Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[CH2:12]1N2CCN(CC2)C1.CN(C=O)C>CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(ccn2C)c1
Temperature: 92.5 °C
Yield: 967 %

Procedure:
To a solution of 5-methoxyindole (1.0 g, 6.79 mmol) in DMC (10 mL), DABCO (0.076 g, 0.68 mmol) is added followed by DMF (2 mL). The resulting solution is heated to 90-95° C. for 7 h. The reaction is cooled to RT, and diluted with EtOAc (40 mL) and H2O (40 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×40 mL) and H2O (4×40 mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 5-methoxy-1-methylindole (about 1.06 g, 97%) as a solid: 1H NMR (CDCl3) δ7.21 (d, 1H), 7.09 (d, 1H), 7.00 (d, 1H), 6.87 (dd, 1H) 6.39 (d, 1H), 3.84 (s, 3H), 3.73 (s, 3H); 13C NMR (CDCl3) δ153.9, 132.1, 129.3, 128.7, 111.8, 109.9, 102.4, 100.3, 55.9, 32.9; MS m/z 161 [M+1]+.
Reaction SMILES: CO[C:3]([C:5]1[C:9]([S:10]([CH3:12])=[O:11])=[C:8]([NH2:13])[N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:6]=1)=[NH:4].Cl.[O:27]([NH2:29])[CH3:28]>CO>[NH2:13][C:8]1[N:7]([C:14]2[C:15]([Cl:25])=[CH:16][C:17]([C:21]([F:23])([F:24])[F:22])=[CH:18][C:19]=2[Cl:20])[N:6]=[C:5]([C:3](=[NH:4])[NH:29][O:27][CH3:28])[C:9]=1[S:10]([CH3:12])=[O:11]
Reactant: CON
Reactant: COC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Agent: Cl
Solvent: CO
Product: CONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 4 h
Yield: 27.2 %

Procedure:
To a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester (1.0 g) in anhydrous methanol was added anhydrous methoxylamine hydrochloride (0.2 g). After 4 hours at 20° C., the mixture was evaporated and dichloromethane and water added. The organic layer was dried (MgSO4), evaporated and chromatographed on a florisil column, eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-methylsulfinyl-1H-pyrazole-3-carboximidamide(0.28 g),m.p. 140-145° C.Compound 49. By proceeding in a similar manner the following compounds were prepared:5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidamide, m.p.169-170° C. Compound 41.; and 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-hydroxy4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidamide, m.p.222-224° C. Compound 40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C@:10]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:11]2[C@@H:12]2[C@@:25]([CH3:28])([CH2:26][CH2:27]3)[C@@:24]3([CH3:29])[C@@H:15]([C@:16]4([CH3:42])[C@@H:21]([CH2:22][CH2:23]3)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=3)=[CH:18][CH2:17]4)[CH2:14][CH2:13]2)[CH:5]=[CH:4][N:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].O[Li].O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C@:10]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:11]2[C@@H:12]2[C@@:25]([CH3:28])([CH2:26][CH2:27]3)[C@@:24]3([CH3:29])[C@@H:15]([C@:16]4([CH3:42])[C@@H:21]([CH2:22][CH2:23]3)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[CH:18][CH2:17]4)[CH2:14][CH2:13]2)[CH:5]=[CH:4][N:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCc3ccnc(F)c3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li]O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ccnc(F)c3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate, TFA (77.7 mg, 0.101 mmol) in THF (3 mL) was added a 0.753 molar aqueous solution of LiOH.H2O (0.539 mL, 0.405 mmol). The reaction mixture was heated to 75° C. After 4 h, the reaction mixture was concentrated. The crude residue was dissolved in THF (1.5 mL) and MeOH (200 μL), filtered and purified by reverse phase preparative HPLC using HPLC method 3 to give 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, TFA (30.6 mg, 0.037 mmol, 36.1% yield) as a white solid. LCMS: m/e 637.7 (M−H)−, 3.12 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=8.24 (d, J=5.2 Hz, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.43 (d, J=5.2 Hz, 1H), 7.24 (s, 1H), 7.20 (d, J=8.5 Hz, 2H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.78 (s, 1H), 4.17 (br. s., 2H), 2.78-2.69 (m, 1H), 2.18-2.10 (m, 2H), 2.09-2.01 (m, 2H), 1.98 (dd, J=3.1, 11.9 Hz, 1H), 1.96-1.88 (m, 1H), 1.83-1.76 (m, 1H), 1.72 (s, 3H), 1.70-1.64 (m, 1H), 1.63-1.40 (m, 10H), 1.39-1.31 (m, 1H), 1.31-1.23 (m, 2H), 1.13 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H). 13C NMR (1:1 CDCl3:MeOD) d ppm 15.3, 16.6, 17.4, 19.5, 20.6, 21.8, 22.2, 26.1, 27.6, 29.0, 29.5, 30.2, 33.9, 34.6, 37.2, 38.2, 38.4, 41.8, 42.8, 43.1, 45.7, 47.2, 49.7, 49.9, 50.3, 50.5, 53.9, 78.8, 123.1, 123.2, 124.9, 129.3, 129.7, 131.0, 147.4, 149.7, 164.0, 166.0, 170.1.
