Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]1([CH2:14][CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][C@H:10]2[CH2:12][CH2:13][C@@H:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>CCN(C(C)C)C(C)C>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH2:15][CH2:14][C:2]1([OH:1])[CH2:11][CH:10]2[CH2:12][CH2:13][CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCCCc1nc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2c2ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCc1nc2ccccc2[nH]1)CCC1(O)CC2CCC1c1ccccc12
Temperature: 110 °C

Procedure:
A mixture of 1000 mg of rac-toluene-4-sulfonic acid (1R*,8R*,9R*)-2-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)ethyl ester and 508 mg of [3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amine in 2 mL of DIPEA was heated to 110° C. for 30 min. The reaction mixture was cooled to rt, quenched with MeOH-water and extracted with EtOAc. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo to obtain 1.0 g as beige solid. A part of the crude product was purified by CC with EtOAc/MeOH (2:1) to obtain the desired compound as beige foam.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[CH:13]=[CH:12]2)C1C=CC=CC=1.B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]=1
Reactant: Clc1cccc(Cl)c1-c1ccc2cc(OCc3ccccc3)ccc2n1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 6-(benzyloxy)-2-(2,6-dichlorophenyl)quinoline 19 (2.5 g) in CH2Cl2 (20 ml) are added, at 0° C., 20 ml of BBr3 (1 M in CH2Cl2). The solution is stirred for 1 h at room temperature. Water (20 ml) is added and the resulting solution is alkalinized with 1 N NaOH. The aqueous phase is extracted with AcOEt (3×20 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated. 2-(2,6-dichlorophenyl)-6-quinolinol 20 is obtained as a yellow solid and is used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:24])[NH:22][CH2:23][C:19]=2[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CCOCC.C(OCC)(=O)C>[ClH:30].[ClH:30].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:24])[NH:22][CH2:23][C:19]=2[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])[C:10]=2[CH:9]=1
Reactant: O=C1NCc2c1c(-c1ccccc1O)cc1[nH]c3ccccc3c21
Reactant: CN(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)CCCOc1ccccc1-c1cc2c(c3c1C(=O)NC3)c1ccccc1n2CCCN(C)C
Product: Cl

Procedure:
98 mg (0.31 mmole) 1,2,3,6-tetrahydro-4-(2-hydroxyphenyl)-3-oxopyrrolo[3,4-c]carbazole (Example 5) are heated under reflux for 72 hours with 80 mg (0.66 mmole) 3-dimethylaminopropyl chloride, 91 mg (0.66 mmole) potassium carbonate and a spatula tip of potassium iodide in 25 ml acetone. After cooling, it is evaporated and the residue partitioned between water and ethyl acetate. The organic phase is separated off, dried over sodium sulphate, and the residue obtained after evaporation chromatographed on silica gel with NH3 -saturated dichloromethane/methanol 9:1. The fraction with the Rf of 0.6 is isolated, dissolved in an ether/ethyl acetate mixture, and the dihydrochloride precipitated with hydrogen chloride in ether. One obtains 4-[2-(3-dimethylaminopropoxy)phenyl]-6-(3-dimethylaminopropyl)-1,2,3,6-tetrahydro-3-oxopyrrolo[3,4-c]carbazole dihydrochloride in the form of beige crystals which decompose above 170° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])[N:37]=[CH:38][C:31]=12>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:30]1[C:31]2[CH:38]=[N:37][N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])[C:32]=2[N:33]=[CH:34][N:35]=1)[C:24]([O:26][CH3:27])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ccccc1Cl

