Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[CH3:2][N+:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH2:14][CH2:15][N:16]3C(=O)C4=CC=CC=C4C3=O)[CH:9]=2)[CH:4]=1.O.NN>C(O)C>[Br-:1].[NH2:16][CH2:15][CH2:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[N+:3]([CH3:2])[CH:12]=[CH:11]2
Reactant: C[n+]1ccc2cc(OCCN3C(=O)c4ccccc4C3=O)ccc2c1
Agent: NN
Agent: [Br-]
Solvent: CCO
Solvent: O
Product: C[n+]1ccc2cc(OCCN)ccc2c1

Procedure:
2-Methyl-6(2-Phthalimidoethoxy)isoquinolinium bromide (900 mg.) and hydrazine hydrate (0.3 g.) in ethanol (50 ml) were heated under reflux for 2 hr. The mixture was cooled and the precipitated hydrazide filtered off. Addition of ether to the filtrate gave a solid which was recrystallised from acetonitrile and had m.p. 173°-176°.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:18])=[C:7]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]([C:5]1[C:6]([O:18][CH3:19])=[C:7]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1OC
Yield: 87 %

Procedure:
Methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate (11.41 g, 45.0 mmol), potassium carbonate (9.34 g, 67.6 mmol), acetone (200 mL), and dimethyl sulfate (6.46 g, 67.6 mmol) were added together. The resultant mixture was then heated to reflux for 16 h. The mixture was then filtered and the solid was washed with ethyl acetate. The resulting organic liquid was then concentrated under vacuum to an oil and redissolved in ethyl acetate (600 mL). The organic solution was then washed with water, dried, filtered and concentrated under vacuum to an oil that was then subjected to purification via column chromatography (gradient of 5% to 40% EtOAc/Hexanes) to yield the title compound as an oil (10.42, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(N)=O)cc1Oc1ccc(F)cc1F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A mixture of 4-amino-3-(2,4-difluorophenoxy)benzamide (0.82 g) and methanesulfonyl chloride (0.39 g) in pyridine (5 ml) was stirred for 15 minutes at 5° C. and for 30 minutes at room temperature. Pyridine was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with diluted hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue (1.1 g) was subjected to column chromatography on silica gel (20 g) eluting with a mixture of toluene and ethyl acetate (1:2). The fractions containing the desired compound were combined and concentrated to give colorless crystals of 3-(2,4-difluorophenoxy)-4-(methanesulfonamido)benzamide (0.74 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1>O1CCCC1>[Cl:20][C:19]1[C:14]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:12])([F:11])[F:3])=[N:15][CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (450 mg, 11.25 mmol) was suspended in anhydrous tetrahydrofuran (10 mL). The suspension was cooled to 0° C. and 1,1,1,3,3,3-hexafluoropropan-2-ol (1.74 g, 10.35 mmol) was added over 15 minutes. The suspension was stirred 30 minutes and 2,3-dichloro-5-nitropyridine (1.50 g, 7.77 mmol) was added portionwise. The reaction was stirred at room temperature overnight then concentrated in vacuo. The crude residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted by ethyl acetate (2×25 mL). Organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to afford the title compound as an orange oil (2.55 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:22]3[S:21][CH:25]=[CH:24][N:23]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1nccs1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-thiazolecarboxylic acid as starting materials, MS (LC/MS): 414.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
The title compound, MS: m/e=282.0 (M+) was obtained as a light yellow solid (7% yield) by the reaction of 6-bromo-pyridine-2-carboxylic acid methyl ester with 3,4-dichlorophenyl boronic acid.
Reaction SMILES: B([O-])=O.[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([S:25][CH3:26])[CH:13]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1.[Cl-].[Ca+2].[Cl-].CC(C)=O>O.C(O)(C)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([S:25][CH3:26])[CH:13]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:14]([OH:19])[C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:8][CH:7]=1
Reactant: CSC(c1ccc(Cl)cc1)C(C(=O)C(C)(C)C)n1cncn1
Agent: O=B[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CSC(c1ccc(Cl)cc1)C(C(O)C(C)(C)C)n1cncn1
Reaction time: 15 h
Yield: 95.9 %

