Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH3:44][O:43][C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)=[O:42]
Reactant: COC(=O)c1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (500 mg), 4-methoxycarbonylphenyl borate (191 mg) and potassium carbonate (266 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (56 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:2→1:1) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(4-methoxycarbonylphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (290 mg).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:43])[C@@H:17]([O:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:38])=[C:27]1[CH3:39])[CH:18]([CH3:20])[CH3:19]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:24]2[CH:23]=[C:22]([CH:42]=[CH:41][CH:40]=2)[O:21][C@@H:17]([CH:18]([CH3:20])[CH3:19])[C:16]([O:15][CH3:14])=[O:43])[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(C)C
Agent: Cl
Product: COC(=O)[C@@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C([C@H](NC(=O)C1C=CC=C(S(C)(=O)=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([S:47]([CH3:50])(=[O:49])=[O:48])[CH:46]=1)[C:41]([OH:43])=O.[CH:51]12[CH2:57][CH:54]([CH2:55][CH2:56]1)[CH2:53][CH:52]2[NH:58][C:59](=[O:74])[C@H:60]([CH3:73])[CH2:61][C@H:62]([OH:72])[C@@H:63]([NH2:71])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>>[CH2:64]([C@H:63]([NH:71][C:41](=[O:43])[C:40]1[CH:44]=[C:45]([S:47]([CH3:50])(=[O:49])=[O:48])[CH:46]=[C:38]([O:37][CH3:36])[CH:39]=1)[C@@H:62]([OH:72])[CH2:61][C@H:60]([C:59](=[O:74])[NH:58][CH:52]1[CH2:53][CH:54]2[CH2:57][CH:51]1[CH2:56][CH2:55]2)[CH3:73])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: COc1cc(C(=O)O)cc(S(C)(=O)=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Product: COc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(S(C)(=O)=O)c1

Procedure:
Prepared in an analogous manner to E1 from 3-methoxy-5-methylsulfonylbenzoic acid (D15) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:27][CH3:28])[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=O)[N:13]=1.B.C(O)(=O)C.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:27][CH3:28])[C:12]1[N:13]=[C:14]([CH2:19][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:15]=[C:16]([CH3:18])[N:17]=1
Reactant: CCN(c1nc(C)cc(C(=O)N2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(CN2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.2 %

Procedure:
A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinylcarbonyl)-2-pyrimidinamine (750 mg, 1.72 mmol) in anhydrous THF (1.4 mL) was stirred at ambient temperature under a nitrogen atmosphere. A solution of borane in THF (1 M, 3.6 mL, 3.6 mmol) was added dropaise. The reaction mixture was then warmed to reflux temperature and stirred for 20 hours. After cooling to room temperature, acetic acid (3.5 mL) was added slowly and the mixture was heated to reflux temperature and stirred for 30 min. After being cooled to ambient temperature, the reaction mixture was poured onto a 3N NaOH solution, mixed and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (EtOAc) of the residue afforded the title compound as an oil (300 mg, 39% yield, Rf 0.3): NMR (CDCl3, 300 MHz): d 7.5 (s, 1H), 7.2 (d, 1H, J=7), 7.15 (d, 1H, J=7), 6.5 ( s, 1H), 4.3-4.1 (m, 1H), 3.8-3.6 (m, 7H), 3.5-3.3 (m, 2H),2.9 (septet, 1H, J=7), 2.55-2.35 (br m, 3H), 2.35-2.25 ( m, 2H), 1.3 (d, 6H, J=7), 1.2 (t, 3H, J=7); CI-HRMS: calcd: 433.1603 (M+H), found: 433.1586.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1)[C:16]#[CH:15]
Reactant: Nc1nc2ccccc2c2[nH]cnc12
Reactant: C#CCBr
Product: C#CCn1cnc2c(N)nc3ccccc3c21
Yield: 15.8 %

