Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38](Br)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])[CH3:28].CN(C=O)C>C(OCC)C.[Cu]I.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>[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:33]=1)=[O:31])[CH3:28]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
6-Chloro-3-tributylstannyl-1H-indazole (1.04 g, 2.35 mmol), copper(I) iodide (17 mg, 0.09 mmol,) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (400 mg, 0.90 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with bubbling nitrogen for 10 min, then tetrakis(triphenylphosphine)palladium (0) (52 mg, 0.045 mmol) was added and the reaction was stirred under nitrogen at 90° C. for 15 h. The reaction mixture was cooled, diluted with diethyl ether (60 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane with 0.5% ammonium hydroxide) to afford 300 mg (65%) of 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a foaming solid. MS: (M+H)+=516.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[Cl:22][CH2:23][C:24]([CH2:26]Cl)=[CH2:25]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:26][C:24]([CH2:23][Cl:22])=[CH2:25]
Reactant: C=C(CCl)CCl
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CCl)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
20 g of 2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenol and 28.8 g of potassium carbonate are introduced into 150 ml of acetonitrile. 26 g of 3-chloro-2-chloromethyl-propene are then added and the mixture is stirred for 2.5 hours at 80° C. The reaction mixture is cooled to room temperature and filtered, and the filtrate is concentrated. After purification over silica gel, 1,3-dichloro-2-(2-chloromethyl-allyloxy)-5-(3,3-dichloro-allyloxy)-benzene is obtained.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I-:16].[Na+]>CC(C)=O>[I:16]/[CH:2]=[CH:3]/[C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(Cc1ccccc1)C(=O)/C=C/Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccccc1)C(=O)/C=C/I

Procedure:
A solution of 5.7 g. of 1-chloro-4,4-dimethyl-5-phenyl-trans-1-penten-3-one in 30 ml. of dry acetone was treated with 4.3 g. of sodium iodide and refluxed under nitrogen for 20 hours. The mixture was cooled, filtered and evaporated. The residue was dissolved in ether, washed with water and dried with magnesium sulfate. Evaporation of the solvent gave 7.6 g. of the title product as an oil, λmaxfilm 3.5, 5.91, 6.4, 6.68, 6.80, 7.7, 9.3, 9.56, 10.0, 10.58, 13.4 and 14.2 μ.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:24])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[N:18]=1)[CH3:11].[H-].[Na+].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](OS(C)(=O)=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].O>CN(C=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([N:22]2[CH:23]=[C:19]([C:17]3[CH:16]=[N:15][C:14]([NH2:24])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[N:18]=3)[CH:20]=[N:21]2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: C[C@@H](Oc1nc(-c2cn[nH]c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Oc1nc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-(1H-pyrazol-4-yl)-pyrazin-2-ylamine (295 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added NaH (60% in mineral oil, 30.7 mg, 0.80 mmol). The mixture was stirred at ambient temperature under nitrogen for 0.5 h, and then 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (223.5 mg, 0.80 mmol) was introduced. The reaction mixture was heated to 90° C. oil bath for 0.5 h under nitrogen, and cooled to ambient temperature. Water was added slowly to the mixture, which was extracted with EtOAc, washed with brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (265 mg, 59% yield).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]1=2.Cl>C(O)(C)C>[N:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[CH2:2][C:3]3[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=3[O:5][C:6]=12
Reactant: OC1c2ccccc2Oc2ncccc21
Agent: Cl
Solvent: CC(C)O
Product: c1ccc2c(c1)Cc1cccnc1O2
