Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.C([O-])(=O)C.[Na+].[Na+].[I-:31]>CC(C)=O>[I:31][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1
Reactant: [I-]
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 0 °C

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (159 mg, 0.5 mmol) and sodium acetate (82 mg, 1 mmol) in acetone (7 mL) was treated with NaI (90 mg, 0.6 mmol). The mixture was refluxed for 2 h, and then it was poured into ice-water. The precipitated solid was collected by filtration, washed with water, and dried. The crude product was crystallized from EtOAc-hexane to give the title compound as yellow rods (105 mg); mp 155-160° C.; 1H NMR (CDCl3) 7.36 (s, 1H), 7.29 (s, 1H), 7.23 (s, 1H), 7.22 (d, J=6.5, 1H), 6.98 (d, J=8.3, 1H), 6.15 (s, 2H), 6.07 (s, 2H), 4.71 (s, 2H). Anal. calcd. for C17H11N2O4.(¼)H2O: C, 46;50; H, 2.62; N, 6.38. Found: C, 46.43; H, 2.53; N, 6.28.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 48 h

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol), 2-fluorophenylboronic acid (380 mg, 2.71 mmol) and tripotassium phosphate (288 mg, 1.36 mmol) were dissolved in 1,4-dioxane (8 ml), then at room temperature, tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.14 mmol) was added. The solution was stirred under nitrogen atmosphere at 95° C. for 48 hours. After cooling to room temperature, aqueous saturated ammonium chloride solution was added to the reaction liquid, followed by stirring at room temperature for 5 minutes. This was extracted twice with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH:12][C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[C:16]([N+:26]([O-])=O)[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH:12][C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[C:16]([NH2:26])[CH:15]=1)[CH2:8][CH:9]([CH3:10])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(CC)Nc1ccc(C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1ccc(C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc1N
Reaction time: 4 h
Yield: 60.8 %

Procedure:
11.5 g of (S)-2-[4-(1-ethyl-propylamino)-3-nitro-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester were dissolved in 100 ml ethanol, 1.0 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 4 h. the catalyst was removed by filtration over celite, and the reaction mixture was concentrated and purified by chromatography (silica, heptane/ethyl acetate) to yield 6.5 g (61%) of (S)-2-[3-amino-4-(1-ethyl-propylamino)-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:16]2[CH:15]=[CH:14][C:13]([CH:17]=O)=[CH:12][C:11]=2[S:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:19]1([NH:25][N:26]=[CH:17][C:13]2[CH:14]=[CH:15][C:16]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([S:10][C:11]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: CCN1c2ccccc2Sc2cc(C=O)ccc21
Solvent: CO
Product: CCN1c2ccccc2Sc2cc(C=NNc3ccccc3)ccc21

