Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[NH:17][C:16](=[O:19])[CH2:15][CH2:14][C:13]=2[C:12]([OH:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.[H-].[Na+].CI.[Cl-].[Na+]>CN(C)C=O>[CH3:22][N:17]1[C:18]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=[C:12]([OH:20])[C:13]=2[CH2:14][CH2:15][C:16]1=[O:19].[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1
Reactant: O=C1CCc2c(O)ccc(OCc3ccccc3)c2N1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CCc2c(O)ccc(OCc3ccccc3)c21
Yield: 55.1 %

Procedure:
5 g of 8-benzyloxy-3,4-dihydrocarbostyril-5-ol-detrahydropyranyl ether (IV) was dissolved in 100 ml of anhydrous dimethylformamide, and 810 g of sodium hydride was slowly added to the solution while stirring, followed by stirring at room temperature for 1 hour. 1.05 ml of methyl iodide was further added dropwise thereto followed by stirring at the same temperature for 2 hours. The reaction mixture was poured into a large volume of a saturated aqueous solution of sodium chloride, extracted with chloroform, washed with water and dried over anhydrous potassium carbonate. The chloroform was evaporated under reduced pressure, and the residue was recrystallized from ligroin to obtain 1.42 g of 1-methyl-8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydropyranyl ether as colorless needle-like crystals having a melting point of 110.5°-111.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1)#[N:9]
Reactant: CC(C)C[C@@H](Nc1ccc(C#N)c(Br)c1)C(N)=O
Reactant: Cc1cc(N)no1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C#N)no1
Reaction time: 18 h
Yield: 19.7 %

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)-4-methylpentanamide (120 mg, 0.387 mmol), 3-amino-5-methylisoxazole (60 mg, 0.612 mmol), BINAP (40 mg, 0.064 mmol), Pd(OAc)2 (30 mg, 0.13 mmol) and K2CO3 (150 mg, 1.08 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 120 C for 18 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(4-cyano-3-(5-methylisoxazol-3-ylamino)phenylamino)-4-methylpentanamide (25 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[H-].[Na+].[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:16]2[CH:17]=[CH:18][N:19]=[C:14]([NH2:13])[N:15]=2)=[CH:5][CH:4]=1
Reactant: Nc1nccc(Cl)n1
Reactant: COc1ccc(CO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccnc(N)n2)cn1
Temperature: 0 °C
Yield: 119.6 %

Procedure:
A mixture of commercially available (6-methoxypyridin-3-yl)-methanol (CAS 58584-63-7, 1 g, 7.19 mmol) and dry THF (9.3 mL) was cooled to 0° C. and sodium hydride (0.38 g of a 60% dispersion, 9.58 mmol) was added portionwise. Stirring was continued at 0° C. before portionwise addition of 2-amino-4-chloropyrimidine (0.62 g, 4.79 mmol). The mixture was heated at 100° C. (bath temperature) for 2 hours. On cooling, the mixture was poured onto ice, extracted with EtOAc (4×) and the combined organic phase washed with brine, dried and concentrated to give the title compound as a beige solid (1.33 g, 65% purity) which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:7]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>[Pd]>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:3]=[N:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(Br)c2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cncc(-c3ccc(OC(F)(F)F)cc3)c2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of step 1 with 4-formylphenyl boronic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11](=O)[CH3:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10])[CH3:2].[CH:14]1([C:20]2[CH:28]=[CH:27][C:23]([CH2:24][O:25][NH2:26])=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C>CO>[CH:14]1([C:20]2[CH:28]=[CH:27][C:23]([CH2:24][O:25][N:26]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH3:12])=[CH:22][C:21]=2[C:29]([F:30])([F:31])[F:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: NOCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Reactant: CCc1cc(C(C)=O)ccc1CO
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanol is added O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES+) 434.2 (M+1)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:21]C(=O)C1C=CC=CC=1)=[N:9]2.S(=O)(=O)(O)O.[N+:35]([O-])([OH:37])=[O:36].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:35]([O-:37])=[O:36])=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH2:21])=[N:9]2
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-((4aS,5S,7aS)-7a-(2-Fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (5.15 g) was dissolved in TFA (75 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 20 mL) was added, followed by fuming nitric acid (2 mL) dropwise over 20 mins. After stirring at 0° C. for 90 mins, the reaction mixture was poured onto ice (200 g) and basified to pH 12 with 6N NaOH (aq.). After allowing the ice to melt, the mixture was extracted with EtOAc (3×500 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound (22.1 g, purity approx. 71%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (d, J=3.8 Hz, 1 H), 3.09 (br. s., 1H), 3.28-3.54 (m, 1 H), 3.80-4.03 (m, 1 H), 4.50-4.70 (m, 3 H), 4.71-4.86 (m, 1 H), 7.21-7.30 (m, 1 H), 8.18-8.28 (m, 1 H), 8.45 (dd, J=6.8, 2.8 Hz, 1 H)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[CH:10]=[CH:11][CH:12]=1.CN(C)[CH:21]=[O:22].C(=O)([O-])O.[Na+]>>[F:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[C:16]([CH:21]=[O:22])[C:15]([CH3:18])=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccn(-c2cccc(F)c2)n1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(-c2cccc(F)c2)cc1C=O
Temperature: 95 °C