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of 10 g of 5-hydroxy-5H-[1]benzopyrano[2,3-b]pyridine, 100 ml of isopropyl alcohol and 10 ml of 20% hydrochloric acid in isopropyl alcohol is refluxed for 3 hours, and the reaction mixture is allowed to stand overnight. The isopropyl alcohol is distilled off under reduced pressure, an aqueous carbonate solution is added to the residue, and then the mixture is extracted with chloroform. The chloroform layer is dried, and the chloroform is distilled off. The residue is recrystallized from isopropyl alcohol to give 7.5 g of 5H-[1]benzopyrano[2,3-b]pyridine as white crystals melting at 87°-88°C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To 2-chloro-5-nitroaniline (2 g, 11.59 mmol) in pyridine (5 mL) at room temperature was added 4-methylbenzoyl chloride (1.6 mL, 12.17 mmol), followed by pyridine (5 mL). The mixture was then stirred at room temperature for 16 h. Ethyl acetate was then added to the solution to give a precipitate, which was filtered off and washed twice with ethyl acetate, and then hexanes. The resulting solid was then washed with aqueous sodium bicarbonate, 1M aqueous sodium hydroxide, water and hexanes to afford (1.4 g, 42%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:35])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 54.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (80 mg, 0.30 mmol), potassium carbonate (84 mg, 0.61 mmol) and tert-butylbromoacetate (67 μL, 0.46 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 afforded 62 mg (62%) 3-(2-pyridyl)-5-(3-cyano-5-(2-tert-butoxy-2-oxoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.91 (t, 1H), 7.50 (t, 1H), 7.28 (s, 1H), 5.30 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][C:31]1(O)[CH2:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:31]2([CH3:30])[CH2:34][CH2:33][CH2:32]2)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Reactant: CC1(O)CCC1
Product: CC1(OC(=O)C#C[C@H]2[C@@H](C(=O)O[C@H](C#N)c3cccc(Oc4ccccc4)c3)C2(C)C)CCC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
Using the procedure of Step A of Example 15, 3.9 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 4.3 g of 1-methylcyclobutanol were reacted with stirring at 20° C. for 18 hours. The product was chromatographed over silica gel and was eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 2.7 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-(1-methyl-cyclobutoxycarbonyl)-ethynyl]-cyclopropane-carboxylate melting at 76° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:25]
Reactant: CCC(=O)c1ccc(B(O)O)c(C)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
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: [K+]
Solvent: COCCOC
Product: CCC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2C)c(C)c1
Temperature: 90 °C
Reaction time: 14 h
Yield: 81.2 %

Procedure:
2.5 g (13 mmol) of 2-methyl-4-propionylbenzeneboronic acid are placed in 100 ml of dimethoxyethane in a round-bottomed flask, and 2.2 g (10 mmol) of 2-bromo-4-nitrotoluene and 13 ml of aqueous 2M potassium carbonate solution are added. The medium is degassed for 10 minutes with a flow of nitrogen, and 580 mg (0.5 mmol) of tetrakis(triphenylphosphine)palladium are then added. The medium is stirred for 14 hours at 90° C. and then worked up as usual. The residue is obtained after chromatography on a column of silica (eluent: 1 ethyl acetate/9 heptane) to give 2.3 g (81%) of the expected product in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1.O>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
