Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:15](=[C:16]([NH:25][CH:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:28][CH2:27]4)[N:17]=[CH:18][N:19]=3)[C:14]1=2)[C:10]#[N:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:38][Li].O.OO>CO>[Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:15](=[C:16]([NH:25][CH:26]4[CH2:27][CH2:28][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:30][CH2:31]4)[N:17]=[CH:18][N:19]=3)[C:14]1=2)[C:10]([NH2:11])=[O:38])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanenitrile (180 mg, 0.33 mmol, 1.00 equiv) in methanol (5 mL) was added LiOH.H2O (40 mg, 0.95 mmol, 3.00 equiv) and 0.5 mL of H2O2 (30%) at 0° C. The resulting solution was stirred for 1 h at 0° C. and then quenched with saturated aqueous Na2SO3, diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 130 mg (70%) of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanamide as a white solid. MS: m/z 560 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH3:7][C:8]1[CH:17]=[C:11]2[N:12]=[CH:13][CH:14]=[C:15]([NH2:16])[N:10]2[N:9]=1.[N+:18]([O-])([OH:20])=[O:19].N>>[CH3:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[C:11]2[N:12]=[CH:13][CH:14]=[C:15]([NH2:16])[N:10]2[N:9]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2nccc(N)n2n1
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1nn2c(N)ccnc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 66 %

Procedure:
27 cc of 98% sulphuric acid were introduced into a 100 cc three-necked flask equipped with a magnetic stirrer, a thermometer and a condenser, after which 5.5 g of 2-methylpyrazolo[1,5-a]pyrimidin-7-ylamine hydrochloride were dissolved portionwise at 5° C. A mixture of 1.98 g of fuming nitric acid and 5 cc of 98% sulphuric acid was then added dropwise over 30 minutes. After reaction for 2 h 30', the medium was poured onto 200 cc of ice-cold water and neutralized with 122 g of 20% aqueous ammonia. The green precipitate which formed was filtered off. After drying under vacuum over phosphorus pentoxide, 3.8 g of 2-methyl-3-nitropyrazolo[1,5-a]pyrimidin-7-ylamine were obtained in the form of a green powder. (Crude yield=66%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH3:13])[CH:5]=1)([O-:3])=[O:2].CC1C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].CO>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[O:9][CH:26]=[N:25][CH:24]=2)=[C:6]([O:12][CH3:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1-c1cnco1
Temperature: 64 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a 5 L three necked round bottom flask equipped with a condenser and a mechanical stirrer was placed 1B (146.3 g, 0.8076 mol), TOSMIC (157.7 g, 0.8077 mol), K2CO3 (116.6 g, 0.8075 mol) and MeOH (2.5 L). The mixture was heated to reflux under N2 and stirred for 3 hours. Water (1.25 L) was added drop-wise while maintaining the pot temperature between 59-69° C. The resulting slurry was cooled to room temperature, and then to 5° C. with an ice-water bath. After stirring for 30 minutes at 5° C., the slurry was filtered. The resulting cake was washed with water (3×400 mL) and dried in a vacuum oven at 45° C. for 20 hours to give 5-(4-nitro-2-methoxyphenyl)oxazole (1C, 148.5 g, 84%) as a yellow-reddish solid. 1H NMR (CDCl3) d 8.02 (s, 1H), 7.97 (d, J=2 Hz, 1H), 7.95 (d, J=2 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 4.11 (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[NH:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)[NH:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCC2)CC1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)N(C3CCCC3)C3CCC(C)CC3)s2)n1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea (Example 202) and ethyl-2-mercapto-1H-imidazole-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](I)[CH2:21][CH2:22][CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+].CC#N>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CCCCCI
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC#N