Procedure:
Using the general method of Example 1, 2.1 g of 1H-imidazo[4,5-c]quinolin-4-amine was reacted with 1.7 g of propargyl bromide to provide 0.4 g of 1-(2-propynyl)1H-imidazo[4,5-c]quinolin-4-amine, m.p. 220°-222° C. The structure was confirmed by nuclear magnetic resonance spectroscopy. Analysis: Calculated for C13H10N4 : %C, 70.3; %H, 4.5; %N, 25.2; Found: %C, 70.5; %H, 4.6; %N, 25.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH3:22])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC)c(O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,4-Dihydroxybenzoic acid ethyl ester (3.00 g, 16.0 mmol) was suspended in DMF (10 ml), potassium carbonate (2.21 g, 16.0 mmol) was added, the mixture was stirred for 5 min at room temperature, and then iodoethane (2.49 g, 16.0 mmol) was added. The mixture was stirred overnight, the addition of potassium carbonate and of iodoethane was repeated, and the mixture was stirred overnight again. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the combined organic extracts were washed with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH:23]4[CH2:37][C@@H:26]5[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:25]5[CH2:24]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH:23]4[CH2:37][C@@H:26]5[CH2:27][NH:28][CH2:29][C@@H:25]5[CH2:24]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@H]2CNC[C@H]2C1
Yield: 197.7 %

Procedure:
1,1-Dimethylethyl(3aR,6aS)-5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy})hexahydrocyclo-penta[c]pyrrole-2(1H)-carboxylate (0.23 g, 0.42 mmol) was taken up in methanol (10 mL) and treated with 4.0M hydrogen chloride in dioxane (excess) and heated briefly to reflux. Concentration in vacuo provided N-(3,4-dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl]oxy}quinazolin-4-amine hydrochloride (0.20 g, 100%). MS (EI) for C22H22Cl2N4O2: 445 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:4]2[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[CH:8][C:3]2=[O:2])=[C:21]([F:27])[CH:22]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: COc1ccc(CCCc2ccccc2)cn1
Product: O=c1ccc(CCCc2ccccc2)cn1Cc1ccc(Cl)cc1F
Yield: 47.7 %

Procedure:
According to Scheme 22 Step 2: The title compound was prepared according to Example 6 Step 2, from 2-methoxy-5-(3-phenylpropyl)pyridine (1 eq, 0.44 mmol, 0.10 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (2 eq, 0.88 mmol, 0.20 g). Reaction conditions: overnight at 90° C. The residue was purified by flash chromatography over silicagel (AIT Flashsmart prepacked column SiO2, cyclohexane/AcOEt 70/30) yielding the title compound (75 mg, 0.21 mmol, 48%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)=[N+:5]2[O-:22].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[N+:5]2[O-:22]
Reactant: COc1ccc(-c2c(=O)[nH]c3cc(Cl)c(Cl)cc3[n+]2[O-])cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[n+]([O-])c1-c1ccc(O)cc1
Reaction time: 20 h
Yield: 71 %

Procedure:
A mixture of p-methoxyphenyl nitrone 128 (2 mmol) and BBr3 (1M in CH2Cl2, 15 mL, 15 mmol) in CH2Cl2 (100 mL) was stirred for 20 h, then evaporated. The residue was evaporated with MeOH (25 mL, repeated twice), then water (50 mL) was added. The reaction mixture was basified with saturated NaHCO3 to pH 8, stirred for 1 h and acidified with 2N HCl to pH 3. The precipitated crude product was filtered, washed with water to a neutral pH, air dried and recrystallized from EtOH to give the title compound. Yield: 71%; mp 276°-278° C. (from EtOH); IR (KBr) 3422, 3069, 1670, 1653, 1609, 1590, 1459, 1361, 1297 and 1226 cm-1 ; 1H NMR (in DMSO-d6) δ6.83 (d, 2H, J=8.7 Hz), 7.41 (s, 1H), 7.99 (s, 1H), 8.27 (d, 2H, J=8.7 Hz), 10.09 (br.s, 1H, O--H), 12.53 (br.s, 1H, N--H); HPLC: 98%; HRMS Calcd for C14H8N2O3Cl2 : 321.9912.
Reaction SMILES: [C:1]([S:5][S:6][CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>CC#N.O>[C:1]([S:5][S:6][CH2:7][CH:8]([NH:9][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)SSC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)O
Reaction time: 0.25 h

Procedure:
To S-tert-butylmercapto-L-cysteine (10 g, 47.8 mmol) in CH3CN (40 mL) was added K2CO3 (16.5 g, 119.5 mmol) in H2O (20 mL). After stirring for 15 minutes, iso-butyl chloroformate (9.4 mL, 72 mmol) was injected slowly. The reaction was allowed to run for 3 hours. The white solid was filtered through Celite; the filtrate was concentrated to remove CH3CN. The residue was dissolved in ethyl acetate (200 mL), washed with 1N HCl (40 ml×3), brine (40×1), dried over Na2SO4. The title compound was obtained after chromatography (5% MeOH/DCM).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.[Cu]I>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(ccn2-c2ccc(C(F)(F)F)cc2)c1
Temperature: 110 °C
Yield: 82.4 %

