Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: OCC1Cc2cc(-c3ccccc3)cc(Br)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(Br)c3O2)cc1
Yield: 79.1 %

Procedure:
Treatment of 3-bromo-4-hydroxybiphenyl (15.7 g, 63.0 mmol) with potassium carbonate (34.84 g, 252.0 mmol) and allyl bromide (9.15 g, 75.63 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromobiphenyl-4-ol. Treatment of 3-allyl-5-bromobiphenyl-4-ol (17.8 g, 61.5 mmol) with 3-chloroperoxybenzoic acid (31.87 g, 184.67 mmol, 77%) followed by potassium carbonate (21.27 g, 153.89 mmol) generally according to the procedure described for Intermediate 9 afforded 15.8 g (84%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol (15.8 g, 51.77 mmol) with p-toluenesulfonyl chloride (14.79 g, 77.65 mmol) generally according to the procedure described for Intermediate 10 gave 18.8 g (79%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.26 mmol) and phenylboronic acid (0.59 g, 4.89 mmol) generally according to the procedure described for Intermediate 35 afforded 1.17 g, (78%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.342 g, 5.26 mmol) generally according to the procedure described for Intermediate 98 afforded 0.39 g (91%) of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.314 g, 1.21 mmol) according to the procedure described in Example 154 afforded 0.34 g (99%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.[CH3:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:1].[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Agent: Cl
Product: CCOC(=O)Nc1ccc(NC2=NCCC2)c(C)c1

Procedure:
The title compound was prepared by the method of Example 21 using 30.5 mmole of ethyl chloroformate and 1.0 g (3.8 mmole) of the product compound of Example 9. Complete reaction, as indicated by thin-layer chromatography (See Example 21), required heating for a second day with an additional 30.5 mmole of ethyl chloroformate. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [Br-].[C:2]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC.[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=O)[CH2:31][CH2:30]2>CS(C)=O>[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[CH2:2])[CH2:31][CH2:30]2
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CS(C)=O
Product: C=C1CCc2cc(Br)ccc21
Yield: 58.5 %

Procedure:
The title compound was synthesized in analogy to example S87 using triphenyl-phospho-nium bromide (1.49 g, 4.17 mmol), n-BuLi (3.26 ml, 1.6M solution in hexane, 5.21 mmol) and 5-bromo-1-indanone (880 mg, 4.17 mmol) in DMSO (10 ml). The residue which was isolated was purified by filtration through a short pad of silica using pentane as eluant to give 5-bromo-1-methylene-indan (510 mg, 59%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.40-7.29 (m, 3H), 5.44 (m, 1H), 5.05 (m, 1H), 2.98-2.94 (m, 2H), 2.83-2.78 (m, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]=[C:14]2[C:19](=[O:20])[NH:18][C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH2:28][C:29](OCC)=[O:30])[C:26]=4[CH2:27][C:16]=3[N:15]2[CH:34]=1)([O:3]CC)=[O:2].[ClH:35]>>[C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]=[C:14]2[C:19](=[O:20])[NH:18][C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH2:28][C:29]([Cl:35])=[O:30])[C:26]=4[CH2:27][C:16]=3[N:15]2[CH:34]=1)([OH:3])=[O:2]
Reactant: Cl
Reactant: CCOC(=O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nc(-c3ccccc3C(=O)OCC)cn12
Product: O=C(Cl)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nc(-c3ccccc3C(=O)O)cn12

