Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:2]1=2.[Br:13]Br.O>C(O)(=O)C.[Fe]>[Br:13][C:7]1[CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:2]2[O:1][CH2:5][CH2:4][C:3]=2[CH:6]=1
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: BrBr
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Br)cc2c1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To an ice-cooled acetic acid solution (5 ml) of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) there was added iron (8 mg, 0.14 mmol) and bromine (0.32 g, 2.0 mmol) in 1 ml of acetic acid. The mixture was stirred at room temperature for 18 hours and then poured into water (20 ml). After cooling in the freezer for 11/2 hours the product was collected on a filter, and recrystallized from ethyl acetate to give 0.24 g (50.3%) of 15b as a white crystalline solid, mp 228°-229° C.
Reaction SMILES: [CH3:1][C:2]#[C:3][CH3:4].CN1C(=O)N(C)CCC1.N#N.C([Li])CCC.I[CH2:22][CH2:23][C@@H:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1.CC1(C)O[C@H](CCO)CO1>C1COCC1>[CH2:23]([C@@H:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:22][C:1]#[C:2][CH2:3][CH3:4]
Reactant: CC1(C)OC[C@@H](CCI)O1
Reactant: CC#CC
Agent: CC1(C)OC[C@@H](CCO)O1
Agent: N#N
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCC#CCC[C@@H]1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a flask cooled to −78° C. under N2 was added 2-butyne gas via syringe needle until approximately ˜3 mL of liquid had condensed in the flask. THF (120 mL) was then added followed by DMPU (18.9 ml, 156 mmol). The flask was purged with N2 and n-butyllithium (2.5M hexanes, 18.7 ml, 46.9 mmol) was added via syringe over 5 min and stirred for an additional 15 min at which time (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (10.0 g, 39.1 mmol) was added as a solution in THF (30 mL) [preparation of enantiopure (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane from commercially available (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol was performed using the procedure described by: Taber. D. F.; Xu, M.; Hartnett, J. C. J. Am. Chem. Soc. 2002, 124, 13121]. The reaction was slowly warmed to rt and stirred a total of 3 h. The mixture was quenched with sat. NH4Cl, and extracted with Et2O (2×). The organics were washed with H2O, and brine, dried over MgSO4, filtered, and concentrated. The material was purified by silica gel chromatography (5% EtOAc in hexanes gradient to 15% EtOAc in hexanes) to give (R)-4-(hex-3-ynyl)-2,2-dimethyl-1,3-dioxolane as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.19 (1H, m), 4.08 (1H, dd, J=8.0, 6.0 Hz), 3.58 (1H, dd, J=7.6, 6.8 Hz), 2.26 (2H, m), 2.15 (2H, qt, J=5.2, 2.4 Hz), 1.81 (1H, m), 1.68 (1H, m), 1.40 (3H, s), 1.36 (3H, s), 1.11 (3H, t, J=7.6 Hz).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([CH2:14][O:15][CH3:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 24.6 mg (0.74 mmol, 60% dispersion in mineral oil) NaH in 5 mL THF at 0° C. was added 0.115 g (0.61 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (prepared using route 15 step a) in 1 mL THF dropwise over 10 minutes, and the reaction was stirred at 0° C. for 30 minutes. 46 μL (0.74 mmol) methyl iodide was added and the reaction was stirred at room temperature for 2 hours. 20 mg (0.61 mmol, 60% dispersion in mineral oil) of NaH followed by 38 μL (0.61 mmol) of methyl iodide were added and the reaction mixture was stirred at room temperature for 16 hours. 5 mL of H2O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO4. After filtration, the solvent was evaporated to give the desired product which was used for the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15]1[C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[O:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:11].[F:24][C:22]1[CH:21]=[CH:20][C:19]2[C:15]([CH2:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)=[N:16][O:17][C:18]=2[CH:23]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: Fc1ccc2c(CCCN3CCC4(CC3)OCCO4)noc2c1

Procedure:
A mixture of 15 g of 1,4-dioxa-8-azaspiro-[4,5]decane, 25 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 29 g of potassium carbonate and a few crystals potassium iodide in 80 ml of dimethylformamide was stirred at 70°-75° C. for two hrs. The mixture was cooled, filtered and concentrated to an oil. The oil was stirred with water and extracted with ether. The organic extracts were washed with water (2×), saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was treated with ethereal hydrogen chloride to give 18 g (48%) or product, mp 170°-173° C. Recrystallization from ethyl acetate/methanol gave the analytical sample, mp 178°-179° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([O:40][CH3:41])[CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[C:34]([O:40][CH3:41])[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1cc(OC)cc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(OC)cc(C(CC(=O)O)NC(=O)CNC(=O)c2cccc(NC=NN)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 858.5 %