Procedure:
10-Ethylphenothiazine-3-carbaldehyde (3 g, 0.012 mol) was dissolved in 30 ml of methanol under mild heating. A solution of 1.9 g (0.018 mol) of N-phenylhydrazine (from Aldrich) in methanol was added to the 10-ethylphenothiazine-3-carbaldehyde solution. The reaction mixture was refluxed for 0.5 hour. The precipitated product was filtered, washed with a large amount of methanol, and then dried. The yield of yellowish crystals of 10-ethylphenothiazine-3-carbaldehyde-N-phenylhydrazone was 3 g (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH:42]1([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:49]3[CH2:50][CH2:51][N:46]([CH2:45][CH:42]4[CH2:44][CH2:43]4)[CH2:47][CH2:48]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(CC(=O)N2CCN(CC3CC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (10 mL) was added DIEA (83 mg, 0.64 mmol), 1-(cyclopropylmethyl)piperazine (60.6 mg, 0.43 mmol) and HATU. The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product (120 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=24:40 within 14 min; Detector, UV 254 nm. This resulted in 47.6 mg (38%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=585.2, RT=2.40 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.51-3.49 (m, 4H), 2.49-2.41 (m, 4H), 2.23-2.21 (m, 2H), 0.87-0.82 (m, 1H), 0.50-0.44 (m, 2H), 0.13-0.08 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[CH3:14][NH2:15]>C(=O)(O)[O-].[Na+].[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[N:15]\[CH3:14])/[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1
Reactant: CN
Reactant: O=C(c1ccc(Br)cn1)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Product: C/N=C(\c1ccc(Br)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanone (1.0 g, 3.93 mol) and methylamine (20 ml, tetrahydrofuran solution) is added titanium ethoxide (0.987 g, 4.33 mmole) at 0° C. then stirred at room temperature for 2 hours. Reaction mixture is diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by column chromatography eluting in 20% ethyl acetate in hexane to give the title compound (0.10 g). 1H-NMR (400 MHz, DMSO) δ: 3.25-3.26 (m, 3H), 7.85-7.90 (m, 2H), 8.49 (s, 1H). LC-MS (m/z): [M+H]=266.8.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1)(=O)=O.[CH:15]12[NH:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][C:17](=[O:23])[CH2:16]2>>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:7]=[N:6][C:5]([N:22]2[CH:15]3[CH2:21][CH2:20][CH:19]2[CH2:18][C:17](=[O:23])[CH2:16]3)=[N:10][CH:9]=1
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Reactant: O=C1CC2CCC(C1)N2
Product: O=C1CC2CCC(C1)N2c1ncc(C(F)(F)F)cn1

Procedure:
The title compound was synthesized from 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine and 8-azabicyclo[3.2.1]octan-3-one in a manner similar to that described in Example 9.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([O:33][CH3:32])[CH:39]=2)[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2cc(F)ccc2OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 82.6 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 3-methoxyphenylboronic acid (28 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (44 mg, 83%). MS m/e 437.29 (M+H+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][C:2]=1[C:10]([NH2:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][C:2]=1[C:10]([NH2:12]=[O:21])=[O:11]
Reactant: NC(=O)c1ccnc(C(N)=O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: NC(=O)c1ccnc(C(=O)[NH2+][O-])c1

Procedure:
From 1 g of pyridine-2,4-dicarboxamide and 1.2 g of MCPBA.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][N:17]=[CH:16]1>C(O)C>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:23][CH2:22][CH2:21][CH2:20][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: NCCCn1ccnc1
Reactant: SC1=Nc2ccc(Cl)c3cccc1c23
Solvent: CCO
Product: Clc1ccc2c3c(cccc13)C(NCCCn1ccnc1)=N2
Yield: 74.6 %

Procedure:
A mixture of 1.0 g of 6-chloro-benz(cd)indole-2-thiol, 540 mg of 3-(1H-imidazol-l-yl) propanamine, 1.26 g of mercuric acetate and 100 ml of ethanol was reacted as described in Example 1, giving 1.0 g of the desired compound, mp 177° C.-178° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)=[N:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2].[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[NH2:30][C:26]1[CH:25]=[C:24]([C:11]2[C:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=3)=[CH:14][N:13]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[N:12]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc([N+](=O)[O-])c2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)n1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
391 mg (0.91 mmol) of N-ethyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine were dissolved in a mixture of 20 ml of dioxane and 4 ml of water. 239 mg (3.64 mmol) of metallic zinc and 485 mg (9.1 mmol) of ammonium chloride were then added to the resulting solution. The reaction was carried out at 100° C. under stirring for 5 hours. The suspension was then filtered through a celite pad and the filtrate evaporated in vacuo. The residue was partitioned between dichloromethane and aqueous sodium hydrogenocarbonate and the organic layer dried over sodium sulphate and concentrated to give a crude purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3; from 9/1 to 7/3), affording 340 mg (93%) of the title compound.
Reaction SMILES: FC(F)(F)C1C=CC(C2ON=C(CO)C=2)=CC=1.C([O:20][C:21](=[O:50])[CH2:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:33][CH2:34][C:35]3[CH:39]=[C:38]([C:40]4[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=4)[O:37][N:36]=3)[CH:29]=2)[O:24]1)C>>[F:48][C:46]([F:47])([F:49])[C:43]1[CH:44]=[CH:45][C:40]([C:38]2[O:37][N:36]=[C:35]([CH2:34][S:33][C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[O:24][CH:23]([CH2:22][C:21]([OH:50])=[O:20])[CH2:32][CH2:31]4)[CH:39]=2)=[CH:41][CH:42]=1
Reactant: CCOC(=O)CC1CCc2cc(SCc3cc(-c4ccc(C(F)(F)F)cc4)on3)ccc2O1
Agent: OCc1cc(-c2ccc(C(F)(F)F)cc2)on1
Product: O=C(O)CC1CCc2cc(SCc3cc(-c4ccc(C(F)(F)F)cc4)on3)ccc2O1

