Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:12](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:13].C(N(CC)CC)C>ClCCl>[N:1]([C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:12]=[O:13]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)N=C=O
Reaction time: 0.5 h
Yield: 298.8 %

Procedure:
Into a 100-mL 3-necked round-bottom flask was placed a solution of tert-butyl 2-amino-2-methylpropanoate (1.2 g, 7.54 mmol, 1.00 equiv) in dichloromethane (20 mL). This was followed by the addition of ditrichloromethyl carbonate (750 mg, 2.53 mmol, 0.34 equiv), in portions at 0° C. After 30 min, triethylamine (2.3 g, 22.73 mmol, 3.02 equiv) was added dropwise with stirring. The resulting solution was stirred for 5 h at room temperature and then concentrated under vacuum. The residue was diluted with 20 mL of ethyl ether. The solids were filtered out. The filtrate was concentrated under vacuum. Purification afforded 1.4 g (crude) of tert-butyl 2-isocyanato-2-methylpropanoate (110.2) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][C:3]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=C[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.Cl.NCC#N>O1CCOCC1>[C:37]([CH2:38][NH:43][C:19]([C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[C:2]([CH3:1])=[C:3]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:4]=1)=[O:21])#[N:36]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCC#N)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
The compound obtained in step (a) (0.2 g, 0.53 mmol) was dissolved in 1,4-dioxane (5 ml), HBTU (0.19 g, 0.5 mmol) and DMA (0.32 g, 2.5 mmol). The mixture was stirred for 10 minutes and aminoacetonitrile hydrochloride (0.55 g, 0.6 mmol) was added. After 1 h the mixture was evaporated and the residue purified by chromatography on silica to give the amide (0.15 g, 72%) as a white solid.
Reaction SMILES: [OH-].[Na+].C(=[C:6]([CH:8]([CH2:10][OH:11])[OH:9])[OH:7])(C)C.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.C(Cl)(=O)C1C=CC=CC=1.C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[CH2:12]([O:11][CH2:10][CH:8]([OH:9])[CH2:6][OH:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)=C(O)C(O)CO
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Product: OCC(O)COCc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 46.1 %

Procedure:
The 50 ml of a 50% (w/v) sodium hydroxide solution are added 33 g (0.25 mole) of isopropylideneglycerol, 30.25 ml (0.25 mole) of benzyl chloride and 1.38 g (4 millimoles) of benzoyl chloride and 1.38 g (4 millimoles) of benzyltri-n-butylammonium. The mixture is stirred at 100° C. for 5 hours, then cooled to room temperature, diluted with 50 ml of water and extracted with ether. The extract is washed with water and then the solvent is distilled off under reduced pressure. To the residue is added 70 ml of 15% (w/v) sulfuric acid, and the mixture is stirred at 100° C. for 2.5 hours. After cooling, the unreacted material is removed by extraction with petroleum ether, the aqueous layer is neutralized and then extracted with ethyl acetate, and the extract is washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure to give about 21 g of a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:12])(=O)[CH2:9][CH3:10].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:35][C:36]1[C:44]([O:45][C@@H:46]2[CH2:51][CH2:50][C@H:49]([NH2:52])[CH2:48][CH2:47]2)=[CH:43][C:42]([CH3:53])=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2>CN(C)C=O>[CH3:35][C:36]1[C:44]([O:45][C@@H:46]2[CH2:51][CH2:50][C@H:49]([NH:52][C:8](=[O:12])[CH2:9][CH3:10])[CH2:48][CH2:47]2)=[CH:43][C:42]([CH3:53])=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2
Reactant: CCC(=O)O
Reactant: Cc1c(O[C@H]2CC[C@@H](N)CC2)cc(C)c2[nH]ncc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N[C@H]1CC[C@@H](Oc2cc(C)c3[nH]ncc3c2C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 110.1 %

