bath was left in place and the solution was stirred for 64 hours while warming to room temperature. The reaction mixture was concentrated to a clear brown liquid (931 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=3.9 Hz, 1H), 6.87 (d, J=3.8 Hz, 1H), 2.81 (d, J=6.7, 2H), 1.68 (b, 1H), 1.34-1.19 (m, 24H), 0.93-0.85 (m, 6H).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C([O-])(O)=O.[Na+]>C(OCC)C>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][CH:17]([F:20])[F:16])(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Temperature: 84 °C
Yield: 64.1 %

Procedure:
Triflic anhydride (27.9 g, 99.1 mmol) was placed in a flask and cooled with an ice bath. 2,2-Difluoroethanol (8.1 g, 99.1 mmol) was added and the reaction was heated to 84° C. for 1 hour. The reaction, was cooled in an ice bath and poured into 100 ml cold 5% NaHCO3 solution. The mixture was attracted with diethyl ether, dried over MgSO4, and concentrated under reduced pressure to remove the ether. The residue was vacuum distilled to give 2,2-difluoroethyl trifluoromethanesulfonate as a clear liquid (13.6 g, 64%, bp −55° C.). 1H NMR (400 MHz, CDCl3) δ ppm 6.17-5.88 (1H), 4.61-4.13 (2H)
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+:42]([C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1)([O-:44])=[O:43]>CN(C=O)C.O>[N+:42]([C:45]1[CH:50]=[CH:49][C:48]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:47][CH:46]=1)([O-:44])=[O:43]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOC2CCCCO2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCOCCOCCOCCOCCOCCOC2CCCCO2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 34 (7.03 g, 13.5 mmol) in anhydrous DMF (24 mL) were added K2CO3 (5.60 g, 40.5 mmol), and 4-nitrophenol (1.88 g, 13.5 mmol). The reaction mixture was heated to 80° C. for 16 h. Upon completion, the reaction mixture was diluted in water, extracted three times with CH2Cl2, and then dried over MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which provided 35 as a yellow oil without further purification (6.30 g, 96%): 1H NMR (300 MHz, CDCl3) δ 8.19 (d, J=9.3 Hz, 2H), 6.97 (d, J=9.3 Hz, 2H), 4.67-4.57 (m, 1H), 4.26-4.17 (m, 2H), 3.95-3.79 (m, 2H), 3.78-3.34 (m, 22H), 1.47-1.84 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Mg+2].[Cl-].[Cl-].[CH2:14]=[O:15].Cl>C(#N)C>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:14]=[O:15]
Reactant: C=O
Reactant: COc1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: COc1cc(Cl)c(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 2-chloro-4-methoxyphenol (25.0 g, 158 mmole) in anhydrous acetonitrile (625 mL) under a dry N2 atmosphere was added MgCl2 (22.5 g, 236 mmole) and TEA (82.3 mL, 591 mmole). The mixture warmed slightly as the MgCl2 was added. Paraformaldehyde (32.0 g, 1.06 mmiole) was then added, the mixture was refluxed for 4.5 h and allowed to stand at room temperature overnight. Additional paraformaldehyde (14.2 g, 474 mmole) was added and reflux was resumed. After 4 h, the mixture was cooled, additional paraformaldehyde (32.0 g, 1.06 mmole) was added and reflux was resumed for another 2.25 h. The mixture was then cooled to room temperature, acidified with 1 N HCl and extracted with ethyl ether (4×500 mL). The combined extracts were washed with brine (250 mL), dried over MgSO4, filtered and concentrated in vacuo to give 30.3 g of a yellow crystalline solid. Recrystallization from isopropanol-H2O gave 11.9 g (41% yield) of the product as a yellow crystalline solid: 1H NMR (dmso-d6/300MHz) 10.47 (brs, 1H, 10.11 (s, 1H), 7.36 (d, 1H, J=3.0 Hz), 7.19 (d, 1H, J=3.0 Hz), 3.73 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:25]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:24]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)[CH2:25]4)[C:12]=3[C:14]([F:15])([F:16])[F:17])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Reactant: c1cc(C2CCNC2)ccn1
Product: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 58 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylic acid (1.05 g, 3.5 mmol) and 4-(3-pyrrolidinyl)-pyridine, a procedure analogous to that given in Example 1 provided the title compound (0.93 g, 58%) as a beige solid, mp 244°-245° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[C:7]([CH2:12][C:13]#[CH:14])[CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[OH:16][C:17]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[OH:16][C:17]1[CH:26]=[C:25]([C:14]#[C:13][CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[S:5][CH2:4][CH2:3][C:2]3([CH3:15])[CH3:1])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CCc1cccc2c1SCCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCc2cccc3c2SCCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
670 mg (3.1 mmol) of 3-(4,4-dimethylthiochroman-8-yl)prop-1-yne, 860 mg (3.1 mmol) of methyl 2-hydroxy-4-iodobenzoate and 33 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 174 mg (0.25 mmol) of bis(triphenylphosphine)palladium(II) chloride and 71 mg of copper iodide are introduced and the reaction mixture is stirred at room temperature for eight hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N) and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with a mixture composed of 99% heptane and 1% ethyl acetate. After evaporating the solvents, 1.50 g (75%) of methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzoate are collected in the form of a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1cccc(-c2ccccc2)c1
Product: CN(C(=O)Oc1cccc(-c2ccccc2)c1)c1ccccc1