Procedure:
To the product from Example 194 (800 mg, 0.00014 mole) in H2O (20 mL) and CH3CN (8 mL) was added LiOH (230 mg, 0.0055 mole). The reaction mixture was stirred at room temperature for 1.5 hours. The pH was lowered to ~3 with TFA and the product was isolated by RPHPLC to yield the title compound (670 mg after lyophilization) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([NH:21][O:22][CH2:23][CH2:24][O:25]C=C)=[O:20])=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1.Cl>CCO.C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20])=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1
Reactant: C=COCCONC(=O)c1nn(C)c(=O)cc1Nc1ccc(SC)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2cc(=O)n(C)nc2C(=O)NOCCO)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
To a solution of 4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (30 mg, 0.077 mmol) in EtOH/THF (2 mL/2 mL) was added 1 N aqueous HCl (0.15 mL, 0.15 mmol, 1 N aqueous solution) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was neutralized to pH 7, diluted with EtOAc (3×), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% EtOAc to 100% CH2Cl2 to 2.5 to 3 to 5% MeOH in CH2Cl2) to afford 6 mg (22%) of the desired product. MS APCI (−) m/z 367 (M−1) detected; −1H NMR (400 MHz, CD3OD) δ 7.35 (t, 1H), 7.18 (dd, 1H), 7.14 (dd, 1H), 5.92 (s, 1H), 4.06 (t, 2H), 3.79 (t, 2H), 3.74 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20]>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH2:21])[CH:17]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: NC(=O)c1cccc(N)c1
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cccc(C(N)=O)c1
Yield: 15.8 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 3-aminobenzamide as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6](C(OC(C)(C)C)=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.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:18][C:19]1[C:24]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:2]=2)[NH:8][N:7]=[CH:6]3)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2[nH]ncc2c1
Yield: 74.3 %

Procedure:
Analogous to the reaction conditions and work-up procedures used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole, 5-(2-chloropyridin-3-yl)-1H-indazole was obtained by heating the mixture of tert-butyl 6-bromo-1H-indazole-carboxylate (7.3 g, 24.6 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (7.0 g, 29.5 mmol), Pd(PPh3)4 (2 g, 1.7 mmol) and aq.Na2CO3 (44 mL, 88 mmol) in 1,4-dioxane (200 mL) under argon atmosphere. The crude concentrate that was obtained after the extractive work-up dissolved in CH2Cl2, adsorbed on to silica gel and dried. Subsequent purification by flash silica gel column chromatography (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent gradient upon dry powder loading) provided 5-(2-chloropyridin-3-yl)-1H-indazole as a white solid (4.2 g, 74%). 1H NMR (DMSO-d6): δ 13.21 (s, 1H), 8.43 (dd, 1H, J=1.7 and 4.7 Hz), 8.12 (s, 1H), 7.93 (dd, 1H, J=1.7 and 7.6 Hz), 7.84 (d, 1H, J=8.5 Hz), 7.59 (s, 1H), 7.52 (dd, 1H, J=4.7 and 7.6 Hz), 7.17 (d, 1H, J=8.5 Hz).LCMS: rt 6.17 min (A), purity 98%, MS (m/e) 230 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C>CO>[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 201 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (500 mg, 1.29 mmol) was dissolved in methanol (30 mL). A 4 N hydrochloric acid/ethyl acetate solution (20 mL) was added, and the mixture was stirred at room temperature for one hour. Concentration under reduced pressure gave 419 mg of the title compound as a white solid (100%). (159b) Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)pyridine-4-carboxylate
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([CH3:12])=[C:6]2[CH:13]([CH3:17])[C:14]([OH:16])=[O:15].Br[CH:19](C)[C:20](OCC)=O.BrCC(OCC)=[O:29]>>[OH:29][C:6]1([CH:13]([CH3:17])[C:14]([O:16][CH2:19][CH3:20])=[O:15])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:8][CH:7]1[CH3:12]
Reactant: CCOC(=O)C(C)Br
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)C(C(C)C(=O)O)=C(C)C2
Product: CCOC(=O)C(C)C1(O)c2cc(OC)ccc2CC1C