Procedure:
The title compound was prepared in a manner analogous to Example 5E using 13B. MS m/z 262 (M+1). Step 4. Preparation of {6-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-2-yl}-acetic acid ethyl ester (Compound 13D)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)(O)[C:11]3[CH:10]=[C:9]4[C:27]5[C:32]([C:33]([CH3:35])([CH3:34])[C:8]4=[CH:7][C:6]=3[C:5]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=3)(O)[C:4]=2[CH:3]=1)=[CH:31][CH:30]=[CH:29][CH:28]=5.[I-].[K+].[PH2]([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=3)[C:6]3[CH:7]=[C:8]4[C:33]([CH3:35])([CH3:34])[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:9]4=[CH:10][C:11]=3[C:12]=2[C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:3]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)C(O)(c1ccc2ccccc2c1)c1cc(Br)ccc1C3(O)c1ccc2ccccc2c1
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2cc3c(-c4ccc5ccccc5c4)c4ccc(Br)cc4c(-c4ccc5ccccc5c4)c3cc21
Reaction time: 5 h
Yield: 71 %

Procedure:
9-bromo-13,13-dimethyl-6,11-di(naphthalen-2-yl)-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (11.87 g, 0.018 mol), Potassium iodide (29.88 g, 0.18 mol), and Sodium hypophosphite (35.63 g, 0.297 mol) were placed in a flask, and were suspended in acetic acid (300 ml). The reaction mixture was stirred for five hours while heating. After the reaction was terminated, the reaction solution was added to an excess of distilled water. The resultant solid was washed, filtered and purified by column chromatography to give 9-bromo-13,13-dimethyl-6,11-di(naphthalen-2-yl)-13H-indeno[1,2-b]anthracene (8 g, yield=71%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([OH:21])[C:13]=1[CH2:22][CH2:23][CH3:24].[OH-].[Na+]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:25])=[O:2])=[C:13]([CH2:22][CH2:23][CH3:24])[C:14]=1[OH:21])(=[O:20])[CH3:19]
Reactant: CCCc1c(OCc2ccccc2C(=O)OC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCc2ccccc2C(=O)O)ccc(C(C)=O)c1O

Procedure:
2-[(4-Acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid methyl ester was allowed to react with 1.0N sodium hydroxide according to the procedure of Example 70 and the product was purified by recrystallization from methanol to give 2-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid, the title compound, m.p. 216°-219°, in 85% yield. Analysis Calculated for C19H20O5 : C, 69.50; H, 6.14. Found: C, 69.39; H, 6.19.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([NH:12][C:13](=[O:29])[CH2:14][C:15]2[CH:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:18]=[CH:19][C:20]=2[CH3:21])([C:8](OC)=[O:9])[CH2:4][CH2:3]1.CN(C)C(=O)C.CC(C)([O-])C.[K+].Cl>O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][C:5]2([NH:12][C:13](=[O:29])[C:14]([C:15]3[CH:16]=[C:17]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH:18]=[CH:19][C:20]=3[CH3:21])=[C:8]2[OH:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(F)cc3)ccc2C)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(-c2ccc(F)cc2)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.80 g (5.94 mmol) of the compound from Example 7A were initially charged in a solution of 8 ml of DMA (N,N-dimethylacetamide), a solution of 5 ml of DMA and 1.75 g (2.5 eq.) of potassium tert-butoxide was added dropwise at 20° C. and the mixture was stirred at room temperature for 4 h. The mixture was poured into 200 ml of water and the reaction was adjusted to pH 2 using concentrated aqueous hydrochloric acid, and the resulting residue was filtered off with suction. Purification by flash column chromatography (silica gel; ethyl acetate/n-hexane 1:1) gave 1.07 g (44% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.Cl[CH2:13][CH2:14][C:15]([NH:17][C:18]1[S:22][C:21]2[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=2[C:19]=1[C:27]([NH:29][CH3:30])=[O:28])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[I-].[K+]>[CH:8]([C:7]1[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][N:5]([CH2:13][CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[CH:6]=1)=[O:9]
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Reactant: CNC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(NC(=O)CCn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Reaction time: 168 h
Yield: 85 %

