Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4.C(N(CC)CC)C.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.Cl>C(Cl)Cl>[CH:26]1([C:29]([N:18]2[CH2:17][CH2:16][C@@:13]34[C:14]5[CH:15]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=5[CH2:6][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: Oc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCOC3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reaction time: 2 h

Procedure:
The product XXXI of Step (a) (0.005 m) and triethylamine (1.5 ml) in methylene chloride (30 ml) is treated with a solution of cyclopropylcarbonyl chloride (0.0055 m) in methylene chloride (5 ml). After stirring for 2 hours the mixture is treated with dilute hydrochloric acid. The layers are separated, the methylene chloride layer is washed with water, and the aqueous layers are extracted with two more portions of methylene chloride. The combined methylene chloride layers are dried (MgSO4), filtered and concentrated to give the title product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[CH2:24](Br)[CH:25]=[CH2:26].O>CN(C=O)C>[CH2:26]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][C:6]=1[N+:21]([O-:23])=[O:22])[CH:25]=[CH2:24]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.2 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in DMF (2.0 ml), 4′-chloro-2′-nitro-p-toluenesulfonanilide (0.30 g (0.92 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, allyl bromide (0.50 ml (5.78 mmol)) was added dropwise. After being stirred for 30 minutes' at 50° C. and for 15 hours at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the crystals separated was filtered and washed to give 0.21 g (62%) of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.P(Br)(Br)(Br)(Br)[Br:22]>>[Br:22][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: BrP(Br)(Br)(Br)Br
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2Cl)cc1
Product: CCOC(=O)C(Br)c1ccc(-c2ccccc2Cl)cc1

Procedure:
To 15.0 g. (0.0476 moles) of ethyl 2'-chloro-4-biphenylylglycolate there is added slowly with stirring at 40°-50°C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-2'-chloro-4-biphenylylacetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[O:10][C:3]=12.[CH3:18][C:19]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[CH3:17][C:12]1[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:28][C:27]3[C:19]([CH3:18])=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)[CH:8]=2)=[C:15]([CH3:16])[O:14][N:13]=1
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: Cc1noc(C)c1-c1cc2nccc(Cl)c2o1
Product: Cc1noc(C)c1-c1cc2nccc(Nc3ccc4[nH]ccc4c3C)c2o1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(3,5-dimethylisoxazol-4-yl)furo[3,2-b]pyridine (25.10 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.49 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (19 mg, 52%). (HPLC (method F): 99%, RT: 3.49 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.13 (s, 1H), 8.49 (s, 1H), 7.98 (d, J=5.5, 1H), 7.37 (t, J=2.7, 1H), 7.29 (d, J=8.5, 1H), 7.07 (s, 1H), 6.99 (d, J=8.4, 1H), 6.51 (s, 1H), 6.17 (d, J=5.5, 1H), 2.52 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H); MS (m/z) 359 [M+H]+, RT: 3.4 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.[C:29](O)(=O)[CH3:30]>>[CH2:29]([N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3)[CH3:30]
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: CC(=O)O
Product: CCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3
Temperature: 55 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
To a solution of (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) in acetic acid (0.28 mL) was added NaBH (30 mg, 0.80 mmol) in 2 portion in 10 min interval at 55° C. The reaction mixture was stirred for 15 h at 55° C. then quenched by addition of H2O. The aqueous solution was basified with 50% NaOH then extracted with CHCl3. The combined organic solution was dried over MgSO4, concentrated in vacuo. The residue was chromatographed (silica gel; CHCl3: MeOH 99:1–98:2) to give the title compound as a yellow oil (26 mg, 81%). 1H NMR (CDCl3, 300 MHz) δ 1.21–1.35 (m, 3H), 2.05–2.30 (m, 5H), 2.53–2.78 (m, 6H), 2.98–3.07 (br, 1H), 3.08–3.18 (br, 1H), 3.27–3.42 (m, 2H), 3.43–3.57 (br, 1H), 3.88 (s, 3H), 6.83 (s, 1H), 6.86 (s, 1H), 7.04 (dd, J=8.8, 2.9 Hz, 1H), 7.20–7.26 (m, 2H) ppm. MS (CI, NH3): 417.1 (base, M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]([NH:14][CH3:15])=[C:10]([NH2:13])[C:11]=1[Cl:12])=[O:5])[CH3:2].[CH2:17](OC(OCC)OCC)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]2[N:13]=[CH:15][N:14]([CH3:17])[C:9]2=[N:8][C:7]=1[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(NC)c(N)c1Cl
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl

Procedure:
2.4 g. of 5-Amino-6-methylamino-4-chloro-2-methylpyridine-3-carboxylic acid ethyl ester (0.01 mol.) and 10 ml. of orthoformic acid triethyl ester are refluxed for 12 hours. After the excess ortho ester has been removed, the residue is recrystallized from ethyl acetate to obtain 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester, m.p. 56°-58°. Yield 2.2 g. (88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](C)(C)[CH3:10])=[C:6](O)[CH:7]=1.C1C=CC=CC=1.CC(C)([O-])C.[K+].BrC1C=CC(CC)=CC=1[N+]([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: CC(C)(C)[O-]
Agent: CCc1ccc(Br)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCc1ccc(Br)cc1

