Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1.[C:21](=[O:23])=[O:22].[OH-].[Na+]>C1COCC1.CCOC(C)=O.O.CCOCC>[F:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: Fc1ccc(I)cc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(I)ccc1F
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a −78° C. solution of iPr2NH (16.80 mL) in 200 mL freshly distilled THF is added n-butyllithium (68 mL) dropwise, maintaining the temperature of the reaction below −65° C. The reaction is stirred for 10 minutes, then 1-fluoro-4-iodobenzene (11.50 mL) as a solution in 10 mL THF is added over 20 minutes. The reaction is stirred at −78° C. or 90 minutes, then cannulated rapidly into diethyl ether (180 mL) and dry ice (approximately 75 g). The reaction is stirred at room temperature overnight. To the ether solution is added 1N NaOH (100 mL) and water (200 mL) and the solution placed in a separatory funnel. The aqueous layer is removed. The organic layer is washed with H2O (2×100 mL). All the aqueous portions are combined, chilled in ice/H2O, and acidified to pH 2 with 6N HCl. This solution is then extracted with diethyl ether (2×200 mL). The ether portions are combined, dried over Na2SO4, filtered, and concentrated to give a pale yellow solid. The solid is dissolved in a minimal amount of EtOAc on the steam bath, and hexanes are added to affect recrystallization. After standing in the freezer overnight, the product is obtained as a crystalline white solid (15.44 g, 58%). Physical characteristics are as follows: m.p. 157-159° C.; 1H NMR (300 MHz, CDCl3) δ8.34, 7.88, 6.97; IR (drift) 3098, 3079, 3051, 3017, 3007, 2998, 2981, 2971, 2881, 2817, 1708, 1681, 1300, 1236, 824 cm−1; Anal. Calcd for C7H4FIO2: C, 31.61; H, 1.52; Found: C, 31.70; H, 1.59.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:15]([O:17]CC)=O)[C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.Cl.ClC1C=CC(NN)=CC=1.C(Cl)Cl.CO.Cl.CCOCC>>[ClH:14].[CH2:1]([C:8]1[C:13]2[C:12]([C:15](=[O:17])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:30]=2)=[CH:11][NH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cncc(Cc2ccccc2)c1Cl
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(-n2nc3c(Cc4ccccc4)c[nH]cc-3c2=O)cc1
Yield: 30 %

Procedure:
Following a similar procedure to that described in Example 4, except using ethyl 3-benzyl-4-chloro-5-pyridinecarboxylate and 4-methoxyphenylhydrazine hydrochloride instead of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate and 4-chlorophenylhydrazine hydrochloride, the title compound was prepared, after trituration with CH2Cl2-Me-OH—HCl—Et2O, in 30% yield as a cream solid, mp 179-185° C.; 1H NMR (360 MHz, DMSO-d6) δ3.78 (3H, s), 4.00 (2H, m), 7.01 (2H, d, J 9.2 Hz), 7.21 (1H, t, J 7.3 Hz), 7.31 (2H, t, J 7.3 Hz), 7.41 (1H, s), 7.42 (2H, d, J 7.0 Hz), 8.05 (2H, d, J 9.2 Hz), 8.56 (1H, s), 12.52 (1H, br s); MS (ES+) m/z 332 [MH]+. Anal. found: C, 65.36; H, 4.86; N, 11.25. C20H17N3O2.HCl requires: C, 65.31; H, 4.93; N, 11.42%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:13][CH2:12][C:11]([F:16])([F:15])[F:10])=[CH:6][N:7]=1
Reactant: Cc1cc(Cl)ncc1O
Reactant: OCCC(F)(F)F
Product: Cc1cc(Cl)ncc1OCCC(F)(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (3.64 g, a pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 3,3,3-trifluoropropan-1-ol (5.72 g, 50.1 mmol) in a similar manner to Step-1 of Intermediate-A17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:25])[N:18]([CH2:19][C:20](OC)=[O:21])[C:17](=[O:24])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:25])[N:18]([CH2:19][CH2:20][OH:21])[C:17](=[O:24])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)CN1C(=O)C2(CCCC2)NC[C@@]1(C)c1cc(F)cc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1CCO
Reaction time: 0.67 h