Reaction SMILES: C1([C@@H:4](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[N:5]2[CH2:10][CH2:9][C@:8]([CH2:17][C:18]([OH:21])(C)C)(C3C=CC=CC=3)OC2=O)CC1.Br[C:39]1[CH:44]=[CH:43][C:42]([C@H:45]([CH:64]2[CH2:66][CH2:65]2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])=[CH:41][CH:40]=1.BrC1C=CC(=O)N(C)C=1>>[CH:64]1([C@@H:45]([C:42]2[CH:43]=[CH:44][C:39]([C:9]3[CH:8]=[CH:17][C:18](=[O:21])[N:5]([CH3:4])[CH:10]=3)=[CH:40][CH:41]=2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])[CH2:66][CH2:65]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(Br)cc2)C2CC2)C(=O)O1
Agent: Cn1cc(Br)ccc1=O
Product: Cn1cc(-c2ccc([C@H](C3CC3)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccc1=O

Procedure:
The title compound was prepared from 3-{(S)-cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one {prepared in analogy to the intermediate in Example 3 from 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one} and 5-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.35 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:31])[N:14]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[CH3:35]O>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:19][CH2:18][CH2:17][CH:16]1[CH:15]([O:20][CH3:35])[N:14]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:13]2=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2CCCC(C(=O)N1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC1C2CCCC(C(=O)N1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
3-(2-Benzyloxyethyl)-2,4-dioxo-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 3, 0.46 g, 1.11 mmol) was dissolved in methanol (15 mL). The mixture was cooled to 0° C., and NaBH4 (0.06 g, 1.66 mmol) was added in portions from the top. The reaction was stirred for 10 minutes at 0° C., and then 4N HCl in dioxane was added to obtain a pH in the range of 1 to 2, and the reaction was stirred overnight at room temperature. The methanol was evaporated, and the residue was dissolved in EtOAc and poured into NaHCO3 saturated aqueous solution, then extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (10 mL), passed over a short plug of Na2SO4, and the solvents were evaporated to give Compound 4 (0.40 g, 85%, mixture of isomers) as a thick pale-yellow oil, which was of sufficiently good quality to be advanced to the next step without further purification. Rf (40% EtOAc/hexanes): 0.45.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7](#N)[CH:8]([CH3:10])[CH3:9].Cl.C([O:15]CC)C>C1COCC1>[CH3:4][CH:3]([C:2](=[O:15])[CH2:1][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:5]
Reactant: CCOCC
Reactant: CC(C)CCBr
Reactant: CC(C)C#N
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CCC(=O)C(C)C
Reaction time: 0.5 h

Procedure:
To a slurry of Mg turnings (3.89 g, 160 mmol) in dry diethyl ether (150 mL), a solution of isoamylbromide (24.59 g, 163 mmol) in diethyl ether (20 mL) is slowly added. As soon as the reaction starts, the mixture is cooled if necessary with a water bath. After complete addition, the mixture is stirred for 30 min, and is then added slowly to a cooled (0° C.) mixture of isobutyronitrile (34.65 g, 501 mmol) and CuBr (1.15 g, 8.0 mmol) in diethyl ether (50 mL) and THF (50 mL). After complete addition (30 min) the mixture is stirred at rt for 1 h before 1 N aq. NaH2PO4 (50 mL) and 1N aq. HCl (100 mL) is added. Stirring is continued at rt for 15 min. The phases are separated and the aq. phase is extracted with additional diethyl ether (100 mL). The combined organic extracts are washed with aq. 1N aq. HCl (2×50 mL), sat. aq. NH4Cl/sat. aq. NaHCO3 1:1 (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and evaporated to give crude 2,6-dimethyl-heptan-3-one (20.1 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10]Cl.