Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH2:11])[O:8][CH:7]=[N:6]1)=[O:4].[O:27]1CCCC1>O.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:4])[CH:5]([NH:6][CH:7]=[O:27])[CH:9]([OH:8])[C:10](=[CH2:11])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: C1CCOC1
Reactant: C=C(CCCCNC(=O)OCc1ccccc1)C1OC=NC1C(=O)OC
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(CCCCNC(=O)OCc1ccccc1)C(O)C(NC=O)C(=O)OC

Procedure:
9.4 g (26.1 mmol) of 5-[6-(N-benzyloxycarbonylamino)hex-1-en-2-yl]-oxazoline-4-carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran and 20 ml of water, a few drops of triethylamine are added and the mixture is heated under reflux for 18 hours. The solvent is removed under reduced pressure and the oil that remains is taken up in a total of 125 ml of methylene chloride, dried over magnesium sulfate and concentrated to dryness by evaporation. 8-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester is obtained.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C:18]1[CH:31]=[CH:30][C:21]2[C@H:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][O:24][C:20]=2[CH:19]=1.[Br:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]2[C:34]=1[CH2:35][CH2:36][C@@H:37]2O.C(P(CCCC)CCCC)CCC>O1CCCC1>[Br:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]2[C:34]=1[CH2:35][CH2:36][C@H:37]2[O:17][C:18]1[CH:31]=[CH:30][C:21]2[C@H:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][O:24][C:20]=2[CH:19]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: O[C@H]1CCc2c(Br)ccc(F)c21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reaction time: 0.5 h

Procedure:
A solution of di-tert.-butyl azodicarboxylate (18 g) in tetrahydrofuran (80 mL) is added dropwise over 45 minutes to a solution of (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (11 g), (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (11.95 g) and tributylphosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 minutes and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. Yield: 10.35 g; LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([NH:12][NH2:13])=[O:11])[CH:7]=[CH:6][C:5]=12.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](O)=O)[CH:19]=[CH:20][CH:21]=1>>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=3)=[N:12][N:13]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc2nccn2c1
Product: FC(F)(F)c1cccc(CCc2nnc(-c3ccc4nccn4c3)o2)c1
Yield: 58 %

Procedure:
In the same manner as in Example 14 and using imidazo[1,2-a]pyridine-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-[3-(trifluoromethyl)phenyl]propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 58%) was obtained as colorless crystals.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]#[CH:18]>>[C:28]1([CH2:27][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][CH2:16][C:17]#[C:18][C:2]2[CH:15]=[CH:14][C:5]([C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Reactant: C#CCOCCCCCCNCc1ccccc1
Product: O=C(c1ccc(C#CCOCCCCCCNCc2ccccc2)cc1)N1CCOCC1
Yield: 40.4 %

Procedure:
4-(4-Iodobenzoyl)morpholine (4.0 g) and N-[6-[(2-propynyl)oxy]- hexyl]benzenemethanamine (3.09 g) were reacted according to the method of Intermediate 31. FCC purification eluting with ethyl acetate-triethylamine (100:1) gave the title compound as a yellow oil (2.21 g), t.l.c. (Ethyl acetate-triethylamine 100:1) Rf 0.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][C:36]4[N:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=4)[CH:31]=3)[O:26]2)=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][C:36]4[N:41]=[CH:40][C:39]([NH:42][C:13](=[O:15])[C:12]5[CH:11]=[CH:10][C:9]([CH2:8][N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[CH:17][CH:16]=5)=[CH:38][CH:37]=4)[CH:31]=3)[O:26]2)=[CH:21][CH:20]=1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Oc4ccc5c(c4)CCC(c4ccc(F)cc4)O5)nc3)cc2)CC1
Reaction time: 3 h

