Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12](I)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH:39]([OH:42])[C:40]#[CH:41])=[O:33])([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>C1COCC1.C(N(CC)CC)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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:41]#[C:40][CH:39]([C:35]3[N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH:38]=[CH:37][CH:36]=3)[OH:42])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(O)c1cccn1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Oc1cc2c(I)c(F)ccc2n1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Oc1cc2c(C#CC(O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 2-tert-butoxycarbonyloxy-5-fluoro-4-iodo-indole-1-carboxylic acid tert-butyl ester (from Example 2 above) (9.85 g, 20.0 mmol), and 2-(1-hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester (from Example 1 above) (7.96 g, 36.0 mmol) in dry THF (85 mL) and triethylamine (Aldrich, 85 mL) was degassed by bubbling argon through the solution for 15 minutes. At this time copper(I) iodide (0.61 g, 3.2 mmol) and (Ph3P)4Pd (Aldrich, 1.85 g, 1.6 mmol) were added, and the reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were successively washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage, 75-S, 9/1 hexanes/ethyl acetate) afforded 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-hydroxy-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester as a light orange amorphous solid. (Yield 9.5 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(F)c(C(=O)O)c1
Product: Cc1ccc(F)c(C(=O)Cl)c1

Procedure:
A mixture of 2-fluoro-5-methylbenzoic acid (41.05 g, 0.266 mol) in thionyl chloride (200 mL) is refluxed for 45 min., during which time it becomes homogeneous. After cooling, the thionyl chloride is evaporated to yield 2-fluoro-5-methylbenzoyl chloride, as a yellow liquid, which is dissolved in CH2Cl2 (500 mL), and cooled to 0° C. To this solution is added 2-(trimethylsilyl)-ethanol (48.65 mL, 40.14 g, 0.34 mol), followed by triethylamine (85.86 g, 118.3 mL, 0.85 mol), and the solution is warmed to room temp. over 1 h. The solution is then washed with 1 N HCl (2×500 mL), water (1×250 mL) and brine (1×100 mL), dried (MgSO4), evaporated and chromatographed (silica, 5% EtOAc/hexane) to yield (2-trimethylsilyl)-ethyl 2-fluoro-5-methylbenzoate, as a yellow oil.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:10](=[O:39])[C@@:11]([OH:38])([CH3:37])[CH2:12][O:13][S:14]([C:17]1[C:34]([CH3:35])=[CH:33][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:19][C:18]=1[CH3:36])(=[O:16])=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:10](=[O:39])[C@@:11]([OH:38])([CH3:37])[CH2:12][O:13][S:14]([C:17]1[C:34]([CH3:35])=[CH:33][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])=[CH:19][C:18]=1[CH3:36])(=[O:15])=[O:16]
Reactant: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)OC[C@@](C)(O)C(=O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Referring to FIG. 37, to a solution of benzyl 2-(4-((((2R,4S)-4-((tert-butoxycarbonyl)amino)-2-hydroxy-2,6-dimethyl-3-oxoheptyl)oxy)sulfonyl)-3,5-dimethylphenoxy)acetate (540 mg, 0.87 mmol) in DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 3 h. Removal of the solvent under reduced pressure gave product, which was used directly in the next step without further purification. LC-MS analysis confirmed the structure.
