Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH2:19]([S:21]([NH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:22])[CH3:20]>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:29]3[CH:30]=[C:25]([NH:24][S:21]([CH2:19][CH3:20])(=[O:22])=[O:23])[CH:26]=[CH:27][CH:28]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Product: CCS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3c(Cl)cccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 3-ethanesulfonylaminophenylboronic acid (79 mg, 0.344 mmol), affords 112 mg (84%) of a mixture of geometric isomers of the title compound (Example 208(a)) as a yellow solid (MS (ES) 424 (M+H); HPLC shows 94% purity). Separate geometric isomers using a chromatatron rotor (10% ethyl acetate/hexanes) to afford 13 mg (10%) of the Z-isomer (Example 208(b)) of the title compound as a white solid, (MS (ES) 424 (M+H), 422 (M−H). HPLC shows 96% purity). Continue to elute and isolate 6 mg (5%) of the E-isomer (Example 208(c))of the title compound as a white solid (MS (ES) 424 (M+H), 422 (M−H); HPLC shows 97% purity).
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:6]([NH:8][C@H:9]([C:14](OC)=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])[CH2:3][CH2:4][CH3:5].[NH3:25]>CO>[C:21]([O:20][C:18]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:25])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])[CH2:3][CH2:4][CH3:5])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)OC
Reactant: N
Solvent: CO
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(N)=O
Reaction time: 8 h

Procedure:
1.81 g (5 mmoles) of BOC-Nva-Met-OMe are dissolved in 20 ml of methanol, and gaseous ammonia is introduced into the solution for 0.5 hours under ice cooling. The reaction mixture is allowed to stand at room temperature overnight, and then stored in a cold place for some hours. The separated crystalline product is filtered off to obtain 1.27 g of the desired product. The filtrate is evaporated, and the residue is recrystallized from 5 ml of ethanol to obtain further 0.35 g of the product. Thus 1.62 g (93%) of BOC-Nva-Met-NH2 are obtained; m.p.: 166°-167° C., Rf2 =0.57, [α]D25 =-40.9° (c=1%, in methanol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][N:22]([C:27](SC)=[N:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:38][NH2:39]>CN(C=O)C>[CH3:38][NH:39]/[C:27](=[N:28]\[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[N:22]1[CH2:23][CH2:24][C:25]2[N:26]=[C:18]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])[S:19][C:20]=2[CH2:21]1
Reactant: CSC(=Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)sc2C1
Reactant: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CN/C(=N\c1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)sc2C1

Procedure:
A solution of methyl 2-({2-[(tert-butoxycarbonyl)amino]phenyl}carbamoyl)-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbimidothioate obtained form step I (1 eq), and methylamine HCl (60 eq) in DMF was heated at 50° C. in a sealed tube for 72 h. Solvent was evaporated and the residue was purified by either column chromatography or preparative HPLC to afford the tert-butyl {2-[({5-[(E)-(methylamino)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}carbonyl)amino]phenyl}carbamate
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Clc1ccccc1CBr
Product: Nc1nc(N)c2c(N3CCN(Cc4ccccc4Cl)CC3)cccc2n1
Yield: 63 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-Chlorobenzyl bromide (76 mg; 0.37 mmol) to obtain 46.6 mg. (63% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 1H), 10.1 (s, 1H), 9.0 (s, 1H), 7.72 (t, J=8.0 Hz, 2H), 7.52 (m, 1H), 7.45 (m, 1H), 7.34 (m, 3H), 7.22 (d, J=8.0 Hz, 1H), 3.68 (s, 2H), 3.03 (br d, J=10.8 Hz, 2H), 2.93 (m, 4H), 2.41 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH:21]=O)=[N:15][NH:16]2>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:21]([C:14]3[C:13]4[C:17](=[CH:18][CH:19]=[CH:20][C:12]=4[F:11])[NH:16][N:15]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=Cc1n[nH]c2cccc(F)c12
Reactant: Cc1cc(N)c(N)cc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3n[nH]c4cccc(F)c34)[nH]c2cc1C
Temperature: 120 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A mixture of 4,5-dimethylbenzene-1,2-diamine (70 mg) and 4-fluoro-1H-indazole-3-carbaldehyde [80 mg, Reference Example 20(b)] in dimethylformamide (8 ml) was heated to 120° C. for 30 minutes and then at 100° C. for 16 hours. The reaction mixture was cooled, then diluted with ethyl acetate and then washed five times with brine. The organic phase was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluding with a mixture of 40/60 petrol and ethyl acetate (1:5, v/v) to give 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole (104 mg) as a light brown solid. MS: 281 (M+H)+. HPLC (METHOD B1): RT=10.08 minutes. (b) 4-Chloro-3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([OH:15])[C:9]=1[F:16])[O:6][CH3:7])C.O[Li].O>C1COCC1.CO.O>[F:16][C:9]1[C:10]([OH:15])=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[CH:5]([O:6][CH3:7])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(OC)c1c(F)ccc(O)c1F
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(C(=O)O)c1c(F)ccc(O)c1F
Yield: 93.4 %