Procedure:
4-(4-Methylpiperazin-1-ylmethyl)benzoic acid (ca 0.19 g), 6-[2-(4-fluoro-phenyl)-chroman-6-yloxy]pyridin-3-ylamine (0.18 g) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.12 g) were added into dichloromethane (12 ml). The mixture was stirred at room temperature and after 4 hours more 4-(4-methylpiperazin-1-ylmethyl)-benzoic acid (ca 0.11 g) and 1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide hydrochloride (0.0.46 g) were added. Stirring was continued for additional 3 hours. Water and dichloromethane were added and organic and water phases were separated. Water phase was extracted with dichloromethane. The product was purified by column chromatography using dichloromethane-methanol (9:1) as an eluent to give N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]-pyridin-3-yl}-4-(4-methylpiperazin-1-ylmethyl)benzamide. 1H NMR (300 MHz, d6-DMSO) δ: 1.90-2.08 (m, 1H), 2.11-2.21 (m, 1H), 2.18 (s, 3H), 2.38 (bs, 8H), 2.68-2.79 (m, 1H), 2.91-3.05 (m, 1H), 3.54 (s, 2H), 5.13 (dd, 1H, J 2.0, 10.1 Hz), 6.86 (d, 2H, J 1.2 Hz), 6.90 (s, 1H), 6.98 (d, 1H, J 8.8 Hz), 7.19-7.27 (m, 2H), 7.43-7.54 (m, 4H), 7.92 (d, 2H, J 8.2 Hz), 8.18 (dd, 1H, J 2.7, 8.9 Hz), 8.48 (d, 1H, J 2.7 Hz), 10.31 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].[CH2:23](C([Sn])=C(CCCC)CCCC)[CH2:24]CC.[F-].[Cs+]>C1(C)C=CC=CC=1.CC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide (prepared as described in WO 00/61569) (1.0 g), tetrakis(triphenylphosphine)palladium(0) (96 mg) and tributylvinyltin (1.15 mL) in toluene (15 mL) was heated at reflux for 3 hours, then cooled to room temperature, diluted with acetone (30 mL) and treated with cesium fluoride (10% aq, 10 mL) at room temperature for 2 hours. The resulting mixture was filtered through celite with further washing with toluene and concentrated. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oil was purified by column chromatography (ethyl acetate:isohexane 100:1 to 80:20) to give the sub-titled compound as a white solid (0.87 g).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7](/[CH:9]=[N:10]/[OH:11])=O)=[CH:3][CH:2]=1.O.[NH2:13][NH2:14]>CO>[N:13](=[C:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH:9]=[N:10][OH:11])[NH2:14]
Reactant: O=C(/C=N/O)c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NN=C(C=NO)c1ccccc1
Yield: 67.8 %

Procedure:
A solution of 2-isonitrosoacetophenone (50 g, 335 mmol) in methanol (500 ml) was treated with hydrazine monohydrate (19.5 ml, 402 mmol). The reaction mixture was stirred at room temperature for 20 h at which time the methanol was evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 20% EtOAc in hexanes) to afford 37 g (227 mmol; 68%) of hydrazono-phenyl-acetaldehyde oxime as a white solid. δH (360 MHz; CDCl3) 7.22-7.42 (3H, m, aromatics), 7.42-7.60 (2H, m, aromatics), 7.99 (2H, br s, NH2), 8.26 (2H, br s, ArC(NNH2)CHNOH); m/z (ES+) 164 (M++H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)[CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: COc1cccc(CCl)c1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cccc(CN(c2ccc(Cl)cc2)c2nc(=O)c3cccnc3s2)c1
Yield: 22.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 2.681 g (9.25 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 162 mg of lithium hydride, 1.50 g of 3-methoxybenzyl chloride and 40 ml of DMF were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform). As a result, 2.288 of 2-[N-(4-chlorophenylimino)-2,3-dihydro-4H-3-(3-methoxybenzyl)pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ethanol) was obtained as a low polarity substance, and 843 mg of 2-[N-(4-chlorophenyl)-N-(3-methoxybenzyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ethyl acetate and diisopropyl ether) was obtained as a high polarity substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>C(Cl)Cl>[C:19]([C:15]1[C:16]([O:17][CH3:18])=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[S:3][C:4]=3[CH:10]=2)[CH:12]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(-c2ccc3nc(NS(C)(=O)=O)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.6 %