Procedure:
A stirred solution of 1.3 g of ethyl 2-(2-carbethoxyphenyl)-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-9-acetate in 45 ml of a 12 N aqueous hydrochloric acid solution is maintained at boiling temperature for 64 hours. After cooling, the insoluble matter is separated by filtration, washed 3 times with a total of 45 ml of distilled water and dried under reduced pressure (0.5 mm Hg; 0.07 kPa) at 45° C. 0.9 g of 2-(2-carboxyphenyl)-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-9-acetic acid chloride is thus obtained in the form of a dark grey solid which decomposes without melting above 260° C. [1H NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz); 3.75 (2H, s, CH2), 4.05 (2H, s, CH2), 7.25 (1H, d, J=7 Hz, arom. CH), 7.40 (1H, t, J=7 Hz, arom. CH), between 7.50 and 8.10 (5H, m, 5 arom. CH), 8.45 (1H, s, imidazole CH), 13.00 (1H, broad s, NHCO)].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][N:11]1[C@@H:7]2[C@@H:6]([CH2:10][CH2:9][CH2:8]2)[C:4]([OH:3])=[C:13]([C:14]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=3[S:16](=[O:29])(=[O:30])[N:15]=2)[C:12]1=[O:31]
Reactant: CCOC(=O)C1CCCC1N(CCN(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Temperature: 60 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
A solution of 2-{(2-dimethylamino-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (25.4 mg, 0.047 mmol) in ethanol (2 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.070 mL) and stirred for 2 h at 60° C. Glacial acetic acid (0.100 mL) was added, the solvents were removed in vacuo, and the crude material was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-{3-[1-(2-dimethylamino-ethyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (5.7 mg, 0.011 mmol, 23.4%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.53-1.67 (3H, m), 2.02-2.19 (3H, m), 2.88 (6H, s), 3.07 (3H, s), 3.24-3.33 (2H, m), 3.38-3.45 (2H, m), 3.92-3.98 (1H, m), 4.08-4.15 (1H, m), 7.52-7.58 (3H, m), 9.27 (1H, s), 10.20 (1H, s). LC-MS (ESI) calcd for C20H27N5O6S2 497.14, found 498.3 [M+H+].
Reaction SMILES: [Sn](Cl)Cl.Cl.[CH3:5][O:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH2:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:14]=2[C:15]#[N:16])=[CH:9][CH:8]=1.[OH-].[K+]>>[NH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:25][CH:24]=2)[C:14]=1[C:15]#[N:16]
Reactant: COc1ccc(OCc2cccc([N+](=O)[O-])c2C#N)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: COc1ccc(OCc2cccc(N)c2C#N)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a cooled (15° C.) and stirred solution of tin (II) chloride (0.37 g, 1.65 mmol) and con. hydrochloric acid (2.0 mL) was added a solution of 2-(4-methoxyphenoxymethyl)-6-nitrobenzonitrile (100.0 mg, 0.35 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was poured on to crushed-ice and potassium hydroxide solution, stirred, extracted with dichloromethane, filtered and dried. Purification by silica gel chromatography (1% methanol in dichloromethane) yielded 65 mg of 2-amino-6-(4-methoxyphenoxymethyl)benzonitrile.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[H-]>CCOCC.C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:14]=[C:13]([C@@H:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[CH:3]=[O:2])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cccc(Cl)c1
Yield: 85.7 %

Procedure:
To a stirred solution of (R)-(3-chloro-phenyl)-(tert-butyl-dimethyl-silanoxy)-acetic acid methyl ester (4.0 g) in anhydrous ether (10 ml) and maintained at <-65° was added dropwise a 1.5M solution of di-isobututylaluminium hydride in toluene (10 ml). When addition was complete the solution was stirred at -65° for a further hour, then quenched with methanol (10 ml). The mixture was allowed to attain room temperature when silica (20 g) was added. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless liquid (3.1 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:30]=[CH:31][C:32]([O:36][CH3:37])=[C:33]([CH:35]=1)[NH2:34])([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:30]=[CH:31][C:32]([O:36][CH3:37])=[C:33]([NH:34][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)[CH:35]=1)([CH3:25])=[O:27]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: COc1ccc(P(C)(C)=O)cc1N
Product: COc1ccc(P(C)(C)=O)cc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(F)(F)F)cn1

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 5-(Dimethylphosphoryl)-2-methoxyaniline.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[OH:27])[C:10]3=[O:28])=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:27][C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]1[N:11]1[C:10](=[O:28])[C:9]2[C:14](=[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]3=[C:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:3][CH:4]=3)[CH:8]=2)[N:13]=[CH:12]1
Reactant: C1COCCN1
Reactant: O=c1c2cc(Cc3ccc(Br)cc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1c2cc(Cc3ccc(N4CCOCC4)cc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Temperature: 100 °C