Procedure:
A solution of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-methoxy-acetic acid ethyl ester (11.6 g) and LiOH.H2O in THF (40 ml), MeOH (40 ml) and H2O was stirred 2 h at 65° C. The organic solvents were evaporated, H2O was added (50 ml) and the pH was lowered with 2 N HCl to pH=2. The product was extracted with AcOEt (3×50 ml). The organic layers were washed with brine (100 ml), combined and dried (Na2SO4). Evaporation of the solvent afforded 9.6 g (94%) of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-methoxy-acetic acid. White solid. MS 217.1 ([M−H]−).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=[CH:9][C:10]=1[Cl:11])(=O)C>O.NN>[NH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CC(=O)Nc1cc(C2=NNC(=O)NC2C)ccc1Cl
Agent: NN
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(Cl)c(N)c1
Temperature: 100 °C
Yield: 94.9 %

Procedure:
A mixture of 6-(3-acetamido-4-chlorophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (34.75 g) and 100% hydrazine hydrate (100 ml) was heated at 100° C. for 3 hours. After cooling, the resulting crystals were recovered by filtration and washed with aqueous methanol to give 6-(3-amino-4-chlorophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (28.04 g).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])=O.[Na+].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH:27]=[O:28])=[CH:20][CH:19]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:28][CH:27]([CH2:26][CH2:25][S:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:29])([F:16])[F:30])=[CH:19][CH:20]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: O=CCCSc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 75.9 %

Procedure:
7.55 Grams of methyl acetoacetate were dissolved in 10 ml of water, and 9.1 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.35 g of sodium formate and 1.61 g of tetrabutylammonium bromide were added thereto and then 54.0 g of a toluene solution containing 17.4% of 3-(4-trifluoromethylphenylthio)propanal were added thereto. The mixture was stirred at 45°-50° C. for 10 hours and then at room temperature for 4 hours. After the mixture had been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 14.88 g of crude 4-hydroxy-6-(4-trifluoromethylphenylthio)2-hexanone (purity: 74.5%, yield: 75.9%).
Reaction SMILES: C(OC(C)(C)C)(=O)C=C.C(O[C:18]([N:20]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32](C)[CH3:33])[CH:24]=1)C)=O)C1C=CC=CC=1.C(OC(N(CC1C2C(=CC=CC=2)N(CC2C=CC=CC=2)C=1)C)=O)C1C=CC=CC=1>>[CH2:32]([N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][NH:20][CH3:18])=[CH:24]1)[CH3:33]
Reactant: CC(C)n1cc(CN(C)C(=O)OCc2ccccc2)c2ccccc21
Agent: C=CC(=O)OC(C)(C)C
Agent: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Product: CCn1cc(CNC)c2ccccc21
Yield: 87.3 %