Procedure:
Triethylamine (108 μl, 0.775 mmol), propionic acid (32 μl, 0.429 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (83 mg, 0.433 mmol) and 1-hydroxybenzotriazole (58 mg, 0.429 mmol) were added in that order to a dimethylformamide solution (2 ml) of the cis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.386 mmol) obtained in Example 658, and the resulting mixture was stirred at room temperature for 20 hours. The reaction was terminated by the addition of water, followed by extraction with ethyl acetate-toluene (1:1). The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was purified by a silica gel chromatography (eluent: chloroform/methanol=100:2) to obtain cis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (134 mg, 100%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:15]>C(O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COc1ccc(N(C(=O)CN)C(C)C)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(N(C(=O)CNc2ccc(F)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
A mixture of 9.06 g of 2,5-difluoro-nitrobenzene (60 mmol) and 12.64 g of 2-amino-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, (60 mmol, 1.0 equiv) were combined in 225 mL of 2:1 ethanol/water and heated to reflux under nitrogen and stirred vigorously overnight (approx. 16 hrs.). The resulting slurry is cooled to ambient temperature, filtered and washed with 2:1 water/ethanol. The wet solid is dissolved in methylene chloride, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue is triturated with hexane, filtered and washed with hexane. The product is dried under high vacuum to provide 9.32 g of 2-(4-Fluoro-2-nitro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an orange solid: 1H NMR (300 MHz, CDCl3) δ7.89 (dd, 1H, J=3.1, 9.3), 7.12 (m, 3H), 6.99 (m, 2H), 6.35 (dd, 1H, J=4.8, 9.2), 5.03 (m, 1H), 3.89 (s, 3H), 3.57 (s, 2H), 1.09 (d, 6H, J=6.8); low resolution MS (ESI)m/e 362 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:29][CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([F:16])=[C:11]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([CH3:29])[CH2:35]4)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Reactant: CC1CNCCN1
Product: CCOC(=O)Nc1c(F)c(N2CCNC(C)C2)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1

Procedure:
In the same manner as described in Example 1 (1), ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (m.p. 189°-190° C.) was allowed to react with 2-methylpiperazine to give ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]([CH2:19][C:20]([O:22]CC)=[O:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]([CH2:19][C:20]([OH:22])=[O:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(c3ccccc3n2CC(=O)O)C1

Procedure:
A stirred solution of ethyl (2-tert.-butoxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate (15 mg, 0.039 mmol) in THF (0.6 ml) is treated with 0.2 N aqueous NaOH (0.29 ml, 0.058 mmol) at rt for 15 min. The reaction mixture is diluted with water (2 ml) and washed with diethyl ether (2 ml), then neutralized with conc. HCl (58 μl), and extracted with dichloromethane. The solvent is evaporated and the crude product is recrystallized from acetonitrile to afford pure compound as a yellow solid: tR (LC-1) 2.16 min; ESI-MS (positive ion): m/z 353.32 [M+Na]+ (calcd 330.38 for C18H22N2O4).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:11]1([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: ClCCCCCCCCOc1cccc2ccccc12
Reactant: Nc1ccccc1
Product: c1ccc(NCCCCCCCCOc2cccc3ccccc23)cc1

Procedure:
7.0 Gm of 1-chloro-8-(1-naphthyloxy)octane was refluxed for 1 hour in 100 ml of aniline. The excess aniline was then removed under vacuum and the residue was distributed between methylene chloride and dilute aqueous potassium hydroxide. The organic solution was dried and evaporated, and the residue was chromatographed on silica gel, eluting with methylene chloride, so as to produce the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.CC(C1C=CC(Br)=CC=1)=O.BrC1C=CC([C@@H](O)C)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Agent: CC(=O)c1ccc(Br)cc1
Agent: C[C@H](O)c1ccc(Br)cc1
Product: C[C@@H](O)c1ccc(Br)cc1
Reaction time: 48 h
Yield: 54 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized soy bean protein for the substrate (±)-1-(4-bromophenyl)ethanol (200 mg) requires 2 days by going through bioconversion to 4-bromoacetophenone accompanying sterically selective oxidation of (S)-1-(4-bromophenyl)ethanol to obtain 108 mg of (R)-1-(4-bromophenyl)ethanol at a yield of 54%. Optical purity was obtained at 88% e.e. Equipment conditions were the same as for immobilized green pea protein.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:35][CH3:36])[C:19]([Cl:37])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:37][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:35][CH3:36])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h

Procedure:
Into a microwave vial was added 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (55 mg, 0.00028 mol) and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (80 mg, 0.0002 mol) in isopropyl alcohol (4 mL, 0.05 mol). To this reaction mixture was added 4N HCl-dioxane (0.03 g, 0.0002 mol). The reaction was subjected to microwaves at 120° C. for 10 min. The reaction mixture was resubject to the microwave conditions (120° C. for 10 min) The reaction mixture was purified by prep HPLC using the Gilson system and a gradient of 30-50% acetonitrile-water. The peaks corresponding to product were combined extracted with methylene chloride and washed with bicarbonate and dried to give 5-Chloro-N*2*-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine a tan solid (34 mg, 30% yield). MP: 180-184° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.66 (broad s, 1H), 8.12 (s, 1H), 7.43 (s, 1H), 7.41 (d, 1H, J=8.84 Hz), 7.15 (d, 1H, J=8 Hz), 6.98 (d, 1H, 8 Hz), 6.71 (s, 1H), 6.54 (d, 1H, J=9 Hz), 3.78 (s, 7H), 3.18 (dd, 4H, J=5, 9 Hz), 2.65 (dd, 2H, J=5, 10 Hz), 1.97 (m, 4H); MS (m/e) 516 (M+1).
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([CH2:13][N:14]([CH2:22][C@@H:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:11]1.[N:31]1([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:33][C@@H:32]1[C:34]([O:36][CH3:37])=[O:35]>C(Cl)(Cl)Cl>[CH2:41]([O:40][C:38]([NH:31][C@@H:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:33][O:30][C@@H:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][N:14]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:13][CH:10]1[CH2:12][CH2:11]1)=[O:39])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COC(=O)[C@H]1CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](O)c1ccccc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)[C@@H](CO[C@H](CN(CC1CC1)C(=O)OC(C)(C)C)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 27.4 %