Procedure:
To a solution of 6-(4-bromobenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (0.050 g, 0.11 mmol) in 1 mL of toluene under an atmosphere of nitrogen was added morpholine (0.038 g, 0.43 mmol), bis(tri-tert-butylphosphine)palladium(0) (2.8 mg, 0.0054 mmol), and potassium tert-butoxide (0.030 g, 0.27 mmol). The mixture was heated to 100° C. for 18 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 471.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.70 (s, 1H), 9.20 (d, J=6.1 Hz, 1H), 8.77 (d, J=6.2 Hz, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 7.22 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 4.64 (s, 2H), 4.22 (br s, 1H), 3.84 (t, J=4.8 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H), 2.20 (br s, 1H), 2.03-1.87 (m, 1H), 1.87-1.72 (m, 4H), 1.56-1.47 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.[NH2:14][NH2:15]>>[NH2:7][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[CH2:5][C:6]([NH:14][NH2:15])=[O:11]
Reactant: NN
Reactant: O=C1Nc2ccc(F)cc2C1=O
Solvent: O
Product: NNC(=O)Cc1cc(F)ccc1N
Temperature: 110 °C

Procedure:
Hydrazine hydrate (55%, 3000 mL) and 5-fluoroisatin (300 g) were heated to 100° C. An additional 5-fluoro-isatin (500 g) was added in portions (100 g) over 120 minutes with stirring. The mixture was heated to 110° C. and stirred for 4 hours. The mixture was cooled to room temperature and the solids collected by vacuum filtration to give crude (2-amino-5-fluoro-phenyl)-acetic acid hydrazide (748 g). The hydrazide was suspended in water (700 mL) and the pH of the mixture adjusted to <pH 3 with 12 N hydrochloric acid. The mixture was stirred for 12 hours at room temperature. The solids were collected by vacuum filtration and washed twice with water. The product was dried under vacuum to give 5-fluoro-1,3-dihydro-indol-2-one (600 g, 73% yield) as a brown powder. 1H-NMR (dimethylsulfoxide-d6) δ3.46 (s, 2H, CH2), 6.75, 6.95, 7.05 (3×m, 3H, aromatic), 10.35 (s, 1H, NH). MS m/z 152 [M+1].
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14](I)=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:18][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[S:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.[Cu](I)I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:19]1[N:20]=[C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[S:22][C:23]=1[C:14]1[C:13]([CH3:16])=[N:12][N:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]([CH3:17])=[N:9][C:10]=12
Reactant: Clc1csc(N2CCOCC2)n1
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 125 °C
Yield: 217.7 %

Procedure:
Combine 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine, (9 g, 26.2 mmol) and 4-chloro-2-morpholino-thiazole (7.5 g, 36 7 mmol) in dimethylformamide (90 mL) previously degassed with nitrogen. Add cesium carbonate (17.8 g, 55 mmol), copper iodide (250 mg, 1.31 mmol), triphenylphosphine (550 mg, 2.09 mmol) and palladium acetate (117 mg, 0.52 mmol). Heat the mixture to 125° C. for 16 h and then cool to 22° C. Add water (900 mL) and extract with methyl-t-butyl ether (3×200 mL). Combine the organic portions and evaporate the solvent. Purify by silica gel chromatography eluting with hexanes/ethyl acetate (4/1) to afford the title compound (6.4 g, 62%). ES/MS m/z (35Cl) 420 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([CH:6]=[O:7])[C:4]=1[OH:11].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[OH-].[Na+]>[OH:11][C:4]1[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:18]([O-:20])(=[O:2])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: COc1cccc(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)([O-])c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of 3-methoxysalicylaldehyde (45.6 g, 299 mM) in NaOH (138 ml, 15% aqueous solution) is treated with benzenesulfonyl chloride (66 g, 373 mM) and the mixture vigorously stirred for 1 hour. The reaction mixture is then poured into ice-water (500 ml) and the resulting white solid filtered, washed with cold water, and then recrystallized from acetic acid to afford the product as a white solid; yield 72.2 g (85%); m.p. 119°-120° C.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[N:15]1([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:25][C:24]3[CH:23]=[CH:22][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:27][CH:26]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCOCC4)cc3)cc21
Reaction time: 8 h
Yield: 52 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol), 4-(4-morpholinyl)aniline (0.26 g, 1.1 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (0.8 mL, 1.2 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a dark residue that was purified that purified by silica gel chromatography eluting with EtOAc. The product fractions were pooled and concentrated to a solid that was crystallized to give 1-ethyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one (94 mg, 52%): mp (2-propanol/hexanes) 219-223° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]([CH2:17][C@@H:18]([NH:23]C(OC(C)(C)C)=O)[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[ClH:32]>CCOC(C)=O>[ClH:32].[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]([CH2:17][C@@H:18]([NH2:23])[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)OC)Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)CN(CC(=O)OC)Cc1cccc2ccccc12
Reaction time: 1 h