Product: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 73.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (50 g) is alkylated using pentyliodide (76.8 g; 0.38 mol) and K2CO3 (53.6 g; 0.38 mol) at 60° C. for 24 h. After aqueous work-up the crude material is de-acetylated under reflux in 2-propanol (500 ml) and hydrochloric acid (6 N; 300 ml). After aqueous work-up pure 5-amino-3,3-dimethyl-6-nitro-1-pentyl-1,3-dihydro-indol-2-one (40.7 g) is obtained by re-crystallization from MeCN.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (10.0 g, 39.0 mmol), methylene chloride (500 mL), and a catalytic amount of DMF (0.2 mL) was stirred under argon, and oxalyl chloride (2M in methylene chloride, 50 mL, 100 mmol) was added dropwise into the mixture over 30 min. The mixture was stirred at room temperature for 1.0 hr and the reaction was concentrated to dryness. Benzene (100 mL) was added and the solution was evaporated to dryness again. The pale yellow solid was re-dissolved in methylene chloride (200 mL) and dripped, under argon, into a solution of 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (10.8 g, 39.0 mmol), and triethylamine (10.2 g, 100 mmol) in methylene chloride (250 mL) over 30 min. The reaction was stirred at room temperature for 1 hr then concentrated and the residue was taken up in EtOAc (500 mL) and washed with hydrochloric acid (0.1N, 200 mL), water (200 mL), saturated sodium bicarbonate solution (200 mL), and brine (200 mL). The organic layer was dried with anhydrous sodium sulfate and filtered. The solvent was removed and the residue was triturated with hexanes to give 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (19.24 g, 96% yield). ES-MS for C27H28F3N3O4 calcd. (m/e) 515, observed 516 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19].[NH2:22]/[C:23](/[CH3:32])=[CH:24]\[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(O)(=O)C>CC(O)C>[C:18]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([CH3:32])[NH:22][C:16]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 93.1 mg (0.93 mmol) of 2,4-pentanedione, 83.5 mg (0.53 mmol) of tert-butyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: dichloromethane/methanol 95:5). 87 mg (40% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@@H:5]1[CH2:22][C:21]2[CH2:20][C:19](=[O:23])[CH2:18][CH2:17][C:16]=2[C@@H:15]2[C@@H:6]1[C@H:7]1[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C@@H:10]([OH:24])[CH2:9][CH2:8]1)[CH3:4]>O1CCCC1.CO>[CH2:3]([C@@H:5]1[CH2:22][C:21]2[CH2:20][C@H:19]([OH:23])[CH2:18][CH2:17][C:16]=2[C@@H:15]2[C@@H:6]1[C@H:7]1[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C@@H:10]([OH:24])[CH2:9][CH2:8]1)[CH3:4].[CH2:3]([C@@H:5]1[CH2:22][C:21]2[CH2:20][C@@H:19]([OH:23])[CH2:18][CH2:17][C:16]=2[C@@H:15]2[C@@H:6]1[C@H:7]1[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C@@H:10]([OH:24])[CH2:9][CH2:8]1)[CH3:4]
Reactant: CC[C@@H]1CC2=C(CCC(=O)C2)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H]1CC2=C(CC[C@@H](O)C2)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Product: CC[C@@H]1CC2=C(CC[C@H](O)C2)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.013 g) was added to a solution of (7α,17β)-7-ethyl-17-hydroxyestr-5(10)en-3-one (Example 2; 0.25 g) in a mixture of tetrahydrofuran (4.2 ml) and methanol (4.2 ml). The reaction mixture was stirred at room temperature for 2 h and then quenched with acetone. The mixture was poured into water and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography afforded (3α,7α,17β)-7-ethylestr-5(10)-ene-3,17-diol, m.p. 98-100° C., and (3β,7α,17β)-7-ethylestr-5(10)-ene-3,17-diol, m.p. 60-65° C.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH:3]([CH2:7][C:8](Cl)=[O:9])[C:4](Cl)=[O:5].[Br:13][C:14]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:16]([C:17]([O:19]C(C)(C)C)=O)[C:15]=1[OH:28].[H-].[Na+]>O1CCCC1.FC(F)(F)C(O)=O>[Br:13][C:14]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:16]([CH2:17][O:19][C:1](=[O:11])[CH2:2][CH:3]([CH2:7][C:8]([O:19][CH2:17][C:16]2[C:15](=[C:14]([Br:13])[CH:26]=[C:25]([Br:27])[CH:24]=2)[OH:28])=[O:9])[C:4]([O:19][CH2:17][C:16]2[C:15](=[C:14]([Br:13])[CH:26]=[C:25]([Br:27])[CH:24]=2)[OH:28])=[O:5])[C:15]=1[OH:28]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1O
Reactant: O=C(Cl)CC(CC(=O)Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(CC(CC(=O)OCc1cc(Br)cc(Br)c1O)C(=O)OCc1cc(Br)cc(Br)c1O)OCc1cc(Br)cc(Br)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tricarballylic trichloride (0.01 mol) (see Emery, Ber., 22:2921 (1989)) in dry tetrahydrofuran (THF) (10 ml) was added dropwise to three equivalents of tert-butyl 3,5-dibromosalicylate (see Delaney et al, Arch. Biochem. Biophys., 28:627 (1984)) previously been treated with a stoichiometric amount of NaH in THF. The mixture was stirred for 5 hours at room temperature, and the solvent was then removed under reduced pressure. The residue was dissolved in diethyl ether and extracted several times with water. The extract was dried over MgSO4, filtered and concentrated. Recrystallization from ethanol gave a pure product; m.p. 100-102° C. The resulting product (2 mmol) was dissolved in anhydrous trifluoroacetic acid (10 ml) and allowed to stand at room temperature. After 30 minutes, the solvent was removed under reduced pressure and the precipitate recrystallized from trifluoroacetic acid; m.p. 186° C. (see Razynska et al, supra).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-:27].[Na+].Cl>FC(F)(F)C(O)=O.O>[OH:27][C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 4 h