Procedure:
The title product was prepared from 3-phenylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (52%, colorless oil). HPLC-MS: m/z=304.2 (M+1); Rt: 4.75 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[C:23]1([C:29](O)=[O:30])([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:29]([C:23]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]3)=[O:30])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1

Procedure:
5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (30.0 mg, 0.1 mmol) and 1,1-cyclopropanedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL), added in HOBt (1.0 eq, 14.0 mg), EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by Gilson to yield 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-cyclopropanecarboxylic acid. 1-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-cyclopropanecarboxylic acid was dissolved in 3 mL DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), added in HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and then was purified by reverse phase hplc using a Gilson (0.1% TFA conditions) to yield 1,1-dimethylethyl (2S)-4-[(5′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)-amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:19][C:20]1[C:21](I)=[CH:22][C:23](=[O:44])[N:24]([CH2:26][CH2:27][C@@:28]([CH3:43])([S:39]([CH3:42])(=[O:41])=[O:40])[C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[CH:25]=1>O1CCOCC1.O.[Pd]>[F:19][C:20]1[C:21]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([F:7])[CH:9]=2)=[CH:22][C:23](=[O:44])[N:24]([CH2:26][CH2:27][C@@:28]([CH3:43])([S:39]([CH3:42])(=[O:40])=[O:41])[C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[CH:25]=1
Reactant: C[C@@](CCn1cc(F)c(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)cc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Pd Encat™ (580 mg, 0.17 mmol) was added to a mixture of potassium carbonate (723 mg, 5.2 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (318 mg, 2.1 mmol), and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (900 mg, 1.7 mmol) in 1,4-dioxane:water (5:1, 24 mL). The reaction was heated to 80° C. and allowed to stir at this temperature overnight. The reaction was filtered through a pad of celite, which was washed with methanol (250 mL). The filtrate was concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in heptanes (20-100%), then 10% methanol in EtOAc to provide the title compound as a light tan residue (800 mg, 99%). MS (LCMS) m/z 495.1 (M−1).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=O)[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(=O)C.[NH4+].[BH3-]C#[N:28].[Na+]>>[NH2:28][CH:13]1[CH2:14][C:15]([CH3:17])([CH3:16])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:20])([CH3:19])[CH2:12]1
Reactant: [BH3-]C#N
Reactant: CCCCCCCCON1C(C)(C)CC(=O)CC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Yield: 61.5 %

Procedure:
4-Amino-N-octyloxy-2,2,6,6-tetramethylpiperidine (16.7 g, 62%) is prepared from N-octyloxy-4-oxo-2,2,6,6-tetramethylpiperidine (95.4 mmol, 27.0 g) by the same method as described above, with the exception of the addition of ammonium acetate (954.5 mmol, 73.5 g), 15 g molecular sieves (10−10 m) and 95% NaBH3CN (95.4 mmol, 6.32 g). 1H-NMR (CDCl3); δ=3.61 (t, J=6.6 Hz, 2H, CH2—O), 2.99 (m, 1H, NH2—CH), 1.63 (d, J=11.4 Hz, 2H, NH2), 1.46 (m, 4H, CH2—CH3), 1.26 (m, 12H), 1.15 (s, 6H, CH3), 1.12 (s, 6H, CH3), 0.87 (t, J=7.4 Hz, 3H, CH2—CH3); 13C-NMR (CDCl3): δ=77.0, 59.8, 50.1, 41.4, 33.2, 31.8, 29.6, 29.2, 28.6, 26.4, 21.3, 21.4, 14.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][SH:13]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[NH:10][CH2:11][CH2:12][S:13]2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: NCCS
Solvent: c1ccccc1
Product: Clc1ccc(C2NCCS2)cn1
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A solution composed of 6-chloronicotinaldehyde (14.2 g), 2-aminoethanethiol (7.7 g) and benzene (80 ml) was heated with stirring for 5 hours while removing water as an azeotrope. After the reaction, benzene was distilled off under reduced pressure, and further volatile materials were removed at 1 mmHg and 70° C. to give 2-(2-chloro-5-pyridyl)thiazolidine (18 g) as a residue. Ten grams of 2-(2-chloro-5-pyridyl)thiazolidine was dissolved in 100 ml of ethanol, and sodium borohydride was added. With stirring, the mixture was gradually heated and thereafter refluxed for 1 hour. Ethanol was distilled off under reduced pressure, and chloroform was added to the residue. Insoluble materials were separated by filtration and the chloroform layer was washed with water and dehydrated. Chloroform was distilled off under reduced pressure to give the desired N-(2-chloro-5-pyridylmethyl)2-aminoethanethiol (8.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[N:8]([CH:13]=[CH:14][CH:15]=3)[N:9]([CH3:12])[C:10]=2[CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:35]N1C(=O)CCC1=O.[Al]>C1COCC1>[Cl:35][C:13]1[N:8]2[N:9]([CH3:12])[C:10]3[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:6](=[O:16])[C:7]2=[CH:15][CH:14]=1
Reactant: Cn1c2cc(Cl)ccc2c(=O)c2cccn21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al]
Solvent: C1CCOC1
Product: Cn1c2cc(Cl)ccc2c(=O)c2ccc(Cl)n21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.6 %