Procedure:
A mixture of methyl indole-5-carboxylate 19a (2 g, 11.4 mmol), 1-bromo-4-trifluoromethyl-benzene 19b (2.8 g, 12.5 mmol), CuI (0.22 g, 1.14 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.54 mL, 3.43 mmol), and K3PO4 (6.06 g, 28.5 mmol) in toluene (12 mL) was heated at 110° C. for 7 h. The reaction mixture was diluted with CH2Cl2 and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give compound 19c (3.0 g).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28]I>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Product: CCOC(=O)C(C)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using ethyl 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate and methyl iodide and by reaction and purification in the same manner as in the method described in Example 121, step 1, ethyl 2-(2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)propanoate was obtained as a colorless oil
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH3:24])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:23])(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCCC.CCOC(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[O:15][CH2:14][C:13](=[O:23])[N:12]([CH2:11][C@H:10]([CH3:24])[CH2:9][OH:8])[C:17]=2[CH:18]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccc(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](CO)CN1C(=O)COc2ccc(F)cc21
Yield: 94.8 %

Procedure:
The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one (111MF01) (4.09 g, 11.6 mmol) and tetrabutylammonium flouride monohydrate (4.30 g, 15.4 mmol) were mixed according to GP8. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF03) (2.63 g, 95%). 1H NMR (CDCl3) δ 6.92 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.80 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.71-6.66 (m, 1H), 4.59 (d, J=0.8 Hz, 2H), 4.17-4.11 (m, 1H), 3.58-3.40 (m, 3H), 2.79 (s, 1H), 2.08-1.96 (m, 1H) 1.04 (d, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ 165.3, 158.4 (d, J=238.44 Hz), 141.5 (d, J=2.7 Hz), 129.5 (d, J=10.4 Hz), 117.9 (d, J=9.3 Hz),110.2 (d, J=23.1 Hz), 103.1 (d, J=28.4 Hz), 67.5, 63.85, 43.8, 34.0, 14.9.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:15]C)=[C:10]([CH:14]=1)[C:11]([OH:13])=O.CN(C=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1.C1C=CC=CC=1.C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:14]=2)=[O:13])[CH:14]=1
Reactant: COc1ccc(Br)cc1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Br)ccc1O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 181.2 %

