Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.C(#N)C>O1CCOCC1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([C:22]1[CH:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1)=[O:35]
Reactant: COc1ccccc1C(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 62 °C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (4.5 g) is added, at a temperature between 62° and 69° C., to a solution of 3'-amino-2-methoxybenzophenone (3.4 g) and triethylamine (3.05 g) in dioxane (90 cc) which is heated to a temperature in the vicinity of 62° C., in the course of 15 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is dissolved in methylene chloride (250 cc). The solution obtained is washed with distilled water (100 cc), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 3 times with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 45° C. A crude product (6.8 g) is thereby obtained, which is dissolved in boiling acetonitrile (60 cc). Decolourizing charocal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (30 cc in total) and 3 times with diethyl ether (60 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-methoxybenzoyl)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (4.1 g) in the form of white crystals, m.p. 184° C., is thereby obtained.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(Cl)c1
Yield: 62.1 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 278 mg of 3-chloro-4-fluoroaniline in place of the 2,4-difluoroaniline. 218 mg of N-(3-chloro-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([Cl:36])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1OC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccccc2F)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(2-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 416 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:13][N:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][N:14]([CH3:13])[CH2:15][CH2:16][N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(NCCN(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N(CCN(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.105 ml, 1.350 mmol) was added to a stirred solution of triethylamine (0.282 ml, 2.024 mmol) and methyl 4-{[2-(dimethylamino)ethyl]amino}benzoate (0.15 g, 0.675 mmol) in CH2Cl2 (2 ml) and the mixture was stirred at room temperature for overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over Na2SO4 filtered and the solvent was evaporated under reduced pressure. The product was purified by reversed phase HPLC (20-100% MeCN/H2O with 0.05% TFA). MS cal'd 301 (MH+), exp 301(MH+).
Reaction SMILES: C(OC([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:11]=1[OH:12])=O)C.P(=O)(O)(O)O>O>[OH:12][C:11]1[N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[C:9]2[N:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Agent: O=P(O)(O)O
Solvent: O
Product: Oc1ccnc2c(-c3ccc(Sc4ccccc4)cc3)cnn12
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A mixture of 3.91 g of 6-ethoxycarbonyl-7-hydroxy-3-(4-phenylthiophenyl)-pyrazolo[1,5-a]pyrimidine obtained in Example 1 and 30 ml of 85% phosphoric acid was heated in a heating bath to 170° C., and stirred for 30 minutes, and the mixture gradually developed foams, and the foams were about to cease, the reaction solution turned to a dark red color. Stopping the heating bath, 200 ml of water was added, and after letting stand for 30 minutes while ice-cooling, the precipitate was filtered, washed in water and dried, and 2.55 g of the title compound was obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([F:22])[CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[CH2:17]2>O1CCCC1.N1CCCCC1>[F:22][C:14]1[CH:15]=[C:16]2[C:20](=[C:12]([NH:11][CH:1]=[O:3])[CH:13]=1)[NH:19][C:18](=[O:21])[CH2:17]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Solvent: O=CO
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: O=CNc1cc(F)cc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A solution of acetic anhydride (0.8 ml) and formic acid (0.6 ml) was stirred for 1 hour at room temperature, and added with 7-amino-5-fluoro-1,3-dihydro-indol-2-one (2.0 g, 12 mmol) obtained from Example 4 in 30 ml of tetrahydrofuran and piperidine (0.02 ml). The resulting mixture was stirred for 3 hours at room temperature until a precipitate was formed. The solid was filtered and recrystallized from methanol to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide (700 mg, 30.4%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31]O)[N:18]=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:40]>O=P(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][Cl:40])[N:18]=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(Cl)c(Oc2c(CO)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cl)c(Oc2c(CCl)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 63.8 %

Procedure:
4.57 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-hydroxymethyl-2-(morpholin-4-yl)-pyrimidin-4-yl]benzenesulphonamide in 50 ml of POCl3 were stirred with 2.03 g of PCl5 at 20° C. for 2 hours. Thereafter, the POCl3 was distilled off and the residue was partitioned between ethyl acetate and aqueous 1N NaOH. The organic phase was washed with water, dried and the solvent was evaporated. The residue was chromatographed over silica gel with dichloromethane and chloroform, thereafter recrystallized from dichloromethane-ethanol. There were obtained 3.01 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, m.p. 170° C., MS: M=581.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:14][N:13]=1.IC(C)C.[NH4+].[Cl-]>CS(C)=O>[CH:2]([N:14]1[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]([C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)=[N:13]1)([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CC(C)I