Procedure:
Employing the same general procedure as for the preparation of 5-bromo-2-tert-butyl-1-[(2′-amino-4′-methyl)phenoxy]benzene (Compound I), 781 mg (3.4 mmol) of 5-bromo-2-tert-butylphenol (Compound H) was converted into crude 5-bromo-2-tert-butyl-1-[4′-ethyl-2′-nitro)phenoxy]benzene using 611 mg (5.0 mmol) of potassium t-butoxide, 1.0 g (5.25 mmol) of cuprous iodide, 770 mg (˜2.78 mmol) of 1-bromo-4-ethyl-2-nitrobenzene (80% purity, obtained from the nitration of 1-bromo-4-ethylbenzene) and 10 mL of pyridine. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) gave crude 5-bromo-2-tert-butyl-1-[(4′-methyl-2′-nitro)phenoxy]benzene as a yellow oil. 290 mg of this crude sample was converted into the title compound using a balloon filled with hydrogen, 31 mg of 10% Pd/C, 4 mL of acetonitrile and 1 mL of methanol. Purification by flash chromatography (silica, 2% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1[OH:11].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:11][C:3]2[C:2]([NH:1][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[Br:10])=[O:19])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: COc1cc(N)c(O)c(Br)c1
Product: COc1cc(Br)c(OC(=O)c2ccc(OC)c(C(F)(F)F)c2)c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 20, Step c, from 2-amino-6-bromo-4-methoxyphenol and 4-methoxy-3-trifluoromethyl benzoyl chloride. The product was obtained as an off-white solid, m.p. 205-208° C.; MS m/e 622 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:28]1[N:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[N:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: Cc1cnc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-5-methyl-pyrimidine in dimethylsulfoxide at 100° C. in the presence of potassium carbonate. LC (method 4): tR=0.81 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:44])[CH2:15][C@H:16]([C:39]1[CH:43]=[CH:42][O:41][N:40]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH2:26][CH3:27])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:45]O.[OH-].[Li+].Cl>C1COCC1.O>[O:41]1[CH:42]=[CH:43][C:39]([C@H:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)[CH2:26][CH3:27])=[CH:21][CH:22]=2)[CH2:15][C:14]([OH:44])=[O:45])=[N:40]1
Reactant: OO
Reactant: CCC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(COc1ccc([C@H](CC(=O)O)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of the oxazolidinone (49.2) (23.0 mg, 0.038 mmol) dissolved in THF (2 mL), was added a 30% hydrogen peroxide solution (43 μL, 0.38 mmol) followed by a 2 M lithium hydroxide solution (94 μL, 0.19 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 49 (5.5 mg). MS ESI (pos.) m/e: 450.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.33 (1H, d, J=1.6 Hz), 7.51 (2H, d, J=8.6 Hz), 7.12 (2H, d), 6.95 (2H, d, J=8.6 Hz), 6.78 (2H, d, J=8.6 Hz), 6.16 (1H, d, J=1.6 Hz), 4.44 (1H, t, J=7.8 Hz), 4.02 (2H, t, J=6.1 Hz), 3.94 (2H, t, J=6.1 Hz), 3.09 (1H, dd, J=16.6, 8.4 Hz), 2.84 (1H, dd, J=16.4, 7.4 Hz), 1.81-1.84 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:21][C@H:22]1[CH2:27][O:26][CH2:25][CH2:24][NH:23]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][C@@H:22]2[CH3:21])[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: CS(=O)(=O)Cc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Temperature: -5 °C

Procedure:
2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred (under nitrogen) at −5° C. Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (3S)-3-Methylmorpholine was dissolved in dichloromethane and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the mixture stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried then evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (19.3 g).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2([C:16](=[O:18])[CH3:17])[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]1([C@H:7]([NH:9][C:10]([C:12]2([C:16]3([O:21][CH2:20][CH2:19][O:18]3)[CH3:17])[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCO
Reactant: CC(=O)C1(C(=O)N[C@H](C)c2ccccc2)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C[C@@H](NC(=O)C1(C2(C)OCCO2)CCC1)c1ccccc1