Procedure:
A solution of 4-{3-[3-[2-(1-Cyclohexenyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (3.7 g., 0.01 mole) in trifluoroacetic acid (20 ml.) is allowed to stand at 25° C. for 4 hours. Excess trifluoroacetic acid is then removed by evaporation at reduced pressure. The oily residue is dissolved in a solution of sodium hydroxide (2.0 g., 0.05 mole) in water (40 ml.). The basic solution is acidified with 2 N hydrochloric acid. The title compound precipitates as a solid. Recrystallization from acetonitrile-water yields the purified title compound, m.p. 147°-148° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18]1[C:22]2[C:23]([OH:27])=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19]1>CN(C)C=O>[CH3:17][CH:18]1[C:22]2[C:23]([O:27][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19]1
Reactant: CC1OCc2cccc(O)c21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1OCc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Temperature: 110 °C
Yield: 92.6 %

Procedure:
In a microwave vial 3-methyl-1,3-dihydro-2-benzofuran-4-ol (Intermediate 98, 24 mg) was dissolved in N,N-dimethylformamide (1.5 ml) to give a pale yellow solution. 2-chloro-5-nitropyridine (24.07 mg, 0.152 mmol) and potassium carbonate (62.9 mg, 0.455 mmol) were added. The reaction vessel was sealed and heated in a microwave Biotage Initiator at 110° C. for 1 hour. After cooling, the reaction mixture was quenched with 5 ml of water and diluted with 25 ml of Et2O. The organic phase was washed with water (3×10 mL) and the phases were separated. The organic phase was passed through a phase separator cartridge and evaporated under vacuum to give the title compound (38.3 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[CH:8][NH:9][C:10](=O)[C:11]=2[CH:12]=1.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:10]1[N:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=[N:5]2
Reactant: O=c1[nH]ccc2ncc(C(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: FC(F)(F)c1cnc2ccnc(Cl)c2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-(trifluoromethyl)-1,6-naphthyridin-5(6H)-one (as prepared in the previous step, 1 g, 4.67 mmol, 1.00 equiv) in acetonitrile (10 mL) and phosphoryl trichloride (10 mL). The reaction mixture was stirred for 2 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:20). The title compound was obtained as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:21]3[C:22]([CH3:29])=[C:23]([OH:28])[C:24]([CH3:27])=[C:25]([CH3:26])[C:20]=3[O:19][C:18]=2[CH3:30])=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.O>C(Cl)(Cl)Cl>[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([O:28][C:23]2[C:24]([CH3:27])=[C:25]([CH3:26])[C:20]3[O:19][C:18]([CH3:30])=[C:17]([C:14]4[CH:15]=[CH:16][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:12][CH:13]=4)[C:21]=3[C:22]=2[CH3:29])=[O:38])=[CH:35][CH:34]=1
Reactant: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccc(C(C)C)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Oc2c(C)c(C)c3oc(C)c(-c4ccc(C(C)C)cc4)c3c2C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
Triethylamine (0.45 mL, 3.21 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,4,6,7-tetramethylbenzofuran-5-ol (0.90 g, 2.92 mmol) and 4-methoxybenzoyl chloride (0.55 g, 3,21 mmol) in chloroform (15 mL) at room temperature, and the mixture was stirred for 3 hours at 60° C. Water (30 mL) was poured into the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with 1 N hydrochloric acid and saturated sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain the title compound (0.52 g, yield 79).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2I)[O:9][C:8]1=[O:24].[CH:34]([C:37]1[CH:38]=[CH:39][C:40]([O:46][CH3:47])=[C:41](B(O)O)[CH:42]=1)([CH3:36])[CH3:35]>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:41]2[CH:42]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:38]=[CH:39][C:40]=2[O:46][CH3:47])[O:9][C:8]1=[O:24]
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1B(O)O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Following the procedure described in EXAMPLE 81, 41 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 17 mg of (5-isopropyl-2-methoxyphenyl)boronic acid gave title compound. Mass spectrum (ESI) 620.4 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3 Hz).