Procedure:
A solution of 2.7 g (0.0703 mol) of sodium boranate in 25 ml of water was added dropwise to a suspension of 33.75 g (0.1 mol) of 1-(4-chlorophenyl)-4,4-dimethyl-1-methylthio-2-(1,2,4-triazol-1-yl)-pentan-3-one and 7.6 g (0.0683 mol) of anhydrous calcium chloride in 200 ml of isopropanol at -5° C. The mixture was then stirred for 15 hours. After having added 20 ml of acetone the mixture was evaporated down in vacuo. The residue was stirred into water and the mixture was repeatedly extracted by shaking with methylene chloride. The methylene chloride phase was dried over sodium sulphate, filtered and evaporated down in vacuo. 32.6 g (96% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-1-methylthio-2-(1,2,4-triazol-1-yl)-pentan-3-ol, of melting point 58°-60° C., were obtained.
Reaction SMILES: [Si]([O:8][CH:9]([C:11]1[O:12][C:13](=[O:28])[C:14]2[C:19]([C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][CH:9]([C:11]1[O:12][C:13](=[O:28])[C:14]2[C:19]([C:20]=1[CH2:21][N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1CN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1oc(=O)c2ccccc2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(morpholinomethyl)-1H-isochromen-1-one (Intermediate B59.3, 0.203 g, 0.503 mmol) was dissolved in THF (7 mL); TBAF (1.0 M solution in THF, 0.33 ml, 0.33 mmol) was added drop-wise and the resulting mixture was stirred at room temperature for 2 hrs. Water (10 ml) was added and the mixture was extracted twice with DCM; the combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude was purified by reverse phase flash chromatography on C18 Biotage cartridge ((H2O:CH3CN=95:5 to 80:20, with 0.1% HCOOH) to afford the title compound (0.145 g). The product was used in the next step without further purifications.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.9 %

Procedure:
3-Hydroxy-2-nitrobenzoic acid (2.00 g) was dissolved in 110 ml of N,N-dimethylformamide, then 1.53 g of 4-chloroaniline, 3.15 g of 1-ethyl-3-[3-(N,N-dimethylamino) propyl]carbodiimide hydrochloride and 2.21 g of 1-hydroxybenzotriazole were added thereto and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated in vacuo, a saturated saline was added to the concentrate and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by means of a silica gel column chromatography using chloroform:methanol (100:1) as an eluate to give 2.97 g of 4′-chloro-3-hydroxy-2-nitrobenzanilide.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[C@H:18]1[C:30]([OH:32])=[O:31].C(Cl)Cl.[C:37]([C@@H:39](O)[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=1)#[N:38]>N1C=CC=CC=1>[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:25][C:26]([Cl:28])([Cl:29])[Cl:27])=[O:23])[C@H:18]1[C:30]([O:32][C@H:39]([C:37]#[N:38])[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:41]=1)=[O:31]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
6.2 g of dicyclohexylcarbodiimide were added to a mixture of 9.5 g of the product of Step B, 30 ml of methylene chloride and 3 ml of pyridine and after stirring for 30 minutes, 6.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added to the mixture. The mixture was stirred for 90 minutes and was filtered and the filtrate was washed with N hydrochloric acid and then with water until the wash water was neutral, dried and evaporated to dryness. The 16.3 g of oil residue were chromatographed over silica gel and eluted with a 97-3 benzene-ethyl acetate mixture to obtain 12 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 101° C.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[CH2:3][O:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[CH2:1][O:2][CH2:3][C:4]=3[CH:9]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: Oc1ccc2c(c1)COC2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)COC3)cc1
Yield: 97.4 %