Procedure:
The procedure of Example 35, part (A) is followed using ethyl α-bromopropionate in equivalent quantities in place of ethyl bromoacetate used therein. There is obtained ethyl α-(1-hydroxy-6-methoxy-2-methyl-1-indanyl)propionate, which is dehydrated to ethyl α-(5-methoxy-2-methyl-3-indenyl)propionate in the same manner.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:9]([OH:28])[CH2:10][N:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])(C)(C)C.N(CCO)(CCO)CCO.[H][H].[OH-].[Na+]>C(O)(C)C.[C].[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:11]([CH2:10][C@@H:9]([OH:28])[C@@H:8]([NH2:7])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: OCCN(CCO)CCO
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
(1S,2R)-{1-benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester (3, 100 g), 10% palladium carbon (10 gm) and triethanolamine (2 gm) were suspended in isopropyl alcohol. The reaction was heated to 40-45° C. and maintained under 4-6 kg/cm2 of hydrogen pressure for 3 hours. After completion of reaction, the mass was filtered and hydrochloric acid (70 mL) was added to the filtered mass. The solution was heated to reflux and maintained for 2-3 hours. After completion of reaction the mass was cooled to 25-35° C., the reaction mass pH was adjusted to 6.0-7.0 with 20% sodium hydroxide solution and distilled out isopropyl alcohol under vacuum at below 55° C. Ethanol (200 mL) and water (400 mL) was added to the distillate, the mass pH was adjusted to 9.0-10.0 with 20% sodium hydroxide solution at 25-35° C. and maintained the stirring for 2 hours at 25-35° C. The mass was cooled to 0-5° C., filtered and wash with water. The wet product was taken into ethanol (350 mL), maintained the stirring for 30 minutes at reflux temperature. The mass was cooled to 2-4° C., stirred for 2 hours, filtered and washed with ethanol (50 mL). The wet product was dried under normal drying to get title compound 1 (Yield 60 g).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN1CCCC1=O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[CH:15][CH2:14][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:18][CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCC=Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCC=Cc1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 96 h
Yield: 86.8 %

Procedure:
18.5 g (0.11 mol) of N-hydroxyphthalimide and 31.4 g (0.11 mol) of 1-bromo-3-(4-bromophenyl)-prop-2-ene were added in succession to 350 ml of dry N-methylpyrrolidone, and 12.1 g (0.12 mol) of triethylamine were then added dropwise at room temperature. The reaction mixture was stirred for four days at 20° C. and then poured onto 1.5 l of ice water, and the product was filtered off and washed with water and isopropanol. Yield: 86.8%; m.p.: 161°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13](SC)[CH:14]=3)[N:9]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:8]=2[CH3:23])=[CH:4][CH:3]=1.[Na].O[O:28][S:29]([O-:31])=O.[K+].[CH3:33]C(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:29]([CH3:33])(=[O:31])=[O:28])[CH:14]=3)[N:9]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:8]=2[CH3:23])=[CH:24][CH:25]=1
Reactant: CC(C)=O
Reactant: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(SC)ccc21
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na]
Solvent: O
Product: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(S(C)(=O)=O)ccc21
Reaction time: 3 h