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[CH:33]1([C:38]([O-:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1.[Cs+].[I-].[Na+].O>C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:40][C:38]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:39])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: O=C([O-])C1CCCC1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)OC(=O)C1CCCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.20 g, 0.41 mmol), cesium cyclopentanecarboxylate (0.20 g, 0.81 mmol) and sodium iodide (0.061 g, 0.41 mmol) in acetonitrile (15 mL) were heated to reflux overnight. Upon cooling to RT, water was added and the reaction mixture was extracted with ethyl acetate and then with dichloromethane. The organic phases were washed with brine, combined, dried over magnesium sulfate, filtered, and conc in vacuo. The isolated residue was subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-4% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 63%. 1H NMR (400 MHz, DMSO-d6): δ 7.39 (dd, 1H), 7.35-7.31 (m, 1H), 7.24-7.20 (m, 1H), 6.73-6.69 (m, 1H), 4.74-4.70 (m, 1H), 4.12-3.93 (m, 2H), 3.88-3.73 (m, 2H), 3.39-3.28 (m, 2H), 3.26 (s, 3H), 3.18-3.11 (m, 1H), 3.06-3.03 (m, 2H), 2.76-2.68 (m, 1H), 2.37 (d, 3H), 2.15-2.06 (m, 2H), 2.00-1.97-(m, 2H), 1.80-1.70 (m, 2H), 1.68-1.56 (m, 2H), 1.54-1.43 (m+dd, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH2:15](O)[CH3:16]>>[CH2:15]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:4]=1)[CH3:16]
Reactant: CCO
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Product: CCOC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Yield: 99 %

Procedure:
To a suspension of 4-chloro-3-sulfamoyl-benzoic acid (50 g, 212 mmol) in 500 mL ethanol is bubbled HCl gas for 10 minutes. The resulting suspension is then heated at reflux for 16 h, cooled and concentrated in vacuo. The resulting residue is recrystallized from isopronanol to yield 55.9 g (99%) of the title compound as an off-white solid.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:21][CH3:22])[N:15]=2)[CH2:8]1)(=O)=O.[CH3:23][NH:24][CH3:25].C([O-])(O)=O.[Na+]>O>[Cl:20][C:18]1[CH:19]=[C:14]([N:9]2[C@H:10]([CH3:13])[CH2:11][O:12][C@H:7]([CH2:6][N:24]([CH3:25])[CH3:23])[CH2:8]2)[N:15]=[C:16]([NH:21][CH3:22])[N:17]=1
Reactant: CNC
Reactant: CNc1nc(Cl)cc(N2C[C@@H](COS(C)(=O)=O)OC[C@H]2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CNc1nc(Cl)cc(N2C[C@@H](CN(C)C)OC[C@H]2C)n1
Temperature: 120 °C
Reaction time: 32 h
Yield: 45 %

Procedure:
A mixture of {(2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl methanesulfonate (161 mg, 0.46 mmol) and dimethylamine (2.0 M in THF, 5.0 mL, 10.0 mmol) was stirred at 120° C. in a sealed tube for 32 hours. The mixture was cooled, poured into saturated aqueous NaHCO3 (15 mL), diluted with water (5 mL), and extracted with EtOAc (3×15 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiO2, CH2Cl2 to 95/5/0.5 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (62 mg, about 85% purity) as an off-white foam. LC-MS (ES) m/z=300, 302 [M+H]+.