Reaction SMILES: C(OC(=O)C[C@@H](C([N:16]1[C@@H:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][O:18][C:17]1=[O:24])=O)CCCCC)(C)(C)C.OO.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH:21]([C@H:20]1[CH2:19][O:18][C:17](=[O:24])[NH:16]1)([CH3:23])[CH3:22]
Reactant: CCCCC[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1
Reaction time: 3 h

Procedure:
A solution of 5 (25.5 g, 71.73 mmol) in THF (300 mL) and water (75 mL) under Ar is cooled to 0° C. To this is added via syringe H2O2 (30% in water, 30.6 mL, 0.300 mol) gradually over a period of 15 minutes. LiOHH2O (4.92 g, 0.12 mol) in water (150 mL) is added via syringe. The mixture is stirred for 3 h after which the septum is removed and Na2SO3 (37.8 g, 0.300 mol) in water (225 mL) is added slowly. The bulk of the THF is removed by rotavap at a bath temperature between 25-30° C. The residue is extracted with CH2Cl2 (100 ml×3). The combined organic layer is washed consecutively with 0.5 N HCl (100 mL), sat. NaHCO3 (100 mL), water (100 mL) and brine ( 100 mL). The solution is then dried over Na2SO4 and concentrated in vacuo. The residue is recrystallized in hexane/ethyl acetate to afford the Evan's chiral auxiliary 2 as white needles. The aqueous layer from the first extraction was acidified to pH 1 and extracted with ethyl acetate (100 mL×3). The combined organic layer is washed with 0.5 N HCl (100 mL) and then brine (100 mL). It is then dried over Na2SO4 and concentrated to yield 6 as a colorless oil (17.198 g, 70.39 mmol, 98%). 1H NMR (400 MHz, CDCl3) δ0.88 (t, J=6.8 Hz, 3 H), 1.21-1.37 (m, 6 H), 1.43 (s, 9 H), 1.40-1.70 (m, 2 H), 2.61 (dd, J=9.3 Hz, 1 H), 2.38 (dd, J=16.4, 5.1, 1 H), 2.61 (dd, J=16.4, 9.3, 1 H), 2.78 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ13.9, 17.5, 17.9, 22.3, 26.5, 27.9, 31.5, 37.0, 41.3, 94.9, 80.0, 171.1, 181.1. HRMS calcd for C13H25O4 (MH+): 245.1752. Found (DCI): 245.1766 (Δ=5.2 ppm).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2
Yield: 93.3 %

Procedure:
A solution of intermediate 6, ethyl 3-benzyloxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.236 g, 0.714 mmol) in a mixture of ethyl acetate (60 ml) and ethanol (20 ml) was treated with 1 atm of hydrogen at 25° C. over 10% palladium on activated carbon (0.10 g) for 2.5 h to give 0.160 g (94% yield) of the title compound as white needles; mp 172–174° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ ppm: 1.47 (3H, t, J=7.3 Hz, CH3), 4.08 (4H, m, 2×CH2), 4.54 (2H, q, J=7.3 Hz, OCH2), 4.72 (2H, s, OCH2), 10.75 (1H, s, OH). Anal. Calcd for C10H12N2O5: C, 50.00; H, 5.03; N, 11.66. Found: C, 50.01; H, 4.95; N, 11.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1)(=[O:27])=[O:26]
Reactant: CCCCCc1cc(CCO)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1cc(CCOS(C)(=O)=O)ccc1OC

Procedure:
1.2 g (0.0054 mol) of the compound 2d) from the previous step, 20 ml of dichloromethane, 0.75 ml (0.0054 mol) of triethylamine and, at 0-5° C., 0.42 ml (0.0054 mol) of methanesulfonyl chloride are placed in a round-bottom flask.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:21][C:22]1[CH:28]=[C:27]([I:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>O1CCCC1>[Cl:21][C:22]1[CH:28]=[C:27]([I:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(I)cc1Cl
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To suspension of 3-fluoroisonicotinic acid (2.00 g, 14.17 mmol, in tetrahydrofuran (50 ml) at −78° C. was added lithium bis(trimethylsilyl)amide (14.3 ml, 17.01 mmol). The dark colored suspension was stirred for 15 min. In another flask, to a solution of 2-chloro-4-iodoaniline (4.7 g, 18.43 mmol) in THF (50 ml) was added lithium bis(trimethylsilyl)amide (24.9 ml, 29.77 mmol) at −78° C. under N2. The resulting green colored solution was stirred for 15 min. To this green colored solution the lithiated acid solution was added. The cold bath was removed, allowed to warm to room temperature, and stirred overnight. The mixture was filtered, and the crude was diluted with EtOAc (400 ml). It was then washed with dilute HCl (25 ml), H2O (25 ml), and dried. During concentration of the solvent, 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid was separated out as an yellow solid. (1.3 g, 24%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([S:13]([NH2:16])(=[O:15])=[O:14])[S:10][N:9]=1.[C:17](OC)(OC)([O:21][CH3:22])[CH:18]([CH3:20])[CH3:19]>CCCCCC>[CH3:22][O:21][C:17](=[N:16][S:13]([C:11]1[S:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:12]=1)(=[O:15])=[O:14])[CH:18]([CH3:20])[CH3:19]
Reactant: COC(OC)(OC)C(C)C
Reactant: Cc1ccccc1-c1nsc(S(N)(=O)=O)n1
Solvent: CCCCCC
Product: COC(=NS(=O)(=O)c1nc(-c2ccccc2C)ns1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g of 3-(2-methylphenyl)-1,2,4-thiadiazole-5-sulfonamide and 11 ml of trimethyl orthoisobutyrate was heated to reflux and stirred for 2 hours. The mixture was allowed to cool to room temperature, whereupon a precipitate formed. Hexane was added and the mixture was stirred for 15 minutes. The solid was filtered and washed with hexane and dried in vacuum (P2O5) to give 3.49 g of solid, m.p. 116°-118°.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:31][CH:29]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][N:23]=2)[CH3:30])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(N)c1cnccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)c1cnccn1