Procedure:
Prepared according to the method for Intermediate AE2 from (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1). 1H NMR (400 MHz, DMSO) δ 0.94 (9H, s), 3.56-3.75 (4H, m), 3.68 (3H, s), 3.90-4.09 (2H, m), 5.80-5.85 (1H, m), 7.29-7.43 (6H, m), 7.50-7.67 (7H, m), 7.67-7.74 (1H, m), 8.43 (1H, s), 8.52 (1H, s); m/z (ESI+) (M+H)+=631; HPLC tR=3.38 min.
Reaction SMILES: F[C:2]1[C:27]([F:28])=[CH:26][C:25]([I:29])=[CH:24][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+].Cl.O>C1COCC1>[F:28][C:27]1[CH:26]=[C:25]([I:29])[CH:24]=[C:3]2[C:2]=1[N:13]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCOC(=O)C(=CNCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2c(F)cc(I)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-[2-(tert-butyldimethylsilyloxy)ethylamino]acrylate (2.3 g, 4.3 mmol) obtained in Step 3 was dissolved in THF (25 ml), sodium hydride (256 mg, 6.4 mmol) was added under ice-cooling and the mixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid (6.4 ml, 6.4 mmol) was added to neutralize the reaction mixture. Water was further added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to ethyl acetate:hexane=2:1) to give the object product (2.0 g, yield 92%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]#[N:14].[OH:15]S(O)(=O)=O>>[OH:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]([NH2:14])=[O:15]
Reactant: Cc1nn(C)c2nc(O)c(C#N)cc12
Reactant: O=S(=O)(O)O
Product: Cc1nn(C)c2nc(O)c(C(N)=O)cc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
6-Hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carbonitrile (0.911 g) was dissolved in concentrated H2SO4 (3.0 mL) and stirred at 40° C. for 24 hrs. The solution was poured into ice-water and the precipitated solid was filtered, washed with water, and dried under high vacuum to give 6-hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-carboxamide as a white solid. A portion of this material (0.122 g) was dissolved in DMF (2.0 mL). 2-Chlorotriethylamine hydrochloride (0.192 g) and potassium carbonate (0.304 g) were added to the solution. The reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and the brine, and dried over Na2SO4. The extract was evaporated under reduced pressure to give 6-[2-(diethylamino)ethoxy]-1,3-dimethyl-pyrazolo[5,4-b]pyridine-5-carboxamide as a white solid. A portion of this material (0.059 g) was dissolved in hot toluene (10 mL) and azeotroped for 2 hrs. The solution was cooled to room temperature. 4-Fluoro-3-(trifluoromethyl) phenylisocyanate (0.098 g) was added to the solution. The mixture was heated at reflux for 23 hrs, and then, cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified with the column chromatography (ethyl acetate). A portion of this material (20 mg) was dissolved in tetrahydrofuran (1.0 mL) and treated with 1N hydrochloric acid solution (1.0 mL). The mixture was lyophilized to give {6-[2-(diethylamino)ethoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13]([O:15]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:6][C:5]=1[C:25]([F:28])([F:27])[F:26].[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13]([NH:30][C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=2)=[O:15])=[CH:6][C:5]=1[C:25]([F:26])([F:27])[F:28]
Reactant: Cc1cnc(N)cn1
Reactant: COC(=O)c1cc(OC)c(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1C(F)(F)F
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(OC)c(NC(=O)Nc2cnc(C)cn2)cc1C(F)(F)F
Temperature: 85 °C

Procedure:
To a stirred solution of 5-methoxy-4-(4-nitro-phenoxycarbonylamino)-2-trifluoromethyl-benzoic acid methyl ester (878 mg, 2.1 mmol) in 4.2 mL NMP at room temperature under nitrogen was added 2-amino-5-methylpyrazine (232 mg, 2.1 mmol) and the reaction heated to 85° C. After six hours the reaction was cooled to room temperature and a precipitate formed. The precipitate was triturated with EtOAc (25 mL) and the urea isolated by filtration as a tan solid (470 mg, 58%).
Reaction SMILES: [NH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)N.Cl.[C:15]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=O)[CH2:16][CH3:17].[OH-].[Na+].[CH2:27](O)[CH3:28]>O>[CH3:17][C:16]1[C:13]2[C:3](=[CH:4][CH:5]=[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:27][CH3:28])=[O:10])[CH:12]=2)[NH:1][C:15]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC(=O)c1cccnc1
Reactant: CCO
Reactant: NNc1ccc(CCC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CCc1ccc2[nH]c(-c3cccnc3)c(C)c2c1