Procedure:
A mixture, of 13.9 g of N-[1-(R)-phenylethyl]-1-acetyl-1-cyclobutanecarboxamide, 15 ml of ethylene glycol, a catalytic amount of p-toluenesulfonic acid and 100 ml of benzene was heated under reflux for 3 hrs. The water formed in the reaction was removed using a Dean-Stark apparatus. After cooling, the mixture was washed with a saturated sodium bicarbonate aqueous solution, then washed with water and then dried. The solvent was removed under reduced pressure to yield 16.5 g of the titled compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[C:33]1([CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:41][CH2:40][CH:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (160 mg, 0.44 mmol) is dissolved in THF (5 mL) under an atmosphere of argon. DIPEA (69 mg, 0.53 mmol) is added followed by 2,2-diphenylethylamine (96 mg, 0.49 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:33])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccccc1-c1cccc(F)c1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=C(c1ccccc1-c1cccc(F)c1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 3′-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C27H23FN4O, 438.51; m/z found, 439.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[N:2]1.[F:7][C:8]1[C:21]([N:22]=[C:23]=[S:24])=[CH:20][C:11]2[CH:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[NH:14][O:15][C:10]=2[CH:9]=1>C1C=CC=CC=1>[F:7][C:8]1[C:21]([NH:22][C:23]([N:2]2[CH2:3][CH2:4][CH2:5][CH:6]=[N:1]2)=[S:24])=[CH:20][C:11]2[CH:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[NH:14][O:15][C:10]=2[CH:9]=1
Reactant: C#CCC1C(=O)NOc2cc(F)c(N=C=S)cc21
Reactant: C1=NNCCC1
Solvent: c1ccccc1
Product: C#CCC1C(=O)NOc2cc(F)c(NC(=S)N3CCCC=N3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
0.32 g of 1,4,5,6-tetrahydropyridazine was dissolved in 20 ml of benzene, and 1.00 g of 7-fluoro-4-propargyl-2H-benzoxazin-3(4H)-one-6-ylisothiocyanate was added thereto. The mixture was stirred at room temperature for 3 hours. After the reaction, benzene was distilled off to obtain a crude product. This crude product was purified by silica gel column chromatography (developing solvent: chloroform) to obtain 0.38 g of the above-identified compound as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH3:40][C:41]([CH3:43])=[O:42]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH2:17][C:41]([OH:42])([CH3:43])[CH3:40])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reactant: CC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-ethan-1-one (Example 2) (1.07 g, 4.3 mmol) in CH2Cl2 (65 mL) is cooled to -78° C., and diisopropylethylamine (0.97 mL, 5.6 mmol) and trimethylsilyltriflate (1.08 mL, 5.6 mmol) are added sequentially via syringe. The reaction is stirred at -78° C. for 10 min and then is allowed to warm to 24° C. and is stirred at that temperature for 45 min. The solution is once again cooled to -78° C., and acetone (0.54 mL, 4.3 mmol) is added, followed by TiCl4 (1M solution in CH2Cl2, 4.3 mL, 4.3 mmol). After 1 h at -78° C., the reaction mixture is allowed to warm to 24° C. and evaporated. The residue is partioned between MeOH/1N HCl and CH2Cl2. The CH2Cl2 layer is dried (MgSO4), filtered, evaporated, and chromatographed over SiO2 using EtOAc/hexane (1:6), to yield 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-hydroxy-3-methylbutan-1 -one.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1.CCCCCC>[C:1]1([C:7]2[C:12]3[S:13][C:14]4[C:19]([B:25]([OH:28])[OH:26])=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccc3c2sc2ccccc23)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1sc1c(-c3ccccc3)cccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
3.5 g (13.4 mmol) 4-phenyldibenzothiophene was dissolved in ˜30 mL anhydrous THF in a three necked 250 mL flask and cooled down to −78° C. To the mixture, 17 mL (27 mmol) 1.6 M BuLi in hexane was added and stirred for 30 minutes. The cooling batch was removed and let reaction kept stirring for overnight. The reaction mixture was cooled down again to −78° C. and 4.5 mL (40 mmol) trimethyl borate was added and stirred at room temperature for 4 hours. ˜100 1M HCl was added and kept stirring for 1 hour. The mixture was extracted by ethyl acetate and the organic extracts were combined. The solvent was evaporated to dryness. The solid was added with ˜100 mL 20% ethyl acetate in hexane was stirred for few hours and then filtered. The filtered solid washed by hexane few times. ˜2.5 g white solid was obtained as product which was confirmed by proton NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:31])[N:10]1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[OH:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:59]([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61].N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:59]([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:31])[N:10]1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[OH:38]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: O=C(NCCc1cccc(O)c1)C1c2ccccc2C(=O)N(C2CCCCC2O)C1c1ccc(Cl)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Oc1cccc(CCNC(=O)C2c3ccccc3C(=O)N(C3CCCCC3O)C2c2ccc(Cl)cc2Cl)c1)C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 121 %

Procedure:
To a mixture of 980 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(3-hydroxyphenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 1160 mg of triphenylphosphine, 1080 mg of tert-butyl (2R)-2-hydroxypropanate, and 30 mL of THF was added 770 mg of diethyl azodicarboxylate at room temperature, followed by stifling for 12 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 1460 mg of tert-butyl (2S)-2-(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenoxy)propanate as a yellow solid.