A solution of 1.48 g of 3-aminobenzene sulfonic acid in 1:1 tetrahydrofuran/water was treated at 0° C. with 1.43 g of sodium bicarbonate. After 5 min, 1.30 g of acetic anhydride was added dropwise and the reaction allowed to warm to ambient temperature under an atmosphere of nitrogen over 14 h. The reaction mixture was passed through a column of Amberlyst 15 ion exchange resin, eluted with water, and concentrated in vacuo to yield an oil which upon treatment with benzene and azeotropic removal of water in vacuo yielded 1.8 g of the title product as a white crystalline solid. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:12]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1ccc(F)cc1F)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2,4-difluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 413.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[CH:21]=[CH:20][S:19][C:18]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:20]1[S:19][C:18]([CH3:22])=[C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])[CH:21]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3ccsc3C)c(C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3cc(Br)sc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-thiophen-3-yl)-imidazo[1,2-b]pyridazine. (0.76 g, 2.42 mmol) and CH2Cl2 (10 mL) is added NBS (0.60 g, 3.37 mmol). The solution is stirred at ambient temperature for 2 hours and concentrated. The solution is dissolved in Et2O (30 mL) washed with water (3×30 mL), brine (30 mL) dried over MgSO4, filtered and concentrated to furnish the title compound (0.95 g, 2.42 mmol, >99%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.93 (m, 4H), 2.31 (s, 3H), 2.42 (s, 3H), 2.51 (s, 3H), 3.29-3.38 (m, 1H), 6.66 (s, 1H), 7.04 (s, 1H). LC/MS (m/z): calcd. for C18H22BrN3S (M+H)+: 392.2; found: 392.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([B:7]([OH:9])[OH:8])[S:5][CH:6]=1.[CH3:10][C:11]([CH2:15]O)([CH2:13]O)[CH3:12]>>[CH3:10][C:11]1([CH3:15])[CH2:13][O:9][B:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)[O:8][CH2:12]1
Reactant: Cc1csc(B(O)O)c1
Reactant: CC(C)(CO)CO
Product: Cc1csc(B2OCC(C)(C)CO2)c1
Yield: 60 %

Procedure:
The title compound (60%, yellow crystals) was prepared from 4-methylthiophen-2-boronic acid and neopentylglycol.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Yield: 69.7 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (2.00 g, 8.03 mmol) and benzoic acid N′-isopropyl-hydrazide (1.72 g, 9.63 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (3.5 mL, 20.07 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 5.62 g, 12.04 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (2.29 g, 70%).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([CH3:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21][CH2:22][O:23][CH3:24])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].[CH3:26]C([N-]C(C)C)C.IC>C1COCC1>[CH2:1]([C:5]12[CH2:17][C:16]([CH3:26])([CH3:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21][CH2:22][O:23][CH3:24])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)C2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)(C)C2
Temperature: -78 °C

Procedure:
A solution of (2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (39 mg, 0.12 mmol) in anhydrous THF (1.0 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated with 0.4M LDA in THF (0.39 mL, 0.16 mmol). After stirring at 0° C. for 30 minutes, the yellow solution was cooled to −78° C. and treated with iodomethane (0.037 mL, 0.6 mmol). The resulting mixture was allowed to gradually warm to room temperature, then stirred at room temperature overnight. Workup as described in Example 18, step 2, afforded a crude product which was purified by PLC on a 0.1×20×20 cm silica gel GF plate, using 10:1 hexanes-EtOAc as developing solvent. The band at Rf 0.18-0.24 afforded 9a-butyl-7-methoxymethoxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (28 mg) as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21]OS(C)(=O)=O.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CC#N>[N:27]1([CH2:21][CH2:20][C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([O:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:12]=3)[NH:16][CH:15]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OCCc1c[nH]c2ccc(Oc3nc4ccccc4s3)cc12
Reactant: C1CCNCC1
Solvent: CC#N
Product: c1ccc2sc(Oc3ccc4[nH]cc(CCN5CCCCC5)c4c3)nc2c1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