Procedure:
To a stirred solution of methyl[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate from Step A (998 mg, 2.83 mmol) in THF (14 mL) cooled to 0° C. via an ice/water bath was added LiAlH4 (1 M in THF, 4.20 mL, 4.20 mmol). After 40 min, the reaction was quenched with water (40 mL), and the resulting mixture was filtered through Celite, washing with saturated NaHCO3 solution (50 mL) and EtOAc (80 mL). The filtrate was separated and the aqueous layer was extracted an additional time with EtOAc (80 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—0:100 to 100:0. The clean fractions were concentrated in vacuo to yield the title compound. MS: m/z=325 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH:15]=1)[C:13]#[N:14].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C(Cl)Cl>O1CCOCC1.O>[CH:16]1([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:15]=2)[C:13]#[N:14])[CH2:18][CH2:17]1
Reactant: N#Cc1cncc(Br)c1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cncc(C2CC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Cesium carbonate (20.8 g, 0.064 mol) was added to a stirred solution of 5-bromonicotinonitrile (6 g, 0.0322 mol) and cyclopropylboronic acid (2.8 g, 0.032 mol) in a mixture of 1,4-dioxan (100 mL) and water (50 mL). The reaction vessel was purged with argon for 20 min and Pd(dppf)2Cl2.DCM (1.3 g, 0.0016 mol) was added to the reaction mixture. The reaction vessel was purged again with argon for 10 min and subsequently allowed to stir at 100° C. for 3 h. The reaction mixture was filtered through a filter bed of CELITE and the filter bed was thoroughly washed with ethyl acetate (3×200 mL). The collected organic fractions were concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford 5-cyclopropylnicotinonitrile. MS (M+1): 144.8.
Reaction SMILES: [CH:1]1[C:6]([C:7]([Cl:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)(=O)=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.O>CN1C(=O)CCC1>[CH:1]1[C:6]([C:7]([Cl:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[CH:21]1[C:16]([NH2:15])=[CH:17][CH:18]=[C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[O:23])[CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Agent: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(S(=O)c2ccc(N)cc2)cc1
Reaction time: 2 h

Procedure:
At room temperature, 4.211 g (20 mmol) of trimellitic acid anhydride chloride (TMA) was added to a solution of 4.966 g (20 mmol) of bis(4-aminophenyl) sulfone in 68 ml of NMP, and the resulting mixture was stirred for 2 hours. Then, 2.9 ml (21 mmol) of triethylamine was added at 5° C. and stirred at room temperature for 10 hours. By dropwise adding the reaction mixture into 1.5 liters of water, there was obtained a polyamic acid (TMA/DDSO) as a solid product in a yield of 9.06 g.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:20][O:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=1)[C:4]([CH3:3])=[C:12]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C)n(-c2ncnc3ccccc23)c2ccc(OC)cc12
Reaction time: 0.25 h

Procedure:
A stirred suspension of sodium hydride (0.24g.) in dry dimethylformamide (20ml.; dried with calcium hydride) was treated at 5°-10° C. with a solution of ethyl 2-methyl-5-methoxyindol-3-ylacetate (2.3g.) in dry dimethylformamide (10ml.). The mixture was stirred at 25°-30° C. for 15 minutes, and the solution obtained was treated with a freshly prepared solution of 4-chloroquinazoline (1.65g.) in dry dimethylformamide (10ml.). The mixture was stirred at 30°-40° C, for 4 hours, and then poured into water (500ml.). The mixture was extracted with ethyl acetate (4 × 100ml.) and the extracts washed successively with water (2 × 100ml.) and brine (100ml.), and then dried (sodium sulphate). Evaporation of solvent gave an oil which was purified by chromatography on silica gel (250g.) using an increasing gradient of ether in petroleum ether (b.p. 40°-60° C.) (the polarity increased by incremental addition of 10% v/v ether) to give ethyl 5-methoxy-2-methyl-1-(quinazolin-4-yl)indol-3-ylacetate, m.p. 121°-123° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.O.[F-:31].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][F:31])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: [F-]
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCOCCBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCOCCF)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of N-cyclopropyl-1-{2-[2-(2-bromoethoxy)ethoxy]-4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (0.23 g) obtained in Example 308a) in acetonitrile (10 ml) was added tetrabutylammonium fluoride monohydrate (0.39 g), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, and the solvent, was evaporated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile-water) and recrystallized from acetonitrile-water to give the title compound as a white powder (0.04 g, 21%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[NH2:16]>>[CH3:23][O:22][C:18]1[CH:17]=[C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])[CH:14]=[C:13]([O:12][CH3:11])[C:19]=1[O:20][CH3:21]
Reactant: CSc1ccc(C#N)cc1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(NC(=N)c2ccc(SC)cc2)cc(OC)c1OC