Procedure:
Add phosphorus oxychloride (20.8 mL, 34.3 g, 223.7 mmol) dropwise with stirring at 95° C. under nitrogen to 1-(3-fluoro-phenyl)-3-methyl-1H-pyrazole (4.38 g, 24.86 mmol) in dimethylformamide (19.2 mL, 18.17 g, 248.6 mmol). Heat at 95° C. for 15 hr., cool to room temperature, pour over ice and neutralize with sodium hydrogen carbonate. Extract the aqueous solution with ethyl acetate (2×150 mL), dry (magnesium sulfate), filter, and pass through an SCX-2 column. Evaporate the solvent to give 1-(3-fluoro-phenyl)-3-methyl-1H-pyrazole-4-carbaldehyde as a solid. (4.22 g, 83%). MS (m/z): 205.1 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[ClH:34].[N:35]12[CH2:42][CH2:41][CH:38]([CH2:39][CH2:40]1)[C@@H:37]([NH:43][C:44]([C:46]1[S:47][C:48]3[C:54]([C:55]4[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=4)[C:58]([OH:60])=O)=[CH:53][CH:52]=[CH:51][C:49]=3[CH:50]=1)=[O:45])[CH2:36]2.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CN(C=O)C>[ClH:34].[N:35]12[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42]1)[C@@H:37]([NH:43][C:44]([C:46]1[S:47][C:48]3[C:54]([C:55]4[CH:63]=[CH:62][CH:61]=[C:57]([C:58]([N:64]5[CH2:69][CH2:68][O:67][CH2:66][CH2:65]5)=[O:60])[CH:56]=4)=[CH:53][CH:52]=[CH:51][C:49]=3[CH:50]=1)=[O:45])[CH2:36]2
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(C(=O)N4CCOCC4)c3)c2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
103 mg (0.27 mmol) of HATU and 70.8 μl (0.41 mmol) of N,N-diisopropylethylamine are added to a solution of 50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 19.7 μl (0.23 mmol) of morpholine in 0.5 ml of DMF at 0° C. The mixture is stirred at room temperature for 18 h. After purification by preparative HPLC, the product fractions are concentrated and, after addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 43 mg (74% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@H:13]([C:18]([NH:20][C:21]2([C:24]#[N:25])[CH2:23][CH2:22]2)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C=O)C>[C:24]([C:21]1([NH:20][C:18](=[O:19])[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[CH:33][C:28]([S:27][CH3:26])=[CH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH:9]([F:11])[F:10])[CH2:23][CH2:22]1)#[N:25]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)F)C(=O)NC1(C#N)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(-c2ccc([C@H](N[C@@H](CC(C)C)C(=O)NC3(C#N)CC3)C(F)F)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A stream of nitrogen was passed through a suspension of the aryl bromide from Step 5 (65 mg), 4-(methylthio)phenylboronic acid (40 mg), 2 M Na2CO3 (0.22 mL) and DMF (1.0 mL) for 5 minutes. PdCl2dppf was then added and the reaction was warmed to 80° C. and stirred under nitrogen for 4 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and poured into a saturated solution of sodium bicarbonate. The ethyl acetate layer was separated and the aqueous further extracted with ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed with brine and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2 using a gradient of hexanes and ethyl acetate (90:10 to 50:50) to afford the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.Cl.[CH3:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][NH:38]2)=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][N:38]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])=[CH:34][CH:33]=1
Reactant: Cc1ccc2c(c1)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
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: Cc1ccc2c(c1)N(C(=O)c1cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn1)CC2

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 62 mg (0.4 mmol) 6-methyl-2,3-dihydro-1H-indole-hydrochloride, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The precipitate formed was suction filtered and dried under HV.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@H:21]4[CH2:23][O:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>O1CCCC1>[NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@H:21]([OH:22])[CH2:23][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@H]1CO1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1C#N
Temperature: 50 °C
Reaction time: 120 h
Yield: 84.2 %