Procedure:
A solution of N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1-naphthylmethyl) glycine methyl ester (5.90 g, 13.8 mmol) in EtOAc (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature for 1 hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[N:23]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cn1cc(C=O)cn1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: Cn1cc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)cn1
Yield: 45.5 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (14.3 mg, 0.130 mmol) were reacted to produce 23 mg (45%) of the title compound. mp: 255-258° C., 1H NMR (300 MHz, DMSO-d6): 11.99 (s, 1H), 7.99 (d, J=8 Hz, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.19 (s, 1H), 6.88 (d, J=8 Hz, 1H), 6.49 (d, J=8 Hz, 1H), 6.35 (m, 2H), 5.30 (t, J=8 Hz, 1H), 4.34 (m, 1H), 3.97 (s, 2H), 3.02 (s, 4H), 2.87 (s, 1H), 2.74 (s, 1H), 2.61 (d, J=8 Hz, 1H), 2.26 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS: 428, 430 (M+H), HPLC: 1.94 min (G method).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26].C([O-])([O-])=O.[Na+].[Na+]>CCO>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: Fc1ccccc1S
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Sc2ccccc2F)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
The product from Example 4a (1.50 g, 5.3 mmol) and 2-fluorobenzenethiol (0.56 mL, 5.3 mmol) in EtOH (15 mL) was added aqueous Na2CO3 solution (0.563 g, 5.3 mmol) dropwise at room temperature. The mixture was heated to reflux fluxed for 1 hour, and then evaporated. The residue was diluted with EtOAc, washed with H2O, 5% KOH and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound as yellow crystal, which was purified by washing with cold n-hexane to give the title product as yellow crystal (1.15 g, 83%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[NH:20][CH:21]=2)[CH2:3][CH2:2]1.Br[CH2:25][CH:26]([CH3:28])[CH3:27].BrCC1CC1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[N:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:21]=2)[CH2:3][CH2:2]1
Reactant: CC(C)CBr
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c[nH]c1=O
Agent: BrCC1CC1
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cn(CC(C)C)c1=O

Procedure:
The title compound from Example 242, step 1 was reacted in a manner similar to Example 242, step 2 except that 1-bromo-2-methylpropane was substituted for bromomethylcyclopropane to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.85-7.82 (m, 2H), 7.56 (s, 1H), 7.53 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 3.94 (d, J=7.2 Hz, 1H), 3.83 (d, J=7.2 Hz, 1H), 3.07 (s, 3H), 2.30-2.26 (m, 1H), 2.23 (s, 3H), 1.28-1.27 (m, 1H), 1.00 (s, 3H), 0.98 (s, 3H), 0.69-0.65 (m, 2H), 0.38-0.35 (m, 2H). LCMS: 390.2 (M+1)+
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([CH3:28])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[F:26])[C:18]2=[O:27])=[CH:12][CH:11]=1)[C:5]([O:7]CC)=[O:6].CO.[OH-].[Na+].Cl>C1COCC1.O>[F:30][C:2]([F:1])([F:29])[CH:3]([CH3:28])[CH:4]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[F:26])[C:18]2=[O:27])=[CH:14][CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(C(=O)O)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
855 mg (2.02 mmol) of ethyl 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoate were dissolved in 5.7 ml each of THF, methanol and water, and 16.2 ml (40.39 mmol) of 10% strength aqueous sodium hydroxide solution were added. The mixture was stirred at RT overnight. The reaction mixture was then diluted with water, acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 457.2 mg (58.2% of theory) of the target compound.