Procedure:
3-(Trifluoromethyl)-1H-pyrazole-4-carbaldehyde (437 mg, 2.66 mmol) and 2-(3-chloropropanamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (801 mg, 2.66 mmol) were dissolved in DMF (15 mL). Potassium carbonate (368 mg, 2.66 mmol) was added followed by potassium iodide (10 mg, 0.06 mmol). The reaction mixture was left to stand for 7 days. Water was added and the reaction mixture extracted into EtOAc (×3). The EtOAc layers were combined and washed with water (×5), brine, dried over MgSO4, filtered and the solvent removed in vacuo to give desired product as a yellow solid (970 mg, 2.26 mmol, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl-].[Cl-].[Cl-].[Al+3].O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
Suspend 4-cyanobenzoyl chloride (2.0 g, 12 mmol) in anhydrous toluene (30 mL). Add aluminum trichloride (2.4 g, 18 mmol) in three portions and stir the reaction mixture at ambient temperature overnight. Cool to 0° C., add carefully water and extract the mixture twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give a solid. Suspend the solid in diethyl ether and filter to obtain the desired intermediate (1.30 g, 49%) that was used without any further purification. GC-MS m/z: 221 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg+].[Br-].OS([O-])(=O)=O.[Na+]>CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[CH3:21])[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution of [4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (11 g, 38.4 mmol) in ether (200 mL), cooled to 0° C., was added MeMgBr (3M in ether, 32 mL, 96 mmol). The mixture was stirred 4 h at rt. 10% aq. NaHSO4 (200 mL) was carefully added. The two layers were decanted and the aq. layer was extracted with EA (100 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 2:1), affording the title methyl ketone as a white solid (7.4 g, 80% yield).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].BrCCBr.Cl[Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]3[C:41](=[O:42])[CH2:40][C:39]([CH3:44])([CH3:43])[O:38][C:27]3=[N:28][C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[CH:20][CH:19]=1>C1COCC1.CCOC(C)=O.[Zn]>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[C:26]3[C:41]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([OH:42])[CH2:40][C:39]([CH3:44])([CH3:43])[O:38][C:27]3=[N:28][C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[CH:22][CH:23]=1
Reactant: CC1(C)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCOC(=O)CC1(O)CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 65 °C

Procedure:
A mixture of ethyl 2-bromoacetate (0.334 mL 3.01 mmol), 1,2-dibromoethane (0.02 mL, 0.23 mmol), Zn powder (0.227 g, 3.47 mmol) and THF (2.5 mL) was heated to 65° C. for 2 min before cooling to rt. Chlorotrimethylsilane (0.015 mL, 0.116 mmol) was added and the reaction was stirred for 5 min at which point the product of Example 1 (1 g, 2.315 mmol) in THF 10 mL was added. The reaction was heated to 70° C. After 1 h the reaction was cooled to rt. The reaction was diluted with EtOAc and washed with 2 M aq HCl and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-10% EtOAc in CH2Cl2 affording the product (LC-2) HPLC/MS: 520.2 (M+1), 522.2 (M+3); Rt=3.97 min.