[C-:12]#[N:13].[K+].COC(C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: Cc1cc(CCl)c(Cl)cc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: Cc1cc(CC#N)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
To a solution of 1,5-dichloro-2-chloromethyl-4-methylbenzene (CAS #101349-87-5, 5.22 g) in dimethyl sulfoxide (20 ml) was added potassium cyanide (1.36 g) and the reaction solution was stirred at room temperature for 6 hours. Potassium cyanide (0.68 g) was added to the reaction solution and the solution was further stirred at room temperature overnight. To the reaction solution were added ice-cold water and tert-butyl methyl ether and the organic layer was separated. The water layer was re-extracted by the tert-butyl methyl ether. The combined organic layer was sequentially washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Walcogel™ C-200; elution solvent:heptane:ethyl acetate 49:1→19:1) to obtain the title compound (1.88 g). The property values of the obtained compound are as follows; 1H-NMR (CDCl3) δ (ppm): 2.38 (s, 3H), 3.78 (s, 2H), 7.38 (s, 1H), 7.43 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]=[C:24](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:23][N:22]=[C:21]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:20]=2[CH:48]=1.C(O)(=O)C>O1CCCC1.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]3[CH:8]=[N:7][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:24]3[CH2:23][N:22]=[C:21]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:20]=2[CH:48]=1
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)(N1CCOCC1)N1CCOCC1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Reaction time: 0.17 h

Procedure:
Potassium t-butoxide, 1.4 g (0.0125 mole), was added to a solution of 1.4 g (0.0124 mole) of ethyl isocyanoacetate in 125 ml of dry tetrahydrofuran. After stirring under argon for 10 minutes, 5.07 g (0.01 mole) of 7-chloro-2-[bis(morpholino)-phosphinyloxy]-5-(2-fluorophenyl)-3H-1,4-benzodiazepine was added and stirring was continued for 30 minutes at room temperature. The reaction mixture was then acidified with glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from ether yielded crystals which were recrystallized from methylene chloride/ether/hexane for analysis, mp 195°-196°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31]([S:35]([Cl:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[ClH:38].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:39])[F:40])[CH:30]=3)(=[O:37])=[O:36])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Product: CS(=O)(=O)Nc1cc(N2CCCNCC2)ccc1NS(=O)(=O)c1cccc(C(F)(F)F)c1
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)- phenyl}methanesulfonamide and 3-trifluoromethylbenzenesulfonylchloride (111 mg, 0.455 mmol) to give before Boc-deprotection 145 mg of a purple solid. M+1 493.1 Calcd 493.11.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[NH4+:15].[OH-]>CC#N.O>[NH2:15]/[C:4](/[O:3][CH2:1][CH3:2])=[CH:5]\[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: CCOC(=CC(=O)C(F)(F)F)OCC