Product: CCOC(=O)c1cc(-c2cccs2)nn1C(C)C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Potassium t-butoxide (0.51 g, 4.5 mmol) was dissolved in DMSO (10 mL) and to this solution was added ethyl 3-(thiophen-2-yl)-1H-pyrazole-5-carboxylate (1.01 g, 4.5 mmol) in small portions and stirred under Ar for 15 min. To this solution was added 2-iodopropane (1.2 g, 6.8 mmol) slowly and stirred for 1 h at RT. Sat. NH4Cl solution was added, the product was extracted with EtOAc (2×40 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography provided ethyl 1-isopropyl-3-(thiophen-2-yl)-1H-pyrazole-5-carboxylate as a pasty mass (0.88 g, 73% yield). 1H NMR (400 MHz, Acetone-d6): δ 7.47 (dd, J=3.2 Hz, 1.2 Hz, 1H), 7.42 (dd, J=4.8 Hz, 1.2 Hz, 1H), 7.12-7.09 (m, 2H), 5.57-5.51 (m, 1H), 4.37 (q, J=7.2 Hz, 2H), 1.50 (d, J=6.8 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 265.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Br
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Br

Procedure:
using isopropyl 2-bromo-4-fluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2-bromo-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta-[d]pyrimidin-3-yl)-benzoate, m.p. 116°-120° C.,
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:16])=[O:7]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(C(F)(F)F)c1

Procedure:
Reaction of 3-trifluoromethylbenzoic acid with thionyl chloride affords 3-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine, affords 3-trifluoromethyl-N,N-diethylbenzamide. Following a procedure similar to that described in Example 22A, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylaminesulfonate affords 3-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 7-trifluoromethyl saccharin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][S:20]([CH3:22])=[O:21])=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][S:20]([CH3:22])(=[O:35])=[O:21])=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CS(=O)(=O)CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 35 from 5-((3,5-dichloropyridin-4-yl)thio)-N-(3-(methylsulfinyl)propyl)-4-nitrothiophene-2-carboxamide (60.0 mg, 0.13 mmol) and MCPBA (67.0 mg, 0.39 mmol). The titled product was obtained as a white solid (45.0 mg, 74% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.91 (1H, m), 8.41 (1H, s), 3.28 (2H, m), 3.13 (2H, m), 2.95 (3H, s), 1.90 (2H, m). MS m/z: 470.11, 472.06 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]([CH3:39])[CH:31]=5)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:40])[CH2:11][CH2:12]2)[CH2:8]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]([CH3:39])[CH:31]=5)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:40][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:12]2)[CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: -15 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
Acryloyl chloride (41.3 mg, 0.46 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 123, 195 mg, 0.42 mmol) in THF (3 mL), cooled in an ice/methanol bath to approximately −15° C. Upon slow addition of the acryloyl chloride a precipitate immediately formed. The mixture was stirred for 1 h while being gradually warmed to 0° C. The mixture was then diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 (50 mL). The resulting aqueous solution was extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave crude solid product after concentration of appropriate fractions in vacuo. This solid was dissolved in the minimum amount of hot CH2Cl2 and triturated with diethyl ether to give the title compound (115 mg, 53%) as a white solid; 1H NMR (CDCl3) 1.77-1.96 (2H, m), 2.15-2.26 (1H, m), 2.29 (3H, s), 2.26-2.37 (1H, m), 2.73 (1H, d), 2.80 (1H, d), 2.83-2.90 (1H, m), 2.95 (1H, td), 3.21 (1H, t), 3.57-3.68 (1H, m), 3.88 (3H, s), 4.00 (3H, s), 5.68-5.74 (1H, m), 6.45 (2H, d), 6.81 (1H, s), 7.20 (1H, d), 7.23-7.31 (2H, m) partially obscured under CDCl3 signal, 7.37-7.43 (1H, m), 7.71 (1H, s), 8.02-8.10 (1H, m), 8.38 (1H, d), 9.09 (1H, s), 9.46 (1H, s), 9.85 (1H, s); m/z: ES+ MH+ 524.25.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[OH-].[K+].Cl[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].C(Cl)Cl>CS(C)=O>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5]2)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-Hydroxyflavane (0.150 g) was dissolved in dry DMSO (5 ml) under nitrogen. KI (0.166 g) and KOH (0.074g) were added and solution was stirred at room temperature for 15 minutes. 2-Chloro-1-nitrobenzene (0.104 g) was added and the solution was stirred at +90° C. for 2.5 hours. Cooled solution was taken up with CH2Cl2 and washed with H2O and 2M NaOH. Phases were separated and water phase was washed CH2Cl2. All organic phases were combined and washed with 1M HCl and then H2O (until pH˜7) and brine. Solution was dried over Na2SO4 and purified with filtration through the small silica column in CH2Cl2:n-heptane (60:40). 1H-NMR (300 MHz; d6-DMSO): δ 8.01 (dd, 1H, J=8.1 Hz; J=1.7 Hz), 7.69 (m, 1H), 7.50-7.31 (m, 5H), 7.31-7.24 (m, 1H), 7.04 (dd, 1H, J=8.5 Hz; J=1.2 Hz), 6.92 (s, 1H), 6.90 (s, 2H), 5.12 (dd, 1H, J=10.1 Hz; J=2.3 Hz), 2.95 (ddd, 1H, J=16.9 Hz; J=11.2 Hz, J=5.8 Hz), 2.73 (ddd, 1H, J=16.9 Hz; J=3.2 Hz, J=1.7 Hz), 2.25-2.10 (m, 1H), 2.08-1.90 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18]C)=[O:17])[NH:7][C:6]=2[CH:22]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([OH:18])=[O:17])[NH:7][C:6]=2[CH:22]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc5ccccc5c4)c(Cl)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Oc2nc3cc(-c4ccc5ccccc5c4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of methyl 5-{[6-chloro-5-(2-naphthyl)-1H-benzimidazol-2-yl]oxy}-2-methylbenzoate in MeOH (3 mL) was added NaOH (2.5 M in water) (0.5 mL, 1 mmol). The mixture was heated at 50° C. and monitored by LC-MS. When the reaction was complete, it was partitioned between EtOAc and 2 M aqueous HCl. The aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. Purification by reverse phase HPLC eluting with MeCN:H2O afforded the title compound as a white solid. LC-MS: calculated for C25H17ClN2O3 428.87, observed m/e 429.5 (M+H)+ (Rt 2.19 min). 1H NMR (500 MHz, CD3OD): δ 7.92-7.84 (m, 5H), 7.58-7.54 (m, 1H), 7.53 (s, 1H), 7.52-7.48 (m, 2H), 7.46-7.39 (m, 3H), 2.62 (s, 3H).