Procedure:
A solution of 1,3-dihydro-2-benzofuran-5-ol (Intermediate 73, 100 mg, 0.734 mmol), 1-fluoro-4-nitrobenzene (109 mg, 0.771 mmol) and potassium carbonate (508 mg, 3.67 mmol) in acetonitrile (10 ml) was stirred under argon at 100° C. in a closed vial for 2 hours. The solid was filtered and washed with dichloromethane. The organic phase was concentrated under vacuum to afford title compound (184 mg, 96% yield)
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:8][CH:9]=2)=[N:22][CH:23]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ncnc3ccccc23)co1
Solvent: ClCCl
Product: O=c1cc(CN2CCCC2)occ1OCCCCCOc1ncnc2ccccc12
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(quinazolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 20 (100 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL). Pyrrolidine (48 μL, 0.575 mmol) was added via syringe. The mixture was stirred at 45° C. for 1.5 h. .CH2Cl2 (75 ml) was added and the solution was washed with NaHCO3 10% (3×50 mL), brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=90:10. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-((pyrrolidin-1-yl)methyl)-4H-pyran-4-one EHT 5317 was obtained (30 mg, 35% yield) as a colourless oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].O>C(Cl)Cl>[C:14]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:17])[CH:15]=[CH2:16]
Reactant: CSCCCO
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCCSC
Temperature: 2.5 °C
Reaction time: 2.5 h
Yield: 60.4 %

Procedure:
To a mixture of 3-methylthio-1-propanol (17) (12.5 g, 117.7 mmol) and triethylamine (17.8 g, 177.0 mmol) in dry CH2Cl2 (110 mL) cooled in an ice bath (0-5° C.), a solution of acryloyl chloride (21.3 g, 235.0 mmol) in dry CH2Cl2 (30 mL) was added drop-wise with stirring over a period of 2.5 hours. The reaction mixture was warmed to a room temperature, and then diluted with more CH2Cl2 (225 mL), and poured into water (250 mL). The CH2Cl2 layer was washed with saturated aqueous NaHCO3 solution (2×175 mL), and water (2.225 mL). Evaporation of the dried (Na2SO4) organic layer gave a yellow oil. Purification by column chromatography, (silica gel, hexanes, 10 wt % ether/hexanes) produced a clear oil compound 18 (11.4 g, 60 wt %), namely 3-methylthio-1-propyl acrylate (18).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:10][N:11]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:57]([C:59]1[CH:72]=[CH:71][C:62]([CH2:63][N:64]2[C:68]([CH:69]=O)=[CH:67][N:66]=[CH:65]2)=[CH:61][CH:60]=1)#[N:58].CN1CCOCC1>ClCCl.CCOC(C)=O>[C:57]([C:59]1[CH:72]=[CH:71][C:62]([CH2:63][N:64]2[C:68]([CH2:69][NH:8][C@@H:9]([CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:10][N:11]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:67][N:66]=[CH:65]2)=[CH:61][CH:60]=1)#[N:58]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)CN(Cc1cccc(Cl)c1)C(=O)OCc1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CC[C@@H](CN(Cc1cccc(Cl)c1)C(=O)OCc1ccccc1)NCc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of the product from Step E (360 mg, 0.686 mmol) in 6 mL of dichloromethane was added at room temperature dropwise 3 mL of trifluoroacetic acid. After 30 minutes, the solution was concentrated in vacuo. The resulting product was reconcentrated from benzene three times to remove excess trifluoroacetic acid. To a solution of the amine salt in 4.2 mL of 1,2-dichloroethane at 0° C. was added 4 Å powdered molecular sieves, followed by sodium triacetoxyborohydride (363 mg, 1.71 mmol). The aldehyde from Step E of Example 1 (159 mg, 0.754 mmol) was added at 0° C., followed by N-methylmorpholine (0.076 mL, 0.69 mmol). The reaction was stirred overnight, allowing it to warm to room temperature. The reaction was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (50-75% acetone/hexane) to provide the titled compound (250 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)(C)C>[OH:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][S:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: O=C(CSCc1ccncc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC(CSCc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Under a nitrogen atmosphere, alpha-(4-picolylthio) acetophenone (852 mg., 3.5 mmoles) was dissolved in 8.75 ml. of isopropyl alcohol. Sodium borohydride (54 mg., 1.4 mmoles, 1.6 equiv.) was added. After stirring for 0.5 hour at room temperature, the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled somewhat and then evaporated to an oil. With stirring, hydrochloric acid (4N, 10 ml.) was added slowly to the oil, so as to control heating and foaming. Once addition was complete and there was no evidence of gas evolution, the acid solution was made strongly basic with 20% sodium hydroxide. The oil which precipitated was extracted into chloroform. The chloroform was back-washed with dilute sodium hydroxide, dried over anhydrous sodium sulfate and concentrated to an oil (0.87 g.) which crystallized to a waxy solid on standing. The solid was triturated with ether and filtered to yield crude product (0.61 g.). Recrystallization from ethyl acetate gave purified 4-(2-hydroxy-2-phenylethylthiomethyl)pyridine [0.42 g.; m.p. 116.5°-119° C. (incomplete); ir (KBr): 3.17, 5.1-5.8, 6.22, 6.88, 9.49, 12.25, 13.88 and 14.25μ; mass spectra: m/e calcd.: 245, found: 245; pnmr/CDCl3 /TMS/delta: 8.73-8.37 (m, 2H), 7.57-7.10 (m, 7H), 4.75 (t, 1H), 3.63 (s, 2H), 3.10 (s, 1H, exchanges with D2O) and 2.72 (d, 2H)].
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1)=[N+]=[N-]>CO.O1CCCC1.[Pd]>[NH2:1][CH2:4][C@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of 6-[(4R)-4-(azidomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (230 mg, 0.877 mmol) in methanol-tetrahydrofuran (5 ml-2.5 ml) was added 10% palladium on carbon catalyst (about 50% aqueous, 130 mg) at room temperature and the mixture was stirred at the same temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration and washed with methanol, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the filtrate was concentrated under reduced pressure so as to yield 188 mg (90%) of the title compound in the form of a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([O:27]CC2C=CC(OC)=CC=2)=[N:10][C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[N:12][CH:13]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9](=[O:27])[NH:10][C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[N:12][CH:13]=1
Reactant: COc1ccc(COc2nc(O[C@@H]3COc4nc([N+](=O)[O-])cn4C3)ncc2-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3cnc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)[nH]c3=O)c(F)c2)C(=O)O1
Yield: 88.3 %