Procedure:
After dissolving 4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline (96 mg, 0.261 mmol) in tetrahydrofuran (2.6 ml) under a nitrogen atmosphere, diethylamine (0.5 ml) was added and the mixture was stirred at 50° C. for 5 days. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (96.9 mg, 0.220 mmol, 84.2%) as light yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]([C:5]1[N:14]=[C:13](O)[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4].C(Cl)(Cl)[Cl:20]>P(Cl)(Cl)(Cl)=O>[Cl:20][C:13]1[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=[C:5]([CH:3]([N:2]([CH3:18])[CH3:1])[CH3:4])[N:14]=1
Reactant: ClC(Cl)Cl
Reactant: CC(c1nc(O)c2c(n1)CCC(C)(C)C2)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(c1nc(Cl)c2c(n1)CCC(C)(C)C2)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A solution of 2-[1-(dimethylamino)ethyl]-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (50 mg, 0.20 mmol) in a mixture of chloroform (1.5 mL) and phosphorous oxychloride (0.5 mL) was heated to reflux for 90 minutes. After cooling to room temperature the reaction mixture was concentrated and the residue was partitioned between saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The mixture was stirred for 15 minutes and pH was maintained above 7 by the addition of solid sodium bicarbonate. The organic layer was separated and washed with water (10 mL) and brine, dried over sodium sulfate, filtered and concentrated to give 1-(4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)-N,N-dimethylethanamine (46 mg, 85%). MS (EI) for C14H22ClN3: 268 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:23])[C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:32]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:23])[C:12]3[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:16][CH:17]=3)=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[S:8][C:7]=2[CH:32]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C=CC(=O)O)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a −5° C. solution of 6-methoxy-3-[4-(2-carboxyvinyl)benzoyl]-2-(4-methoxyphenyl)benzo[b]thiophene (900 mg, 2.0 mmol) in 40 mL of anhydrous CH2Cl2 under N2 was added BBr3 (0.76 mL, 8.0 mmol) slowly via syringe. After warming to 5° C., the mixture was stirred for 1 h at 5° C., then quenched by pouring into ice water (100 mL). The mixture was extracted with EtOAc (3×100 mL). The organic was then dried (Na2SO4) and concentrated in vacuo to a solid residue that was chromatographed (SiO2, 1% MeOH/CHCl3) to provide 730 mg (86%) of (E)-6-hydroxy-3-[4-(2-carboxyvinyl)benzoyl]-2-(4-hydroxyphenyl)benzo[b]thiophene as a yellow solid. mp 155-160° C. 1H NMR (DMSO-d6) δ 12.55 (bs, 1H), 9.81 (s, 1H), 9.73 (s, 1H), 7.67 (s, 4H), 7.54 (d, J=16.0 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.18 (d, J=9.0 Hz, 2H), 6.89 (dd, J=9.0, 2.5 Hz, 1H), 6.65 (d, J=9.0 Hz, 2H), 6.58 (d, J=16.0 Hz, 1H). FD mass spec: 416. Anal. Calcd. for C24H16O5S: C, 69.22; H, 3.87. Found: C, 68.95; H, 3.73.
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)[O:12]C2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=2)[NH:40][N:39]=1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>ClCCl>[CH3:7][O:10][P:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:12])[O:47][C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[NH:40][N:39]=[C:38]2[C:30]1[NH:29][C:37]2[C:32]([CH:31]=1)=[CH:33][CH:34]=[CH:35][CH:36]=2
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
Phenylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester is prepared according to procedure F using 230 mg of phenyl-phosphonic acid bis-(4-nitrophenyl) ester in solution in 4 ml of dichloromethane to which is added a solution of 120 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol and 72 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene in 4 ml of dichloromethane. After stirring for 2 hours at ambient temperature, the medium is treated with 4 times 50 ml of a saturated sodium bicarbonate solution, and then with 2×50 ml of a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and then concentrated to dryness to obtain 200 mg of crude phenylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH:18]([CH3:20])[CH3:19].C([O:23][C:24](=[O:36])[CH2:25][C:26]1[C:27]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:28]=2[S:29][CH:30]=1)C.C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[Na+]>C(#N)C.C(O)C>[CH:18]([C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:7][C:3]=1[CH2:2][O:35][C:32]1[CH:33]=[CH:34][C:27]2[C:26]([CH2:25][C:24]([OH:36])=[O:23])=[CH:30][S:29][C:28]=2[CH:31]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloromethyl-4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole (100 mg, 0.31 mmol) and (6-Hydroxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (75 mg, 0.31 mmol) in acetonitrile (3 mL) is added Cs2CO3 (200 mg, 0.62 mmol). The mixture is stirred at room temperature overnight, ethanol (1 mL) is added, followed by NaOH (5 N, 1.0 mL). The mixture is heated at 50° C. for 2 hrs, solvent is evaporate, the residue is diluted with water, acidified by 5N HCl and extracted with ethyl acetate. Concentration and reversed phase HPLC purification yields the title product. MS (ES): 490.0 (M+−1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]1=2.Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:14]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([C:16]1[N:17]=[CH:18][N:19]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=1)([O:3][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:13][CH2:12][CH2:11]2)#[N:15]
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCCc2cc(C#N)ccc21

Procedure:
1.9 mmol of sodium hydride (60% dispersion in oil) are added in portions to a solution of 1.3 mmol of 5-hydroxy-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile in 10 ml of tetrahydrofuran, and the mixture is stirred under reflux for 1 hour. 3.0 mmol of ethyl bromoacetate [105-36-2] are added and the reaction mixture is stirred under reflux for 8-16 hours. The reaction mixture is cooled and poured into saturated sodium bicarbonate solution and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of its Rf by flash chromatography (SiO2 60F).