Procedure:
To the product from step (ii) (0.32 g) in acetone (4 ml) and water (4 ml) was added solid sodium bicarbionate (0.57 g) followed by oxone (0.69 g in water (2.5 ml)) and the reaction was stirred for 3 h. The reaction was quenched with sodium bisulfite and partitioned between ethylacetate/water. The organics were dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-60% ethylacetate/iso-hexane.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([O:24][C:25]([C@H:27]1[C@@H:32]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C@H:31]2[CH2:42][C@@H:28]1[CH2:29][CH2:30]2)=O)C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:33]2[C:17](=[O:18])[C:16]([C:11]3[NH:10][C:9]4[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=4[S:13](=[O:14])(=[O:15])[N:12]=3)=[C:25]([OH:24])[C@H:27]3[C@@H:32]2[C@H:31]2[CH2:42][C@@H:28]3[CH2:29][CH2:30]2)=[CH:40][CH:39]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 23 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 1.88 kg, 5.63 mol) and (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 1.72 kg, 5.91 mol) were dissolved in acetonitrile (18.8 L) at 23° C. N-Methylmorpholine (1.25 kg, 12.4 mol) was added and the resulting suspension was stirred at 23° C. for 1 h. The suspension was cooled to 0° C. and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.19 kg, 6.20 mol) was added in one portion. The mixture was stirred at 0° C. for 3 h, and was then allowed to warm to 23° C. and stirred overnight. Triethylamine (1.88 kg, 18.6 mol) was added and the mixture was then heated at 50° C. for 3 h. The mixture was partially concentrated in vacuo at 45° C., and was then diluted with ethyl acetate (22.5 L) and washed with 2.0 M aqueous hydrochloric acid solution (22.6 L). The resulting aqueous fraction was extracted with ethyl acetate (2×9.4 L). The combined organic extracts were washed with 1.0 M aqueous hydrochloric acid solution (10.4 L) and then with water (18.8 L). The resulting organic fraction was filtered through Celite (600 g), and the filtrate was then partially concentrated in vacuo at 45° C. Absolute ethanol (5.6 L) was added to the residue, and the mixture was then heated at 50° C. with stirring. Dichloromethane (400 mL) was added in portions until crystallization initiated. Absolute ethanol (20.7 L) was added in portions over 1 h, and the resulting mixture was stirred at 23° C. overnight. The mixture was filtered and the solid was then washed with absolute ethanol (1.9 L). The solid was further dried in vacuo at 45° C. to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (2.46 kg, 4.39 mol, 78%), as an off-white crystalline solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]=4[N:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH:6]([CH2:29][CH3:30])[CH2:5]1)=[N+]=[N-].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.CCOC(C)=O>[CH2:29]([CH:6]1[CH:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:15]=4[N:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:8][CH:4]([NH2:1])[CH2:5]1)[CH3:30]
Reactant: CCC1CC(N=[N+]=[N-])CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1CC(N)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 45 °C
Yield: 80.5 %

Procedure:
A round bottom flask was charged with 1-(-4-azido-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.650 g, 1.52 mmol, prepared using D from Preparation #25 with NaOH, KK, P with NaBH4, IIII, JJJJ with NaN3), THF (8.0 mL), and water (1.6 mL). To the flask was added triphenylphosphine (0.480 g, 1.83 mmol). The reaction mixture was heated to about 45° C. for about 7 h. The reaction mixture was cooled to room temperature and EtOAc (20 mL) and water (15 mL) were added. The layers were separated and the organic solution was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give an oil that solidified upon standing. The crude material was purified via flash silica gel chromatography eluting with a gradient of 1-10% DCM/MeOH/DEA (900:90:10) in DCM. The product containing fractions were combined and concentrated under reduced pressure to give an oil that was then dried on a vacuum pump overnight to give 3-ethyl-4-(6((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine as a tacky oil (0.49 g, 80%): LC/MS (Table 1, Method b) Rt=1.85 min; MS m/z 401 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:27]1([C@@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([CH2:8][C:9]([NH:35][C@H:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[O:11])[CH2:6][CH2:7]1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C(O)CC1CCC(=O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)CC1CCC(=O)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 143.2 %

Procedure:
A solution of 4-oxocyclohexaneacetic acid (28.39 g) (Example H) and triethylamine (30.4 ml) in 800 ml of dichloromethane at -10° C. is treated dropwise with isobutyl chloroformate (26.0 ml). The reaction mixture is stirred at this temperature for 15 minutes and 1(S)-phenylethylamine (26.51 g) is added via syringe. After 30 minutes at -10° C., the mixture is stirred at room temperature for another 30 minutes. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (1000 ml) and 1 N hydrochloric acid solution (400 ml). The organic extract is washed with 1 N sodium hydroxide solution and brine, dried (magnesium sulfate), and concentrated in vacuo to leave 67.5 g of crude (S)-4-oxo-N-(1-phenylethyl)cyclohexaneacetamide as a white solid; mp 110°-151° C.
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCCCl)=C(N)N=1)CCC.FC(F)(F)C(O)=O.[CH3:30][O:31][C:32]1[N:33]=[C:34]2[C:39]([N:40]=1)=[C:38]([NH2:41])[NH:37][C:36]([O:42][C@@H:43]([CH3:46])[CH2:44][CH3:45])=[N:35]2.Br[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][Cl:53]>>[Cl:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][N:33]1[C:32]([O:31][CH3:30])=[N:40][C:39]2[C:34]1=[N:35][C:36]([O:42][C@@H:43]([CH3:46])[CH2:44][CH3:45])=[N:37][C:38]=2[NH2:41]
Reactant: ClCCCCCBr
Reactant: CC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 14 from 8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-5-chloropentane.