Procedure:
According to the procedure of Preparation 17 (c), except substituting 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-isopropyl-1H-indole (0.99 g, 2.98 mmole) for the 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole, the title compound (0.49 g, 82%) was prepared as a white solid: MS (ES) ml/e 405 (2M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:14])[O:5][C:6]1[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]([F:12])=[CH:8][C:7]=1[Cl:13])[CH3:2]
Reactant: CCOC(=O)Oc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of the product from Example 73A (0.88 g, 4.03 mmol) in concentrated sulfuric acid (2 mL) cooled in an ice bath was added fuming nitric acid (0.27 mL, 6.45 mmol) slowly to maintain the temperature at 0° C. The mixture was stirred for an additional 2 hours, then ice water (10 mL) was added to the solution and the resultant solid was collected by filtration washed with water and dried in a vacuum oven to provide the title compound (0.87 g, 82%).
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[NH:7])[NH2:6].CCO/[CH:21]=[C:22](/[CH:24]=O)\[CH3:23].C[O-].[Na+]>CO>[CH3:24][C:22]1[CH:21]=[N:7][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:23]=1
Reactant: CCO/C=C(\C)C=O
Reactant: COC(=O)c1cccc(C(=N)N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(-c2ncc(C)cn2)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
2.41 g (10 mmol) of methyl 3-carbamimidoylbenzoate acetate are suspended in 40 ml of methanol, 1.31 ml (11 mmol) of 3-ethoxymethacrolein and 2.04 ml of 30% sodium methoxide in methanol are added, and the mixture is stirred at 50° C. for 15 h. The reaction mixture is evaporated to dryness, and 100 ml of water are added. The precipitate formed is filtered off with suction and dried in vacuo. The crude product is reacted further without further purification; product: 1.65 g; ESI: 229 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:38]1[CH2:42][CH2:41][C:40]2([CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:39]1)=O)(C)(C)C>>[CH2:39]1[C:40]2([CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:42][N:38]1[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCC5(CCNC5)C4)c3)nc12

Procedure:
1-{2-[3-(2,7-Diaza-spiro[4.4]non-2-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=404.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13]OC1C=CC(B(O)O)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:24]([C:27]1[CH:32]=[CH:31]C(CCC(O)=O)=[CH:29][CH:28]=1)([OH:26])[OH:25].C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][CH2:12][C:13]1[CH:31]=[CH:32][C:27]([B:24]([OH:26])[OH:25])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: O=C(CCCOc1ccc(B(O)O)cc1)OCc1ccccc1
Agent: BrCc1ccccc1
Product: O=C(CCc1ccc(B(O)O)cc1)OCc1ccccc1
Yield: 62 %

Procedure:
Using a procedure analogous to that used to prepare 1B, 3-(4-boronophenyl)propanoic acid (388 mg, 2.00 mmol) was reacted with benzyl bromide to afford 4A (355 mg, 62%) as a white solid. 1H NMR (400 MHz, tetrahydrofuran-d8) δ 2.71 (t, J=7.9 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 5.10 (s, 2H), 7.25-7.35 (m, 5H), 8.12 (d, J=7.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:16]2[CH:24]=[CH:25][CH:26]=[C:15]2[CH2:14]1)=[O:12])[C:5]([NH2:7])=[O:6].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>>[CH3:29][N:30]([CH:32]=[N:7][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][N:16]3[CH:24]=[CH:25][CH:26]=[C:15]3[CH2:14]2)=[O:12])=[C:2]([Cl:1])[CH:3]=1)[CH3:31]
Reactant: NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1