Reaction SMILES: Cl.I[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[CH2:25]([NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>C(COC)OC.O.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>[CH2:25]([NH:27][C:28](=[O:29])[NH:30][C:31]1[N:32]=[CH:33][C:34]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][CH:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]3=[O:24])=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[CH:36]=1)[CH3:26]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCNC2)cn1
Temperature: 75 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A tall vial was charged with ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 126, 1.5 g, 3.24 mmol), 6-(3-ethylureido)-4-(4-trifluoromethylthiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 17, 1.41 g, 3.9 mmol) and sodium bicarbonate (1.1 g, 12.9 mmol) in dimethoxyethane (10 mL) and water (2 mL). The reaction mixture was purged by N2 for about 5 minutes, then trans-dichlorobis(triphenylphosphine)palladium (II) (228 mg, 0.324 mmol) was added. The reaction was stirred for 1 h at 75° C. The reaction mixture was cooled to room temperature, and water (10 mL) was added. A solid precipitated and was collected to give ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (1.6 g, 80.4%) as a light brown solid after drying in a vacuum oven at 40° C. overnight.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[O:5]1[CH2:32][CH:6]1[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:31])[C:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16]2)=[CH:11][CH:10]=1>>[CH:1]1([NH:4][CH2:32][CH:6]([OH:5])[CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:31])[C:14]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16]3)=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Reactant: NC1CC1
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(OCC(O)CNC3CC3)ccc12
Yield: 25 %

Procedure:
The amine was prepared according to Method B from cyclopropylamine and 7-(2,3-epoxypropoxy)-2,3-diphenylchromone and purified by high pressure liquid chromatography to give white crystals, m.p. 135°-137° (MeOH-ether), in 25% yield.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[OH-:19].[Na+]>O.C(Cl)(=O)C1C=CC=CC=1>[C:4]([O:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5])(=[O:19])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:2]=1
Reactant: [OH-]
Reactant: CCc1ccc(O)c(C(=O)c2ccc(Cl)cc2)c1
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: CCc1ccc(OC(=O)c2ccccc2)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Hydroxy-5-ethyl-4'-chlorobenzophenone (5 g, 0.019 mole) was stirred vigorously in a solution of NaOH (7.5 g, 0.187 mole) in water (75 ml) and benzoyl chloride was added dropwise over 5 minutes. The temperature rose to around 50° C. The mixture was stirred for 1.5 hours at room temperature and was then extracted with ether, the ether washed with saturated NaCl solution, dried (Na2SO4), filtered and evaporated to leave the product, which was recrystallised from n-hexane to give white crystals of the desired product, m.p. 79°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:18][C:19](=[CH2:21])[CH3:20].[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(C(=O)OC(C)(C)C)ccc1C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of 3-methoxy-4-methylbenzoic acid (10.0 g), concentrated sulfuric acid (1 ml), and condensed isobutylene (200 ml) in methylene chloride (200 ml) was placed in a pressure vessel and stirred for 16 hours. The vessel was then opened to vent unreacted isobutylene. The remaining liquid was poured into 10% (w/v) sodium hydroxide solution (150 ml) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash chromatography, eluting with 1:9 ethyl acetate:hexane, to give t-butyl 3-methoxy-4-methylbenzoate (9.1 g, 70%) as a colorless oil; NMR (80 MHz, CDCl3): 1.6[s, 9H, C(CH3)3 ], 2.27(s, 3H, CH3), 3.86(s, 3H, OCH3), 7.11(d, 1H), 7.49(m, 2H).