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCO/C(N)=C/C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one (7.94 g, 37.4 mmol) in MeCN (30 mL) at room temperature was dropped 28% solution of NH4OH in water (7 mL). It was stirred at room temperature overnight. After solvent was removed under reduced pressure, to it was added CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one as solid (6.371 g, 93%). 1H NMR (300 MHz, CDCl3) δ 9.79 (br, 1H), 5.66 br, 1H), 5.13 (s, 1H), 4.15 (q, 2H), 1.38 (t, 3H); LC-MS (ESI) m/z 184 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:23])=[C:4]([CH3:24])[N:3]=1.[CH:25]([C:28]1[CH:36]=[CH:35][C:34]2[NH:33][N:32]=[CH:31][C:30]=2[C:29]=1B(O)O)([CH3:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].O>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:25]([C:28]1[C:29]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][O:13][C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=3[CH3:23])=[C:4]([CH3:24])[N:3]=2)=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2)([CH3:27])[CH3:26]
Reactant: CC(C)c1ccc2[nH]ncc2c1B(O)O
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C(C)C)ccc3[nH]ncc23)c2ccccc12
Temperature: 100 °C
Yield: 44.1 %

Procedure:
A solution of 1-chloro-4-chloromethyl-3-methyl-isoquinoline (150 mg, 0.66 mmol) is added to a mixture of carvacrol (199 mg, 1.33 mmol) and CsCO3 (645 mg, 1.98 mmol) in DMF (8 ml). After stirring overnight at room temperature, water is added and the mixture is extracted with ether. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is chromatographed on silica gel to give 220 mg of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline. A mixture of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline (220 mg, 0.65 mmol), 5-isopropylindazole-4-boronic acid (173 mg, 0.85 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol), and Na2CO3 (1.3 ml of 2M in H2O) in dioxane (8 ml) The mixture is heated for 18 h at 100° C. After cooling to room temperature, water is added and the resulting mixture is extracted with EtOAc. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel to give 133 mg of 1-(5-isopropyl-1H-indazol-4-yl)-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline
Reaction SMILES: C([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[C:4]=1[CH2:16][CH3:17])C.[Br:18]N1C(=O)CCC1=O.C1(=O)O[CH:29]([CH3:30])CO1>O>[Br:18][C:3]1[CH:4]=[CH:16][C:17]2[C:11]3[C:12](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:13]([CH2:29][CH3:30])([CH2:5][CH3:6])[C:14]=2[CH:15]=1
Reactant: CC1COC(=O)O1
Reactant: CCc1ccc2c(c1CC)Cc1ccccc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Product: CCC1(CC)c2ccccc2-c2ccc(Br)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a solution of diethylfluorene (22.2 g., 0.1 mol.) in propylene carbonate (100 ml), N-bromosuccinimide (17.8 g., 0.1 mol.) was added at 57° C. in portions and the mixture was stirred for 30 minutes at 60° C. The mixture was diluted with 1200 ml of water and extracted with 500 ml of toluene. The toluene extract was washed 3 times with 300 ml portions of water, dried and concentrated. The crude product from 3 batches of the same size totaled 117 g. of oil. This was distilled at 2 mm. The first fraction, b.p. 90-93° C., 22.33 g. was found to be propylene carbonate. The second fraction, b. p. 155-165° C., 81.0 g. (89.7% yield) was the desired product. Mass Spec: (m/z): 300, 302 (M+).