Procedure:
To a solution of (S,S)—N-(3-{3-Fluoro-4-[4-(4-methoxy-benzyloxy)-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyrimidin-5-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (60 mg, 0.092 mmol) in TFA/methylene chloride (3.0 mL, 1/1) was stirred at rt for 1 h. Solvents were evaporated and triturated with ether to give the title product (43 mg, 88%) as a pale yellow solid. ESI MS m/z 530.4 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:11][C:10](C)(C)O[C:8](=[O:14])[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2].C=[N:22][C:23]([CH3:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24]>C1(C)C(C)=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[O:11][CH2:10][N:22]([C:23]([CH3:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:8](=[O:14])[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)c1ccccc1
Solvent: Cc1ccccc1C
Product: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1
Yield: 72 %

Procedure:
A mixture of 6-acetyloxymethyl-2,2-dimethyl-5-phenyl-2H,4H-1,3-dioxin-4-one (Compound No. 241, 5.0 g) and N-methylene-1-methyl-1-phenylethylamine (2.9 g) was dissolved in xylene (40 ml) and allowed to react by refluxing for 30 minutes. The reaction mixture was purified by silica gel chromatography to afford the captioned compound (yield 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (9.0 g, 21.6 mmol) was suspended in THF/water (1:1; 200 mL). Into this solution was added lithium hydroxide monohydrate (5.31 g, 126.5 mmol) and the reaction stirred at ambient temperature overnight. The solution was cooled in an ice-bath and concentrated hydrochloric acid added until the solution reached pH 4. The precipitate was collected, washed with water and dried over P2O5 to yield off-white solid (8.642 g, 99%).