Procedure:
Boron trifluoride diethyl etherate (0.10 mL, 0.84 mmol) was added to a solution of tert-butyl cyclopropylmethyl[(2S)-2-hydroxy-2-phenylethyl]carbamate (2.45 g, 8.39 mmol) and 1-benzyl 2-methyl (2R)-aziridine-1,2-dicarboxylate (1.97 g, 8.39 mmol) in chloroform (20 mL). After 3 h, the reaction was concentrated. Purification by silica gel chromatography (100% hexanes→30% ethyl acetate/hexanes) gave the title compound (1.21 g).
Reaction SMILES: [N:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5](O)=[O:6])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[N:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([Cl:14])=[O:6])=[N+:2]=[N-:3]
Reactant: CCCC(N=[N+]=[N-])C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(N=[N+]=[N-])C(=O)Cl
Yield: 89 %

Procedure:
A solution of (2R and 2S) 2-azidopentanoic acid (2.213 g, 15.46 mmol) in dry dichloromethane (20 ml) was treated with oxalyl chloride (1.57 ml, 18.55 mmol) and a drop of N,N-dimethyl formamide. After the evolution of gas had ceased (2 h), the solvent was evaporated under reduced pressure and the residual liquid was distilled off (bulb to bulb) under vacuum to give 2.224 g (89%) of a clear oil: bp 50°-55° C./5 torr (air bath temperature); ir (film) νmax : 2105 (N3), 1785 cm-1 (C=O), 1Hmr (CDCl3) δ: 4.1 (1H, dd, J=7, J=6, H-2), 2.2-1.2 (4H, m, H-3 and H-4) and 0.98 ppm (3H, distorted t, J=6, H-5).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[O:28]=[C:29]1[N:36]2[C@H:31]([CH2:32][O:33][C:34]([CH:49]3[CH2:53][CH2:52][CH2:51][O:50]3)=[C:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:38])[C@@H:30]1[NH:54]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:54][C@@H:30]2[C:29](=[O:28])[N:36]3[C@@H:31]2[CH2:32][O:33][C:34]([CH:49]2[CH2:53][CH2:52][CH2:51][O:50]2)=[C:35]3[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)=[O:38])=[O:10])[N:6]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: COc1ccc(COC(=O)C2=C(C3CCCO3)OC[C@@H]3[C@H](NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)N23)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C3CCCO3)OC[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2-(Z)-methoxyimino-2-(2-aminothiazol-4-yl)acetic acid (III) (54 mg) and N,N-diisopropylethylamine (0.047 ml) in dimethylformamide (0.3 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.021 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of 4-methoxybenzyl (6S,7S)-7-amino-8-oxo-3-(tetrahydrofuran-2-yl)-1-aza-4-oxabicyclo[4.2.0]oct-2-ene-2-carboxylate (II) (91 mg) in dimethylformamide (1 ml) was added, followed by p-ndine (0.022 ml). The mixture was then stirred at 0° C. for 1 h and then at room temperature for 0.5 h. The mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase was washed twice with water, then brine, dried over magnesium sulphate and evaporated. Column chromatography (silica gel, ethyl acetate as eluent) gave the title compound (88 mg. νmax (CHCl3) 1769, 1709, 1679 and 1613 cm-1 ; δ(CDCl3) 1.72-2.12 (4H, m), 3.35 (3H, s), 3.68-3.96 (4H, m), 3.76 (3H, s), 4.64 (1H, dd, J 9.19 and 15.89 Hz), 5.13 (3H, s), 5.20 (1H, t, J 6.77 Hz), 5.72 (1H, dd, J 4.14 and 8.91 Hz), 6.80 (1H, s), 6.93 (2H, d, J 8.68 Hz), 7.24 (2H, s), 7.37 (2H, d, J 8.66 Hz), 9.23 (1H, d, J 9 Hz).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:12][C@@H:11]([N:23]2[C:52]3[N:51]=[C:45]([NH:46][C:47](=[S:50])[NH:48][CH3:49])[N:44]=[C:27]([O:28][C:29](=[O:43])[N:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)(C(C)(C)C)(C)C.COC1C=CC(C(OC[C@H]2O[C@@H](N3C4N=C(NC(=O)NC)N=C(OC(=O)N(C5C=CC=CC=5)C5C=CC=CC=5)C=4N=C3)C[C@@H]2O)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[C:37]1([N:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:29]([O:28][C:27]2[C:26]3[N:25]=[CH:24][N:23]([C:52]=3[N:51]=[C:45]([NH:46][C:47](=[S:50])[NH:48][CH3:49])[N:44]=2)[C@@H:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:9]([OH:8])[CH2:10]2)=[O:43])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c2n1
Agent: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)O3)c2n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (900 mg, 1.17 mmol) was azeotroped with anhydrous tetrahydrofuran three times and dissolved in anhydrous tetrahydrofuran (6.0 mL), and triethylamine 3 hydrogen fluoride (574 μL, 3.51 mmol) was added thereto. The mixture was stirred at room temperature overnight, and then toluene (5 mL) was added thereto. The solvent was evaporated under reduced pressure. To the residue, methanol (5 mL) and hexane (25 mL) were added for precipitation. The resulting precipitate was purified by filtration to give 6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (504 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: COC(=O)c1ccccc1O
Reactant: CS(=O)(=O)Cl
Product: COC(=O)c1ccccc1OS(C)(=O)=O