Procedure:
The title compound was prepared in the same manner as described in Example 80, employing 3-chloro-4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzamide (1.83 g) and dimethylformamide dimethylacetal (5.3 ml), MS (EI), m/z::420 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH:17]=[CH2:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-:27].[K+].Cl.[OH2:30]>>[CH3:1][C:2]1[C:3]([CH:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH:17]=[CH2:18])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1.[CH3:1][C:2]1[C:3]([CH:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]([OH:30])=[O:27])=[CH:21][CH:20]=2)[CH:17]=[CH2:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: [OH-]
Reactant: O
Agent: C=CC(c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Product: C=CC(c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A suspension of the derivative (E) 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-propenyl]benzonitrile (0.22 g, 0.64 mmol) prepared previously in alcoholic potassium hydroxide (0.94 g, 16.8 mmol KOH in 0.55 ml H2O and 3.3 ml EtOH) is heated to 70° C. under magnetic stirring for 6 hours. The progress of the reaction is followed by HPLC. After cooling of the reaction medium, it is taken up in water (50 ml), acidified by 1N HCl, extracted with ether (4×20 ml) and the ether phase dried with MgSO4, filtered and evaporated to obtain a raw product which is purified by washing with hexane. After drying at 50° C. (3 hours) in a desiccator under vacuum, 0.18 g of a whitish product, the acid (E) pure 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-propenyl]benzoic acid is obtained (yield=75%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].Br[CH2:11][C:12]1[CH:24]=[CH:23][C:15]2[S:16][C:17]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:18][C:14]=2[CH:13]=1>CN(C=O)C>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][CH2:11][C:12]1[CH:24]=[CH:23][C:15]2[S:16][C:17]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:18][C:14]=2[CH:13]=1
Reactant: CN(C)CCS
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCSCc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a stirred solution of 2-dimethylaminoethanethiol hydrochloride (14.17 g, 0.10 mol) in 125 ml of dry DMF was added portionwise 60% sodium hydride in mineral oil (8.0 g, 0.2 mol) under a nitrogen atmosphere over 1/2 hour with warming on the steam bath. The mixture was stirred an additional 1/2 hour and then cooled in ice. To the cold suspension was added dropwise a solution of 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (7.66 g, 0.025 mol) in 25 ml of DMF. The mixture was stirred for an additional 1 hour at ice bath temperature. The mixture was filtered and the filtrate was concentrated in vacuo at 0.5 mm at room temperature. The solid residue was combined with the filtered solid and was dissolved in 3N HCl (100 ml). The acid solution was extracted with CHCl3 (3×50 ml), neutralized with NaHCO3 and concentrated to dryness in vacuo. The residual solid was extracted with CHCl3 (3×100 ml). The CHCl3 extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature. The solid obtained contained some polar inpurity which was removed by trituration with hot water. There was recovered 2.8 g of product (Yield 34%); m.p. 132-133%.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:39])[C@H:6]([O:14][C:15]1[C:20]([Br:21])=[CH:19][C:18]([C:22]2[C:34]3[C:33]([CH3:35])=[C:32]([CH3:36])[S:31][C:30]=3[C:29]([Br:37])=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[CH:27]3)=[CH:17][C:16]=1[Br:38])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>C1COCC1>[Br:21][C:20]1[CH:19]=[C:18]([C:22]2[C:34]3[C:33]([CH3:35])=[C:32]([CH3:36])[S:31][C:30]=3[C:29]([Br:37])=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[CH:27]3)[CH:17]=[C:16]([Br:38])[C:15]=1[O:14][C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:39])=[O:4]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(Br)c3)c2c1C
Yield: 94.5 %