Temperature: 165 °C
Yield: 55.6 %

Procedure:
This compound (40 mg, 55% yield) as a yellow crystalline solid was prepared according the procedures described for Example 318, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (54 mg, 0.18 mmol), 1-(pyrazin-2-yl)ethanamine (45 mg, 0.36 mmol) (Essen Scientific LLC, cat # ES10-0543) and DIEA (64 μL, 0.36 mmol) in 2 mL of DMSO (heated in a microwave at 165° C. for 45 min). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br.), 8.87 (1H, m), 8.59 (1H, m), 8.50 (1H, d, J=2.5 Hz), 7.87 (1H, d, J=7.2 Hz), 7.67 (1H, d, J=7.0 Hz), 7.57 (1H, d, J=7.4 Hz), 7.32 (1H, t, J=7.8 Hz), 6.99 (1H, br.), 6.90 (1H, d, J=2.2 Hz), 5.41 (1H, m), 3.48 (2H, m), 3.03 (2H, m), 2.68 (3H, s), 1.74 (3H, d, J=7.0 Hz). m/z (ESI, +ve) 400.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:15])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(N)CN>[CH2:3]([OH:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH3:14]
Reactant: CCCCCCCCC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: NCCN
Product: CC#CCCCCCCCCCO
Temperature: 70 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
NaH (7.5 g, 60% oil dispersion, 326 mmol) was added portionwise to a stirring, 0° C. solution of dodec-3-yn-1-ol (10.0 g, 54.95 mmol; GF Smith) in ethylenediamine (40 mL). After 1 h, the temperature was raised to 70° C. After another 8 h, the reaction mixture was cooled to 0° C., carefully quenched with ice cold water (100 mL), and extracted with ether (3×60 mL). The combined ethereal extracts were washed with water (100 mL). The aqueous wash was back extracted with ether (3×60 mL). The combined organic extracts were concentrated in vacuo and the residue subjected to column chromatography using 10% EtOAc/hexanes afforded dodec-10-yn-1-ol (7.4 g, 74%) contaminated with 3-5% of other regioisomers. TLC: 30% EtOAc/hexane, Rf≈0.4; 1H NMR (300 MHz, CDCl3) δ 3.66 (t, 2H, J=7.3 Hz), 2.14-2.21 (m, 2H), 1.93 (t, J=1.9 Hz, 1H), 1.20-1.63 (m, 16H). Lit. ref: R. V. Novikov; A. A. Vasil'ev; I. A. Balova Russ. Chem. Bull., Internat. Ed. 2005: 54, 1043-1045.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([Li])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([C:20]1([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]23[CH2:15][CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=42)[C:5]2[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:18][CH2:19]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: [Li]CCCC
Product: CCCCC1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in example 49 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing n-butyllithium, the title compound was formed as a white solid, mp 194°-196° C. TLC analysis on the free base (Rf 0.22, 30% ethyl acetate in hexane). free base: 1H NMR (CDCl3, 250 MHz) 7.20 (m, 4H), 6.94 (m, 4H), 4.26 (s, 1H), 3.41 (s, 2H), 2.73 (m, 2H), 2.60 (d, J=2.0 Hz, 2H), 1.53 (m, 10H), 0.9 (t, 3H) MS (CI, CH4) m/z 362 (M+1,100), 390 (M+29,13), 344 (47), 304 (44) hydrochloride salt:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[CH:15]=[C:16]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[CH2:20][CH2:19][C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]2[C:16](=[CH:15][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[C:17]3[CH:31]=[CH:30][CH:29]=[CH:28][C:18]=3[CH2:19][CH2:20][C:21]=2[CH:26]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: FC(F)(F)c1ccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)cc1

Procedure:
Following procedures essentially as described in Example 219, below, and using 4-(trifluoromethyl)phenylboronic acid (114 mg, 0.60 mmol) and 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (156 mg, 0.48 mmol) provides the title compound. GC/MS data: retention times in minutes (MS data for M+.ion): 18.52 (384), 18.78(384)Mass Spec (EI+) 384.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[CH2:23][OH:24])[N:9]([CH3:25])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>ClCCl>[C:26]([O:24][CH2:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[N:10]1[N:9]([CH3:25])[CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)[C:11]1=[O:15])(=[O:28])[CH3:27]
Reactant: CN1Cc2cc(C(C)(C)C)ccc2C(=O)N1c1cccc(Cl)c1CO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1c(Cl)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Temperature: 45 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