Procedure:
To a solution of the product from Example 83 (0.35 g, 0.83 mmol) in anhydrous CH2Cl2 (50 mL) was added methanesulfonyl chloride (194 μL, 2.49 mmol) and pyridine (1.34 mL, 16.6 mmol). The resulting mixture was stirred at room temperature for 16 h and concentrated in vacuo. The crude product was purified by C-18 reverse-phase HPLC using an acetonitrile:H2O (0.1% TFA) gradient to give the title compound (19 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H) 11.41 (d, J=1.84 Hz, 1H) 7.96 (d, J=1.47 Hz, 1H) 7.77 (d, J=8.09 Hz, 1H) 7.57 (dd, 1H) 7.42 (d, J=8.09 Hz, 1H) 7.25-7.32 (m, 2H) 5.64 (dd, J=8.09, 2.21 Hz, 1H) 3.25 (s, 3H) 3.02 (s, 3H) 1.40 (s, 9H).
Reaction SMILES: Cl.[CH2:2]([O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH:34]C=O)[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]3[S:20][CH:21]=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]>CO.O1CCCC1>[CH2:2]([O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]3[S:20][CH:21]=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.4 %

Procedure:
Conc. hydrochloric acid (0.85 g.) was added under ice-cooling to a stirred solution of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 g) in a mixture of methanol (23 ml.) and tetrahydrofuran (23 ml.), and the mixture was stirred for 2.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (pH 7.0). The aqueous solution was washed with ethyl acetate and adjusted to pH 3.5 with conc. hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give powder of 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.865 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:21])[CH3:20]>CO>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:16])[F:17])[N:21]([CH2:19][CH3:20])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Solvent: CO
Product: CCn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Reaction time: 0.17 h
Yield: 52 %

Procedure:
5-Benzyloxy-2-difluoromethyl-pyran-4-one (2.0 g, 7:93 mmol) was suspended in 15 mL of methanol. A 2.0M solution of ethylamine in methanol (8.0 mL) was added at room temperature, and the reaction slowly turned into a clear yellow/green solution over 10 min. After 4 h, the reaction mixture was concentrated in vacuo to an oil. The oil was diluted with 10 mL of ethyl acetate and stirred until a solid precipitated out. The solid was collected by suction filtration, thoroughly washed with ether, and dried to afford the title product (1.14 g, 52% yield). HPLC purity (peak area percent) is 97.5% at λ=280 nm using HPLC Method 1 as described above.
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([O:6][CH:3]1[CH2:4][CH2:5][CH:1]([OH:7])[CH2:2]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC1CCC(O)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(OC1CCC(O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To a solution of 1,3-cyclopentanediol (500 mg) in pyridine (10 mL) was added benzoyl chloride (688 mg), and the mixture was stirred for 18 hours at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N-hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1 to 1:1) to give 3-hydroxycyclopentyl benzoate as a colorless oil (630 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16]OS(C)(=O)=O)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](=[O:31])[CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][CH:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH3:32])[C:29](=[O:31])[CH3:30])[C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Cc1ccccc1C
Reactant: CC(C)OC(=O)C(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1ccccc1C
Reaction time: 30 h
Yield: 65.6 %

Procedure:
To a solution of 2 (181.2 g, 0.557 mol) in THF (1 L) was added TEA (84.6 g, 0.836 mol) in portions at 15-20° C. The mixture was stirred for 30 h. After the reaction was complete, the solution was concentrated to give crude 7. To a solution of 35 (82.5 g, 0.557 mol) and Cs2CO3 (91 g, 0.279 mol) in DMSO (1 L) was added slowly crude 7 in DMSO (500 mL) over 30 min at 15-20° C. The mixture was stirred for 1 h. After the reaction was complete, the mixture was partitioned with water and MTBE (5 L), and extracted with MTBE twice. The combined organic layer was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-10% EtOAc/PE) to give 36 (138 g, 65% yield).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[CH:31]1[CH2:37][O:36][CH2:35][CH:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33][CH2:32]1)=[O:23])=O)(C)(C)C.Cl>O1CCOCC1.CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[CH:31]1[CH2:32][CH2:33][CH:34]([NH2:38])[CH2:35][O:36][CH2:37]1)=[O:23]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(NC(=O)OC(C)(C)C)COC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CCC(N)COC1
Yield: 32 %