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.C[Li].C(OCC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].[C:21]1(=[O:27])[CH2:26]C[CH2:24][CH:23]=[CH:22]1>O1CCCC1.[Cu](I)I>[CH3:16][Si:17]([CH3:19])([CH3:18])[O:27][C:21]1[CH2:22][CH2:23][CH2:24][CH:3]([CH3:4])[CH:26]=1
Reactant: CN(C)CCN(C)C
Reactant: O=C1C=CCCC1
Reactant: C[Si](C)(C)Cl
Agent: I[Cu]I
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1C=C(O[Si](C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.9 %

Procedure:
Under nitrogen atmosphere, a suspension of N,N,N′,N′-tetramethylethylenediamine (0.94 mL, 6.24 mmol) and copper iodide (0.42 g, 2.18 mmol) in anhydrous tetrahydrofuran (4 mL) was stirred at room temperature for 5 minutes. The reaction mixture was cooled to −78° C. and a 1.6 M methyl lithium solution in diethyl ether (1.30 mL, 2.08 mmol) was added. After stirring for 20 minutes at the same temperature, trimethylsilyl chloride (0.66 mL, 5.20 mmol) and a solution of cyclohexenone (0.20 g, 2.08 mmol) in anhydrous tetrahydrofuran (2 mL) were added. The reaction mixture was stirred 20 minutes at −78° C. and quenched with a saturated solution of ammonium chloride (10 mL). Diethyl ether (20 mL) was added and the mixture was allowed to reach room temperature. Layers were separated and the organic layer was successively washed with 0.5N hydrochloric acid (15 mL), and a saturated solution of sodium bicarbonate (15 mL), then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane) to provide trimethyl[(3-methylcyclohex-1-en-1-yl)oxy]silane (17a) (0.20 g, 1.08 mmol, 52%).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13]O)[O:10][N:9]=1)=[O:7])[CH3:4].CCN(CC)CC.S([Cl:26])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][Cl:26])[O:10][N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc(CO)on1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-hydroxymethyl-isoxazole-3-carboxylic acid ethyl ester (3.00 g, 17.53 mmol) in dry CH2Cl2 (30.0 mL) was treated at 0° C. with Et3N (3.17 mL, 22.79 mmol) followed by DMAP (214 mg, 1.75 mmol) and Ms-Cl (2.04 mL, 26.29 mmol). The reaction mixture was stirred at rt for 4 h before being quenched with water (50 mL), extracted with CH2Cl2 (50 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 5-chloromethyl-isoxazole-3-carboxylic acid ethyl ester as an orange oil. A solution of 1.01 g of this crude material in acetone (8.0 mL) was treated, under inert atmosphere (N2) with K2CO3 (1.260 g, 9.12 mmol) followed by 4-nitro-1H-pyrazole (343 mg, 3.04 mmol) and TBA bromide (195 mg, 0.61 mmol). The resulting mixture was stirred at rt overnight. Water (50 mL) and EA (50 mL) were added. The aq. layer was extracted with EA (50 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 hept-EA)=0.31. LC-MS-conditions 02: tR=0.86 min.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10](=[S:13])[S:9][C:8]=2[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2].C(OO)(=[O:20])C>C(Cl)(Cl)Cl>[N+:1]([C:4]1[C:12]2[S:11][C:10](=[S:13]=[O:20])[S:9][C:8]=2[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2sc(=S)sc12
Reactant: CC(=O)OO
Solvent: ClC(Cl)Cl
Product: O=S=c1sc2cc(C(F)(F)F)cc([N+](=O)[O-])c2s1

Procedure:
To a stirred solution of 7.35 g., (24.7 mmoles) of 4-nitro-6-trifluoromethyl-1,3-benzodithiole-2-thione in 150 ml. of chloroform was added dropwise a solution of 5.17 g., (24.7 mmoles) of 40% peracetic acid in 50 ml. of chloroform over a period of 20 minutes, the temperature being maintained at 8°-12° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.O>ClC(Cl)(Cl)Cl.ClC(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(=O)NS(C)(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)NC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a solution of 4-methyl-N-(methylsulfonyl)benzamide (Preparation 55, 550 mg, 2.58 mmol) in tetrachloromethane (10 mL) was added N-bromosuccinimide (459 mg, 2.58 mmol) and diphenylperoxyanhydride (62.5 mg, 0.258 mmol) and the mixture was heated at reflux under nitrogen for 4 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with DCM (50 mL). The organic layer was dried over magnesium sulphate and evaporated in vacuo to yield a cream solid. The solid was re-dissolved in trichloromethane (10 mL), diphenylperoxyanhydride (62 mg, 0.25 mmol) and N-bromosuccinimide (300 mg, 1.69 mmol) were added and the mixture heated at reflux for 6 hours then cooled to room temperature and evaporated in vacuo. The resulting residue was partitioned between DCM (50 mL) and water (50 mL), the aqueous further extracted with DCM (50 mL) and the combined organics dried over magnesium sulphate and concentrated in vacuo to yield a cream solid (625 mg). A portion of this material was purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound as a white solid (25 mg).