Procedure:
Aqueous potassium hydroxide (1 N, 2.00 mL, 2.00 mmol) was added to a stirred solution of (R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionic acid methyl ester (0.699 g, 0.99 mmol) in THF (12 mL)/methanol (7mL). After 3 h the solution was concentrated, diluted with water (100 mL) and acidified with 10% aqueous HCl. The solid was filtered, washed with water and triturated with petroleum ether and dried in vacuo to provide the title compound as a white solid (0.645 g, 94%): [a]D25=+14.29° (8.75 mg(m CHCl3); NMR (DMSO-d6); δ 8.19 (d, J=8 Hz, 1H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.61 (s, 2H), 7.52 (ddd, J=8, 7, 1 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.38-7.20 (m, 5H), 5.27 (t, J 7 Hz, 1H), 3.37 (dd, 14, 6 Hz, 1H), 3.28 (dd, 14, 7 Hz, 1H), 2.43 (s, 3H), 1.59 (s,3H); MS (+FAB): 3 bromine isotope pattern 686 (20%), 688 (75%), 690 (75%), 692 (25%); Anal. Calc. for C29H21Br3O3S: C, 50,53, H, 3.07, N, 0.00. Found: C, 50.04, H, 3.11, N, 0.05.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:9]=[N:8][N:7]([CH3:10])[C:6]=1[C:11]([OH:13])=O)=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][N:19]2[CH:22]=[C:23]([C:25]3[CH:26]=[C:27]([O:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=3)[N:24]=[C:18]2[N:17]=1>>[C:32]([O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[N:24]=[C:18]3[N:17]=[C:16]([NH:15][C:11]([C:6]4[N:7]([CH3:10])[N:8]=[CH:9][C:5]=4[C:3](=[O:4])[N:2]([CH3:1])[CH3:14])=[O:13])[CH:21]=[CH:20][N:19]3[CH:22]=2)[CH:26]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Oc1cccc(-c2cn3ccc(N)nc3n2)c1
Reactant: CN(C)C(=O)c1cnn(C)c1C(=O)O
Product: CC(=O)Oc1cccc(-c2cn3ccc(NC(=O)c4c(C(=O)N(C)C)cnn4C)nc3n2)c1

Procedure:
The title compound was prepared in analogy to example 82, step 3, from 4-dimethylcarbamoyl-2-methyl-2H-pyrazole-3-carboxylic acid (step 2, example 85; 44.1 mg, 224 μmol) and acetic acid 3-(7-amino-imidazo[1,2-a]pyrimidin-2-yl)-phenyl ester (50 mg, 186 μmol). Yield: 53 mg (60%). Yellow solid. MS (m/z)=448.2 [M+H+].
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([O:12]C1CCCCO1)[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].O1CCCC1CC(O)=O.O>>[Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C)(C)C(/C=C/Br)OC1CCCCO1
Agent: O=C(O)CC1CCCO1
Solvent: O
Product: CCCCC(C)(C)C(O)/C=C/Br

Procedure:
A mixture of 3.19 g. (10 moles of 1-bromo-4,4-dimethyl-3-tetrahydropyranyloxy-trans-1-octene (Example 1173) and 90 ml. of 3:1:1 tetrahydrofuran-acetic acid-water is stirred at ambient temperatures for 20 hours. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel. The title compound is isolated using 10-20% ethyl acetate in benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].[Br:28]Br>C(O)(=O)C>[Br:28][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:5]([CH3:27])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[C:12]=2[CH:11]=1
Reactant: BrBr
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(Cl)cc3C2C)cc1
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccc(Cl)cc3C2C)cc1
Yield: 61.3 %

Procedure:
The title compound was prepared from 8-chloro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.95 g, 2.38 mmol), bromine (0.12 mL, 9.50 mmol), and glacial acetic acid (24 mL) according to the procedure and in the same manner as described in Example 4, step a. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:3 to 1:1 gradient) to yield 2-bromo-8-chloro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.70 g, 1.46 mmol, 61%) as a white solid;
Reaction SMILES: [F:1][C:2]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7].[CH3:29][O:30][CH2:31][CH2:32][CH2:33]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:1][C:2]1[C:26]([O:27][CH2:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(O)c1F
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(OCCCOC)c1F
Yield: 97 %

Procedure:
This compound was prepared from (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2,6-difluoro-3-hydroxy-benzyl) ester and toluene-4-sulfonic acid 3-methoxy-propyl ester according to the procedure described in Example 207 to give the product as a colorless oil (117 mg; 97%); MS (ISP): 490.4 (M+NH4)+.