Procedure:
To a solution containing 7-chloro-5-methylpyrrolo[1,2-b]cinnolin-10(5H)-one (3.0 g) and a catalytic amount of dibenzoyl peroxide in 50 ml of THF was added portionwise N-chlorosuccinimide (1.74 g) over 15 min. The flask was covered with aluminum foil and the solution stirred at room temperature for 24 hrs. The solution was then concentrated and the residue purified by HPLC (silica, dichloromethane) to give 2.43 g of a yellow powder. This powder was recrystallized from ethanol to give 2.23 g of pale yellow crystals, mp 129°-131°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:17])[N:13]2[CH3:16])=[CH:8][CH:7]=1.[I-:18].[Na+].C(#N)C>O>[I:18][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:17])[N:13]2[CH3:16])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: Cn1c(=O)ccc2ccc(OCCCCl)cc21
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)ccc2ccc(OCCCI)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
7-(3-Chloropropoxy)-1-methyl-1H-quinolin-2-one (2.5 g) and sodium iodide (3.0 g) were added to 30 ml of acetonitrile. The mixture was stirred for 18 hours while heated under reflux. After cooled to room temperature, water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with sodium sulfate and was condensed under reduced pressure to give the title compound (2.4 g) as a pale brown powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[CH:22]1([C:27]2[C:31]([CH2:32]O)=[C:30]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[O:29][N:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:22]1([C:27]2[C:31]([CH2:32][O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:9]=[C:10]5[C:15](=[CH:16][CH:17]=4)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]5)=[CH:4][CH:3]=3)=[C:30]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[O:29][N:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OCc1c(C2CCCC2)noc1C1CCCC1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(C5CCCC5)noc4C4CCCC4)cc3)ccc2n1
Temperature: 100 °C
Yield: 34.6 %

Procedure:
Methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (109 mg, 0.39 mmol), (3,5-dicyclopentyl-4-isoxazolyl)methanol (92 mg, 0.39 mmol), triphenyl phosphine (102 mg, 0.39 mmol), diisopropyl azodicarboxylate (0.075 mL, 0.39 mmol) and dichloromethane (3.9 mL) were placed in a microwave reaction tube, sealed and heated in a microwave reactor to 100° C. for 10 minutes. The solution was concentrated and the residue was purified by chromatography (silica gel, hexane to 1:1 ethyl acetate:hexanes). Fractions containing the product were combined and concentrated. The residue was recrystallized from ethyl acetate and filtered to yield methyl 6-(4-{[(3,5-dicyclopentyl-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylate (67 mg, 35%). 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, J=9 Hz, 1H), 8.33 (s, 1H), 8.19 (s, 2H), 8.12 (d, J=8 Hz, 1H), 7.84 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.94 (s, 3H), 3.41-3.37 (m, 1H), 3.16 (m, 1H), 1.98-1.94 (m, 4H), 1.76-1.56 (m, 12H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]([O-])=[O:14].[Na+].OS(O)(=O)=O>[OH-].[Na+]>[N:13](=[C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1])[OH:14]
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccccc2C(=O)C1=NO
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a mixture of 3.21 g (19.9 mmol) of 2,4-dihydroxyquinoline and 1.87 g (27.1 mmol) of NaNO2 in 60 mL of 0.2N NaOH in an ice-bath was added dropwise 40 mL of aqueous 2N H2SO4. The mixture was stirred in an ice bath for 1 h after addition of H2SO4, filtered and dried to leave 3.41 g of orange solid which was crystallized by boiling with 150 mL of ethanol (95%) and filtered. The filtrate was cooled to and kept at room temperature for 5 h. The crystalline precipitate was filtered and dried to leave 1.88 g (50%) of 10a as a red solid, mp 206° C. (decomposed, lit 208° C., dec.). 1H NMR (CDCl3 +DMSO-d6), 6.65-6.78 (m, 2), 7.15 (m, 1), 7.556 (d, 0.30, J=8.1), 7.605 (d, 0.70, J=8.1), 10.887 (s, 0.3), 11.346 (s, 0.7). MS, 190 (100, M+), 173 (25), 146 (55). High resolution MS, Calcd for C9H6N2O3, 190.0375, found 190.0400.