To a solution of methanesulfonic acid 2-[5-(benzothiazol-2-yloxy)-1H-indol-3-yl]-ethyl ester (100 mg, 0.26 mmol) in MeCN (3 mL) was added piperidine (0.03 mL, 0.31 mmol) and the reaction mixture was heated (80° C., 2 h). The reaction mixture was cooled (rt), filtered and purified by basic reverse phase HPLC to provide the title compound as a white solid (47.2 mg, 49%). MS (ESI): mass calcd. for C22H23N3OS, 377.5; m/z found, 378.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.08 (s, 1H), 7.77 (d, J=7.6, 1H), 7.65 (d, J=8.0, 1H), 7.59 (d, J=2.3, 1H), 7.43-7.36 (m, 2H), 7.26 (s, 1H), 7.18 (dd, J=8.7, 2.3, 1H), 7.14 (s, 1H), 3.02-2.90 (m, 2H), 2.71-2.63 (m, 2H), 2.51 (s, 4H), 1.63 (dd, J=11.3, 5.6, 4H), 1.47 (s, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:14])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5].[F:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[F:27]>>[NH2:14][C:7]1[C:6]([C:4]([C:22]2[C:21]([O:23][CH3:24])=[C:20]([O:25][CH3:26])[CH:19]=[C:18]([F:27])[C:17]=2[F:16])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CON(C)C(=O)c1cnc(SC)nc1N
Reactant: COc1cc(F)c(F)cc1OC
Product: COc1cc(F)c(F)c(C(=O)c2cnc(SC)nc2N)c1OC

Procedure:
The compound was prepared from 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 168) and 1,2-difluoro-4,5-dimethoxy-benzene (Aldrich) in an analogous manner as described in Example 169. HR-MS (ES, m/z) calculated for C14H14N3O3SF2 (M+) 341.0646, observed 341.0644.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])[CH2:3][C:4]([CH3:7])(O)[CH3:5].OS(O)(=O)=O>O>[CH3:7][C:4]1([CH3:5])[CH2:3][C:2]([CH3:1])([CH3:8])[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:15]1
Reactant: CC(C)(O)CC(C)(C)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CC(C)(C)c2ccccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2.98 g (14.3 mmol) of 2-(1,1,3-trimethyl-3-hydroxybutyl) phenol (Compound 83) and 40 ml of 20% aqueous H2SO4 was heated at reflux, under nitrogen, for 4 h. The mixture was stirred at room temperature for a further 72 h and then diluted with 50 ml of water. The mixture was extracted with 3×20 ml of hexanes. The organic extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in vacuo to give the title compound as a colorless oil. PMR (CDCl3): & 1.36 (6H, s), 1.37 (6H, s), 1.83 (2H, s), 6.71 (1H, dd, J~8.2 Hz, 1.5 Hz) 6.92 (1H, td, J~8.2 Hz, 1.5 Hz), 7.09 (1H, td, J~8.2 Hz, 1.5 Hz), 7.29 (1H, dd, J~8.2 Hz, 1.5 Hz).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>>[NH:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[CH2:37][N:13]1[C:12](=[O:24])[C:11]2([CH2:25][CH2:26][N:8]([C:6](=[O:7])[C:5]3[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=3)[CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:14]1=[O:23]
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: ClCc1nc2ccccc2[nH]1
Product: Cc1ccccc1N1C(=O)N(Cc2nc3ccccc3[nH]2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=630.0 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 2-(chloromethyl)-benzimidazole.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][NH:5][C:6]([C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7].[OH-].[Li+].Cl>O1CCOCC1>[CH3:17][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:6]([NH:5][CH2:4][C:3]([OH:18])=[O:2])=[O:7]
Reactant: COC(=O)CNC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(C(=O)NCC(=O)O)cc2ccccc21
Yield: 93.2 %

Procedure:
(1-Methylindole-2-carbonyl)glycine methyl ester (1.687 g, 6.85 mmol) was dissolved in 1,4-dioxane (10 mL) and was treated with 1 N lithium hydroxide (7.0 mL, aq) with stirring. The reaction mixture turned clear immediately and was acidified with 1N HCl and concentrated to remove 1,4-dioxane to result in a purple precipitate. The precipitate was filtered, washed with water, and dried in vacuo to give the title product as a purple powder (1.482 g, 93%). TLC: (methylene chloride:methanol:acetic acid, 20:1:1, silica gel): Rf=0.28; 1H NMR (CD3OD): δ 7.61 (dt, J=8.2, 1H). 7.44 (dd, J=8.5, 0.8, 1H), 7.32-7.26 (m, 1H), 7.13-7.09 (m, 1H), 7.04 (s, 1H), 4.08 (s, 2H), 3.99 (s, 3H).