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (4.1 g, 27 mmol) and 3,4,5-trimethoxyaniline (5 g, 27 mmol) by following the procedure described in preparation 10 (7.8 g, yield 86.32%). 1H-NMR (CDCl3):δ 2.51 (s, 3H), 3.8 (s, 9H), 4.9 (bs, 2H, D2O exchangeable), 6.23 (s, 2H), 7.24-7.30 (m, 2H), 7.78-7.8 (d, 2H). MS m/z:333.5 (M+).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=4)=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:13][C:12]=1[C:38]([F:41])([F:40])[F:39]>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:37][S:2]([CH3:1])(=[O:5])=[O:3])[N:32]=4)=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:13][C:12]=1[C:38]([F:40])([F:39])[F:41]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reaction time: 20 h

Procedure:
378 mg (2.17 mMol) methansulfonic acid anhydride are added in 3 portions to a solution of 300 mg (0.68 mMol) 6-(2-amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (Step 10.3) in 4.5 ml CH2Cl2 and 7.5 ml pyridine. After 20 h, the solution is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2/THF 50:1-9:1) gives the title compound: m.p.: 246° C.; MS: [M−1]=519.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][OH:24])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O>CS(C)=O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH:23]=[O:24])[N:22]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(-c2c(-c3nc(CO)cs3)cnn2C(C)(C)C)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2c(-c3nc(C=O)cs3)cnn2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.2 %

Procedure:
To a solution of the compound (663 mg, 1.93 mmol) obtained in step 2 and TEA (0.807 mL, 5.79 mmol) in DMSO (14 mL) was added a sulfur trioxide-pyridine complex (922 mg, 5.79 mmol) at room temperature, and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate) to give 2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazole-4-carbaldehyde (607.5 mg, 1.779 mmol, 92%) as a white powder.
Reaction SMILES: Br[C:2]1[N:3]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH3:17])[C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:7]([C:4]1[N:3]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH3:17])[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: Cc1cc(C#N)ccc1-n1c(Br)ccc1C=O
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc(C=O)n2-c2ccc(C#N)cc2C)cc1
Temperature: 90 °C
Yield: 57.1 %

Procedure:
A mixture of compound 50C (24 mg, 0.083 mmol), compound 4-methoxyphenylboronic acid (15.2 mg, 0.1 mmol) and sodium carbonate (17.6 mg, 0.166 mmol) in a mixture of DME (5 mL) and water (1 mL) was degassed, and [11′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (96 mg, 0.008 mmol) was added. The reaction mixture was heated at 90° C. for 10 hours, poured into water, and extracted with ethyl acetate (10 mL×3). The combine organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrate under reduced pressure, and purified by preparative TLC to afford the compound 50D (15 mg, 57%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH2:7]([O:14][C:15]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CO)NC(=O)OCc1ccccc1
Yield: 100.3 %