Procedure:
2-Methanesulfonyloxybenzoic acid methyl ester is prepared according to the general procedure outlined in Example 4, Step B, using 2-hydroxybenzoic acid methyl ester and methanesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1.C(OC=CC)C>C(Cl)(Cl)Cl.O>[Br:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:19]([CH3:24])[CH:20]=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Br)ccc1C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC=COCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cnc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
A 1 L round bottom flask fitted with a stirbar, a Dean-Stark trap for solvents heavier than water, and a condenser was charged with 2-amino-4-bromobenzaldehyde (20 g, 100 mmol), sodium sulfate (71.0 g, 500 mmol), and p-toluenesulfonic acid monohydrate (4.75 g, 25.00 mmol). The solids were taken up in anhydrous chloroform (498 mL) and the suspension treated with 1-ethoxyprop-1-ene (14.39 mL, 130 mmol). The mixture was then heated to reflux with stirring overnight. The reaction mixture was cooled to room temperature and transferred to a 2 L separatory funnel. The solution was extracted twice with 200 mL saturated aq sodium bicarbonate and once with 200 mL water. The organic layer was isolated and the aqueous layers were combined and re-extracted twice with an additional 100 mL dichloromethane. The organics were then pooled, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was purified by flash chromatography (0.2-1.9% methanol:dichloromethane). Fractions containing the desired material were pooled and concentrated to afford the title compound as a bright orange solid (5.603 g, 25.2 mmol, 25% yield). MS(ES)+ m/e 221.8 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2C3CCN(C(OC(C)(C)C)=O)CC3O[C:4]=2[CH:3]=1.[C:22]([N:29]1[CH2:34][CH:33]=[CH:32][CH:31]([OH:35])[CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].BrC1C=C(OC)C=CC=1O>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:35][CH:31]3[CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33][CH:32]3[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=CC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Agent: COc1ccc(O)c(Br)c1
Product: CC(C)(C)OC(=O)N1CCC2c3cc(I)ccc3OC2C1

Procedure:
Tert-butyl 6-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate was synthesized as described for tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P01 starting from N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2-bromo-4-methoxyphenol. MS m/z 402 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10](COCC[Si](C)(C)C)[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=3)[N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)c1ccc(Cn2nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 3 %

Procedure:
To a solution of 4-{[3-[[(5-chloro-2-thienyl)sulfonyl]({[2-(trimethylsilyl)ethyl]oxy}methyl)amino]-4-(methyloxy)-1H-indazol-1-yl]methyl}-N,N-diethylbenzamide (for a preparation see Intermediate 79) (125.5 mg, 0.189 mmol) in dichloromethane (DCM) (1 ml) was added dropwise TFA (0.292 ml, 3.78 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 30 h. Reaction mixture was concentrated under a stream of nitrogen in a blowdown unit. The residue was purified using the high pH-MDAP and further purified by MDAP to give the title compound (3 mg, 3%) LCMS (System A) RT=1.19 min, ES+ve m/z 533/535 (M+H)+.