In a 100 mL round-bottomed flask, 6-tert-butyl-2-(3-chloro-2-(hydroxymethyl)phenyl)-3-methyl-3,4-dihydrophthalazin-1(2H)-one (500 mg, 1.39 mmol, Eq: 1.00), acetic anhydride (711 mg, 657 μl, 6.97 mmol, Eq: 5) and pyridine (331 mg, 338 μl, 4.18 mmol, Eq: 3) were combined with dichloromethane (10.0 ml) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 8 h. Cooled to room temperature and stirred for 48 h. The crude reaction mixture was concentrated in vacuo to a tan oil. The crude material was purified by flash chromatography (silica gel, 20%-30% ethyl acetate/hexanes gradient) to give 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-chlorobenzyl acetate (489 mg, 88%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H) 2.03 (s, 3H) 2.62 (s, 3H) 4.45 (s, 2H) 5.33 (s, 2H) 7.23 (d, J=1.51 Hz, 1H) 7.35-7.39 (m, 2H) 7.43-7.52 (m, 2H) 8.03 (d, J=8.31 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:22])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-])=O)=[O:5])[CH3:2]>CO.C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:22])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH2:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cnn(C)c1Nc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
Zinc powder (26.17 g, 400 mmol) was added to a suspension of 5-(4-chloro-2-nitro-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester from Example E1.1 (26.0 g, 80 mmol) in methanol/acetic acid (10:1, 330 ml) at room temperature. After the exothermic reaction which followed, the resulting suspension was stirred at room temperature for 18 h before being filtered through Celite® filter agent. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc, and the solution was washed with saturated NaHCO3 and brine, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 65% EtOAc:35% pet ether to 80% EtOAc:20% pet ether) to yield the title compound (18.41 g, 78.0%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([CH3:36])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[O:21])[CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([CH3:36])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[O:21])[CH2:10]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(O[Si](C)(C)C(C)(C)C)C3)ccc2C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(O)C3)ccc2C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of methyl 3-[[5-[3-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (0.4 g, 0.78 mmol) in THF (20 ml) is added Bu4NF 1.0 M in THF (0.409 g, 1.56 mmol) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 1 hour, the reaction mixture is diluted with ice-water and extracted twice with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 3% methanol in dichloromethane to afford the title compound as a white solid (0.3 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O>>[CH:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:26]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc4ccccc4c3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-naphthylboronic acid according to Method C (Example 178). Yield: 142 mg (70%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.C1COCC1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2nn(C)c3ccccc23)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc(C(=O)Nc2cc(F)c(CC(=O)O)cc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
To ethyl (5-chloro-2-fluoro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (1.40 g, 3.59 mmol) were added THF (36 ml) and 0.25N NaOH (21.5 ml, 5.39 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was poured in 1N HCl (6.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (5-chloro-2-fluoro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetic acid (1.23 g, 95%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][CH3:12])[CH:5]=1.C([O-])(=O)C.[Na+].[Br:18]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:12][O:11][CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=[CH:8][C:7]=1[Br:18]
Reactant: COCc1cccc(COC)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCc1ccc(Br)c(COC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
To a solution of m-xylylene dichloride (25.0 g) in methanol (125 ml) was added a 28% methanol solution (82.6 9) containing sodium methoxide at room temperature, and the mixture was stirred with heating at 60° C. for 3 hr. The solvent was evaporated and water (150 ml) was added to the residue. The mixture was extracted twice with heptane (80 ml) and heptane was evaporated under reduced pressure to give m-xylylene glycol dimethyl ether (25.3 g). m-Xylylene glycol dimethyl ether (25.3 g) was dissolved in acetic acid (125 ml) and sodium acetate (68 g) was added, which was followed by dropwise addition of bromine (68 g) at room temperature. The mixture was stirred at room temperature for 3 hr and poured into 10% aqueous sodium sulfite solution (750 ml), which mixture was extracted twice with heptane (350 ml). The heptane layer was extracted twice with 10% aqueous sodium hydroxide solution (150 ml) and once with water (150 ml). The solvent was evaporated and the residue was purified by silica gel column chromatography using heptane-ethyl acetate (15:1) as an eluent to give the title compound (10.4 g, yield:29.7%) as a colorless transparent oil.