Procedure:
A procedure similar to that described in Preparation 7 was repeated, except that 7.00 g of 2-amino-2-methylpropanol, 13.47 g of benzyloxycarbonyl chloride, 13.13 g of potassium carbonate, 35 ml of ethyl acetate and 35 ml of water were used, to give 17.59 g of the title compound having an Rf value of 0.72 (on silica gel thin layer chromatography, using a 3:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32](OC(F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:40][S:41](C1C=CC(B(O)O)=CC=1)(=[O:43])=[O:42]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([S:41]([CH3:40])(=[O:43])=[O:42])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(methylsulfonyl)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 86% yield using 4-methanesulfonyl phenylboronic acid as the reagent (0.0997 g, 0.000498 mol).
Reaction SMILES: Cl.[C:2]1([C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:5])[OH:3].[CH3:10][C:11]([CH3:13])=O>>[CH3:10][C:11]1([CH3:13])[O:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[O:3]1
Reactant: CC(C)=O
Reactant: Oc1ccccc1O
Agent: Cl
Product: CC1(C)Oc2ccccc2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
Hydrogen chloride gas was introduced into a solution of 110.1 g of pyrocatechol in 370 ml of acetone for 2 hours while stirring and cooling with ice 10°-15° C. internal temperature, and then for an additional 30 minutes at 0° C. The mixture was poured into ice/water, made alkaline and extracted three times with 1 l of ether. The organic phase was washed neutral three times with 500 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue was distilled in vacuo (b.p. 11 mm/59°-60° C.). There were obtained 39.0 g (26.0% of theory) of 2,2-dimethyl-1,3-benzodioxole.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:36])[CH3:35])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.020 g, 0.000056 mol) and potassium carbonate (0.016 g, 0.00012 mol) in anhydrous N,N,-dimethylformamide (1 mL) was added acetic anhydride (0.009 g, 0.000084 mol) at room temperature. The reaction mixture was stirred for 1 hours. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 5 μm, 100×20 mm; 20%-85% over 7.5 min with 0.05 M ammonium acetate, 25 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetany}-1-ethanone (0.014 g, 0.000035 mol).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](CN)=[C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:4]=1.FC1C=CC([C:21]#[N:22])=C(N2C=NC=N2)C=1.Cl>C(O)C.[Pd]>[N:11]1([C:5]2[CH:6]=[CH:7][C:8]([C:21]#[N:22])=[C:3]([F:2])[CH:4]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: N#Cc1ccc(F)cc1-n1cncn1
Reactant: NCc1ccc(F)cc1-n1cncn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(-n2cncn2)cc1F
Yield: 99 %

Procedure:
(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride). 4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile, (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL). To this was added 1N HCl (15 mL) followed by 10% Pd—C (200 mg). The mixture was treated with H2 at 55 psi for 4 h in a Parr shaker then filtered over Celite® and the solvent removed under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The aqueous phase was separated and lyophilized to afford the title compound as a white powder (2.96 g, 99% yield). 1H NMR (500 MHz, CD3OD) δ ppm: 9.51 (1H, s), 8.63 (1H, s), 7.85 (1H, dd, J==8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 7.49 (1H, td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd for C9H10N4F: 193.08; found: 193.16.
Reaction SMILES: [OH-].[Na+].Br[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][N:5]=1.[CH2:11](B(CC)CC)[CH3:12].OO>C1COCC1.CC#N.CC#N.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:11][CH3:12])=[N:5][CH:6]=1
Reactant: CCB(CC)CC
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: OO
Solvent: CC#N
Solvent: C1CCOC1
Product: CCc1ccc(Br)cn1
Yield: 90 %

Procedure:
280 mL of 5N sodium hydroxide (1.4 mol, 2.09 eq) was added to a solution of 158 g of 2,5-dibromopyridine (0.67 mol, 1 eq) in 1.4 L of THF. To the resulting solution, 700 mL of 1N triethylboron in THF (0.70 mol, 1.04 eq), 195 mg of bis(acetonitrile)palladium(II) chloride (0.75 mmol, 0.0011 eq) and 414 mg 1,1'-bis(diphenylphosphino)ferrocene (0.75 mmol, 0.0011 eq) were added. The reaction was slowly heated to a very slight reflux for 3 hours. It was then cooled down to 0° and treated sequentially with 140 mL of 5N sodium hydroxide (0.70 mol, 1.04 eq) and 53 mL of 30% hydrogen peroxide (0.70 mol, 1.05 eq) at such a rate that the temperature never exceeded 10° C. The mixture was extracted with ether, and the ether extracts washed with sodium hydroxide, water, brine and dried over MgSO4. The ether solution was then concentrated and the brown residue was distilled under vacuum (40° C., 1 Torr) to give 112 g of the title compound as a clear oil slightly contaminated with the starting material and 2,5-diethylpyridine. Yield ~90%. The 1H NMR is comparable to that reported by J. W. Tilley and S. Zawoiski; J. Org. Chem., 1988,53, 386-390. The material is suitable for use in the next step without further purification.