Procedure:
To a suspension of p-hydrazinohydrocinnamic acid (Manske and Kulka, J. Can. Res., 25B: 376 (1947), 4.50 g) in 50 ml of absolute ethanol under nitrogen at room temperature was added while stirring 10 ml of a saturated ethanolic hydrogen chloride solution. A solution resulted in approximately 5 minutes. To the red-orange solution was added 3-propionylpyridine (3.37 g, 0.025 mole), the reaction mixture was heated to reflux and maintained at reflux for 18 hours. The resulting solution was cooled in an ice-water bath and the resulting yellow crystals of ethyl 3-methyl-2-(3-pyridyl)indole-5-propionate hydrochloride were collected, m.p. 249°-51°. The free base, ethyl 3-methyl-2-(3-pyridyl)indole-5-propionate was prepared by suspending the hydrochloride salt in water, basifying with 3N sodium hydroxide and extracting with ether.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34](=[O:44])[NH:35]CCN2CCCCC2)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[NH:54]1[CH2:59][CH2:58][CH:57](N)[CH2:56][CH2:55]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[C:34](=[O:44])[NH:35][CH:57]2[CH2:58][CH2:59][NH:54][CH2:55][CH2:56]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C(=O)NCCN4CCCCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: NC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(/C=C\C(=O)NC4CCNCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Example 272 (50 mg, 0.12 mmol), N,N-diisopropylethylamine (90 μL, 5.1 mmol), 4-piperidinamine (0.24 mmol), and DMF (2.5 mL) was treated sequentially with 0.5M HBTU in DMF and 0.5M HOBt in DMF. The reaction was stirred for 18 hours at ambient temperature, diluted with water, and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified using normal or reverse phase chromatography. LCMS m/e 581.3; Rt=2.67 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl-].[Ca+2].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[C:21]1(C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C2C(CCCC2)CCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:24]3[CH:23]=[CH:22][C:21]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:26][CH:25]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: Cc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCC2CCCCC2C1
Product: c1cc(N2CCOCC2)ccc1Nc1ccc(N2CCOCC2)cc1
Temperature: 0 °C
Yield: 58.4 %

Procedure:
In a 300-ml four-necked flask were charged 68 ml of decahydronaphthalene (boiling point: 190° C.) as a solvent and 17.8 g (0.50 mol) of 4-morpholinoaniline, followed by the addition of 15.4 g (0.138 mol) of anhydrous calcium chloride and 18.5 g (0.138 mol) of anhydrous aluminum chloride under stirring. The resulting mixture was reacted at 200 to 210° C. for 5 hours under a nitrogen atmosphere. After cooling, the reaction mixture was added with 76 ml of toluene, followed by charging in 96 g of ice water. The resulting mixture was stirred and allowed to stand, and then, the resulting water layer was separated out. The organic layer was washed successively with 90 ml of a 5% aqueous solution of hydrochloric acid, 60 ml of a 5% aqueous solution of sodium bicarbonate and 60 ml of water. After removal of the organic solvent by distillation under reduced pressure, 48 ml of isopropyl alcohol was added to the residue and the mixture was crystallized overnight at −3 to −8° C. The resulting crystals were collected by filtration, washed with 18 ml of isopropyl alcohol and then dried, whereby 44.9 g (yield: 58.4%) of the title compound was obtained as white crystals. As a result of HPLC. analysis (column: YMC-A-312, detection UV: 280 nm, flow rate: 1.0 ml/min, eluent: acetonitrile/water 7/3), the compound was found to have a purity of 99.7%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[BrH:17].[Br:18]Br>CC(O)=O>[Br:17][C:3]1([Br:18])[CH2:4][CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])[S:9][C:10]=2[C:2]1=[O:1]
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: Br
Reactant: BrBr
Solvent: CC(=O)O
Product: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)(Br)CC2
Temperature: 45 °C
Yield: 937.5 %

Procedure:
A solution of 1-(7-oxo-4,5,6,7-tetrahydro-2-benzothiazolyl)-3-ethyl-urea 4 (5.00 g, 20.9 mmol), 48% HBr (aq) (1.20 mL, 2.09 mmol, 0.1 eq) and AcOH (451 mL) was treated dropwise with a solution of Br2 (2.21 mL, 42.8 mmol, 2.05 eq) in AcOH (5 mL) with stirring. The reaction mixture was heated at about 45° C. with stirring for about 16 hours with a condensor on top of the reaction flask. An orange colored suspension was obtained. The solid was filtered off and washed with Et2O (20 mL), toluene (50 mL) and Et2O (3×30 mL). After drying under vacuum, 7.78 g (94%) of compound 5 was obtained. 1H NMR (DMSO) δ 11.35 (br s, 1H, NH), 6.78 (br s, 1H, NH), 3.18 (m, 2H, CH2), 3.12 (t, 2H, J=5.6 Hz, CH2), 2.91 (t, 2H, J=5.6 Hz, CH2), 1.08 (t, 3H, J=7.2 Hz, CH3); LC/MS 396 (MH+); RP-HPLC RT 3.04 minutes.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+:11].[NH4+].[OH2:13].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(C)(C)C>[C:16]([NH2:11])(=[O:13])[CH:15]=[CH2:14].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [NH4+]
Reactant: O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: C=Cc1ccccc1
Solvent: CC(C)(C)O
Product: C=CC(N)=O