Procedure:
10.07 ml (138.8 mmol, 2.2 eqv) SOCl2 was added to a solution of 14.77 g (63.9 mmol) 5-Bromo-2-methoxy-benzoic acid (17) in 140 ml dry toluene, followed by 0.5 ml (6.5 mmol, 0.1 eqv) DMF. After stirring this solution for 1.5 h at 70° C. the solvent was evaporated and the the crude acyl chloride was dissolved in 75 ml of dry benzene. This solution was then added cautiously under stirring to a suspension of 10.30 g (77.3 mmol, 1.2 eqv) AlCl3 in 80 ml dry benzene at 10° C. After complete addition the resulting mixture was refluxed for 5 h and then quenched by adding H2O and conc. hydrochloric acid. The aq. layer was extracted with EtOAc and the comb. org. fractions were dried over NaSO4 and evaporated. Column chromatography (CH2Cl2) yielded 16.03 g (57.9 mmol, 90%) 18 as a yellow solid: Rf (CH2Cl2) 0.67; 1H NMR (500 MHz, CDCl3) δ 6.99 (d, 1H, J=8.99 Hz), 7.52-7.68 (m, 6H), 7.70 (d, 1H, J=2.36 Hz), 11.91 (s, 1H); LRMS (EI) m/z 278 (80), 277 (100), 276 (86), 275 (92), 201 (31), 200 (22), 199 (30), 198 (20), 105 (63), 77 (57), 63 (19); HRMS (EI) Calcd. for C13H9BrO2: 275.978591. Found: 275.977717.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-carboxyphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 28.9, 32.0, 42.6, 60.5, 127.2, 127.4, 127.7, 130.2, 130.5, 140.1, 142.7, 142.7 and 167.0.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1>CN(C=O)C.O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:15]=1
Reactant: OCC(F)(F)F
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1cncc(Br)c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a slurry of sodium hydride (60% dispersion in mineral oil, 0.54 g, 14 mmol) in DMF (15 mL) was added commercially available 2,2,2-trifluoroethanol (0.97 mL, 14 mmol) at room temperature. After stirring for 15 minutes, a solution of 3,5-dibromopyridine (3.2 g, 14 mmol) in 5 mL of DMF was added dropwise. The reaction mixture was heated overnight at 70° C. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was chromatographed on silica (5% ethyl. acetate/hexanes) to give the title compound (1.6 g, 46% yield) as clear oil. 1H NMR (CDCl3) δ 8.42 (d, 1H, J=1.7 Hz), 8.32 (d, 1H, J=2.5 Hz), 7.46 (m, 1H), 4.42 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:25][N:26]=3)[S:21][C:14]=12>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[O:23][C:22]([C:20]3[S:21][C:14]4[C:15](=[N:16][CH:17]=[CH:18][C:13]=4[NH:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)[CH:19]=3)=[N:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2cnc(-c3cc4nccc(Cl)c4s3)o2)cc1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: COc1ccc(-c2cnc(-c3cc4nccc(Nc5ccc6[nH]c(C)cc6c5)c4s3)o2)cc1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-[5-(4-methoxy-phenyl)-oxazol-2-yl]-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ11.00 (s, 1H), 8.79 (s, 1H), 8.21 (d, 1H), 7.98 (s, 1H), 7.79 (m, 2H), 7.76 (s, 1H), 7.24 (m, 2H), 7.08 (s, 1H), 7.06 (s, 1H), 6.85 (d, 1H), 6.60 (d, 1H), 6.10 (s, 1H), 3.79 (s, 3H), 2.42 (s, 3H); RP18-HPLC RT: 6.55 minutes; API MS: 453 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].[CH2:14]([O:16]C(=O)OCC)C.Cl>C1C=CC=CC=1>[OH:9][C:8]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[O:11][C:14](=[O:16])[CH:10]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(C)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc2c(O)cc(=O)oc2c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A solution of 42 g (0.28 mol) of 2-hydroxy-4-methylacetophenone in benzene (150 mL) was added over 30 min. to a suspension of NaH (50% oil), 30 g, 0.63 mol) in 400 mL of benzene at reflux. Then, diethylcarbonate (67.8 mL, 0.56 mol) in benzene (500 mL) was added over 15 min. The reaction mixture was refluxed for 16 s h and more NaH (13 g, 0.28 mol) was added followed by more diethylcarbonate (33 g, 0.28 mol). After another 6 h at reflux the reaction mixture was cooled to r.t. and HCl (2N) was added (1.5 L) to form a white precipitate. The solid was then filtered and added to a solution of NaOH (4N) (800 mL). The resulting basic solution was then extracted with Et2O (2×500 mL) and the basic solution acidified with HCl conc. to give a white solid which after filtration and dried gave 38.7 g (79%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([C:11]([F:14])([F:13])[F:12])[CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH2:5].N1C=CC=CC=1.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[Br:23][C:24]1[S:28][C:27]([S:29]([NH:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]([C:11]([F:13])([F:12])[F:14])[C:2]([F:15])([F:16])[F:1])(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(NS(=O)(=O)c1ccc(Br)s1)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 77.4 %

Procedure:
A solution of ethyl 4,4,4,4′,4′,4′-hexafluoro-dl-valinate (1.64 g, 6.48 mmol), prepared as described (J. Med Chem. 1981, 24, 1043-1047), in CH2Cl2 (10 mL) was stirred under N2 atmosphere at 25° C. Pyridine (0.81 mL, 10.04 mmol) was added dropwise followed by 5-bromothiophene-2-sulfonyl chloride (2.034 g, 7.77 mmol) in one portion and the resulting solution stirred for 19 h at 25° C. After this time period, the reaction was complete by TLC (1:4 EtOAc-hexane). After quenching with water (2.0 mL), the mixture was diluted with CH2Cl2 (40 mL). The organic layer washed sequentially with 1N aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and brine (15 mL), dried over MgSO4, filtered, and concentrated to obtain a crude oil (3.3 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford ethyl N-[(5-bromothien-2-yl)sulfonyl]-4,4,4,4′,4′,4′-hexafluoro-dl-valinate as a white solid (2.40 g, 80.0%). Mass Spectrum (−ESI): 477 (M−H)−.