Procedure:
tert-Butyl N-[6-[4-[[5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]oxepan-3-yl]carbamate was stirred with 4N HCl in dioxane (5 mL) and methanol (2 mL) at room temperature for 3 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 143 (24 mg, 32%). 1H NMR (400 MHz, DMSO) δ 9.73, 9.56 (s, 1H), 7.83, 7.78 (s, 1H), 7.62-7.42 (m, 3H), 7.36-7.18 (m, 2H), 3.96-3.71 (m, 6H), 3.59 (ddd, J=71.3, 12.2, 4.1 Hz, 1H), 3.03-2.91 (m, 1H), 2.94-2.79 (m, 1H), 2.10-1.89 (m, 1H), 1.85-1.68 (m, 1H), 1.68-1.56 (m, 1H), 1.54-1.39 (m, 1H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)cn1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)cn1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
3-(3-Fluoro-4-(4-methylimidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (11.8 g, 40.5 mM) was stirred in a mixture of pyridine (200 ml) and triethylamine (4.86 g, 48.2 mM) under nitrogen in an ice-bath. Methanesulfonyl chloride (5.16 g, 45 mM) was added dropwise, and the mixture stirrd for 2 hours, allowing the temperature to rise to ambient. Solvent was evaporated, and the residue stirred vigorously with a mixture of aqueous sodium bicarbonate (5%, 200 ml) and isohexane (200 ml). The precipitate was filtered, washed with water then isohexane, and dried. The residue was recrystallised from hot acetone (200 ml) by dilution with isohexane (300 ml) to give the title product (11.7 g), mp 151–153°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[I:11]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]cc(I)c12

Procedure:
The tricyclic nucleoside 6.7 was synthesized starting from 4-chloro-1H-pyrrolo[2,3-d]pyrimidine 2.1. The nucleobase 2.1 was treated with N-iodosuccinimide in THF at room temperature for 4 hr to provide 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 6.1. Then 6.1 was converted to the corresponding sodium salt with sodium hydride in acetonitrile and reacted with bromo-sugar 2.4 ((i)Helv. Chim. Acta. 1995, 78, 486; (ii) WO 02/057287, 2002), to give nucleoside 6.2. which was directly converted to 4-amino-5-iodo-7-[3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-methyl-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine 6.3. A Stille coupling reaction between nucleoside 6.3 and Z-3-tributylstannylacrylate provided compound 6.4. The cyclization of compound 6.4 was accomplished by heating in DBU/dioxane overnight to afford the protected tricyclic nucleoside 6.5, which was then treated with boron trichloride in CH2Cl2 to produce nucleoside 6.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH2:17]O)=[C:5]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23].S(Cl)([Cl:26])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH2:17][Cl:26])=[C:5]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1c(CO)n(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC2CC2)c(=O)c2ccc(Br)cc12
Yield: 95.6 %

Procedure:
To a solution of 6-bromo-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone (5.70 g, 15 mmol) in toluene (50 mL) was added thionyl chloride (2.2 mL, 30 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-bromo-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone (5.72 g, 95.7%) as crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[BrH:17]>C(OCC)(=O)C>[Br:17][CH:4]1[CH2:3][CH:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12]
Reactant: CC1CCC(=O)c2ccccc21
Reactant: Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1CC(Br)C(=O)c2ccccc21

Procedure:
Commercially available 4-methyl-1-tetralone, 32.0 grams, contained in 250 ml. of chloroform and 50 ml. of ethyl acetate is heated to boiling. A mixture of 98.3 grams of cupric bromide and 50 ml. of ethyl acetate is heated to its reflux temperature. After all of the hydrogen bromide is evolved, the mixture is maintained at its reflux temperature for an additional hour. The reaction mixture is filtered while hot, the residue washed with boiling chloroform and the combined filtrates evaporated to dryness in vacuo. The residue is dissolved in a minimum of methylene chloride, placed upon an alumina column and eluted with methylene chloride. The eluate is concentrated and the desired 2-bromo-4-methyl-1-tetralone obtained as a dark oil.