Procedure:
A copolymer of acrylamide (95.0 wt. %) and styrene (5.0 wt. %) is prepared according to a modification of the procedure of Example 1C using 0.5 wt. % n-C12SH, 0.2 wt. % ammonium persulfate and a solvent medium consisting of 75 wt. % deionized water and 25 wt. % t-butanol. The modification is that the styrene monomer is mixed into the chain transfer agent solution and fed into the reaction flask in that solution. Upon completion of the polymerization, the t-butanol is removed via a steam sparge to afford the product at 17.0% solids in water with a Brookfield Viscosity of 28,000 cps.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13]([NH:15][NH:16]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:12][C:11](=O)[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CO.Br[CH2:37][C:38](=O)[CH3:39]>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13]2[N:15]=[N:16][CH:37]=[C:38]([CH3:39])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(C)ccc3Cl)C2)cc1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1ccc(Cl)c(C2CCc3c(C)cnnc3C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(2-chloro-5-methylphenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.03 g), anhydrous potassium carbonate (1.73 g) and methanol (20 ml) was stirred at room temperature for 30 minutes, and to the mixture were added 1,2-dimethoxyethane (10 ml) and bromoacetone (0.891 g). The mixture was stirred at 80° C. for 4.5 hours. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (200 ml) and water (30 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin,-5-one (0.804 g) as brown crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][NH:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14].C(N(CC)CC)C>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2](/[CH:17]=[CH:16]/[S:13]([NH:12][CH3:11])(=[O:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CS(=O)(=O)NC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Yield: 28.9 %

Procedure:
A mixture of 5-bromoindole (6.6 g), N-methylethenesulphonamide (5.1 g) palladium (II) acetate (75 mg), tri-o-tolylphosphine (0.2 g), triethylamine (12 ml), and acetonitrile (5 ml) was heated at 100° in an autoclave for 3 h. The reaction mixture was cooled and partitioned between hydrochloric acid (1N, 300 ml) and ethyl acetate (2×150 ml). The combined extracts were dried, (Na2SO4) and evaporated in vacuo to give an oil which was purified by `flash` chromatography (Q, 7 cm dia. col.) to give the title compound as a solid (2.3 g) m.p. 164√-166°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+].CN(C=O)C>O>[C:24]([O:27][C:2]1[C:7]([C:8](=[O:9])[NH2:10])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cnc3ccccc3c2)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(Nc2cnc3ccccc3c2)c(C(N)=O)c(OC(C)=O)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
To a mixture of 4-chloro-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidine-5-carboxamide (Preparation Example 344) (0.68 g) and sodium acetate (0.80 g), DMF (7 mL) was added and stirred at 100° C. for 6 hours. After the reaction liquid was returned to room temperature, water was added, and the resulting solid was collected by filtration to give 5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-yl acetate (0.71 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[CH:19]=[CH:20][C:21]=2[CH:22]=[CH2:23])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].CN1C[CH2:40][O:39]CC1.[OH2:42]>ClCCl.[Os](=O)(=O)(=O)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][CH:23]([OH:42])[CH2:40][OH:39])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc(N(CC)CC)c(C(C)(C)C)c1
Reactant: CN1CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2ccc(CC(O)CO)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
150 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylate obtained in Example 32b are dissolved in 10 mL of dichloromethane under a nitrogen atmosphere. 45 mg of N-methylmorpholine are added to the reaction medium, and 0.5 mL of a commercial 2.5% solution of osmium tetroxide in water is then added dropwise and the reaction medium is stirred at room temperature for 3 hours. The reaction is then stopped by adding 10 mL of water and extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and filtered through a sinter funnel. The solvent is evaporated off and the residue obtained is purified by chromatography on silica (eluent: 7/3 heptane/ethyl acetate). 20 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate are obtained in the form of a white solid.