Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH:19]3[CH2:21][CH:20]3[C:22]([O:24]CC)=[O:23])[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1.C1CC(NC2C3C(=CC(Cl)=C(Cl)C=3)C(C3C=CN=CC=3)=NN=2)CC1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH:19]3[CH2:21][CH:20]3[C:22]([OH:24])=[O:23])[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC1c1c(-c2ccncc2)c(-c2ccc(F)cc2)nn1CCO
Agent: Clc1cc2c(NC3CCCC3)nnc(-c3ccncc3)c2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC1c1c(-c2ccncc2)c(-c2ccc(F)cc2)nn1CCO

Procedure:
To a solution of ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylate prepared in accordance with Example A-196 (0.21 g, 0.00045 mol) in 10 mL of methanol was added a solution of sodium hydroxide (0.09 g, 0.0022 mol) in 2 mL of water. The reaction mixture was stirred at reflux for 6 hours. After the solvent was removed, the residue was dissolved with 10 mL of 1N HCl and stirred for 30 minutes. The pH was then adjusted to 5-6 by addition of 1N sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ethanol and ether to give 0.1 g of product, 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylic acid, as a white solid (60% yield), mp: 253-255° C.; 1H NMR (CD3OD): δ 8.46 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 4.39 (t, J=5.0 Hz, 2H), 4.03 (m, 2H), 2.60 (m, 1H), 1.51 (m, 2H), 0.97 (m, 2H); Anal. Calc'd For C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C, 64.92; H, 4.77; N, 11.20.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCC(O)CC1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OC1CCN(C(=O)c2ccccc2)CC1

Procedure:
Then, 8.16 g of the 1-benzoyl-4-hydroxypiperidine and 3.53 g of diketene were reacted similarly as in Reference Example 1, and the reaction mixture was concentrated to obtain 12.0 g of almost pure oily acetoacetic acid-N-benzoyl-4-piperidinyl ester on thin layer chromatography. This was used directly in the reaction of Example 3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[CH:8][N:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=4)[CH2:6][CH2:5]3)[C:11]=2[CH:12]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc2ncn(C3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2ncn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Yield: 35.9 %

Procedure:
1-(Piperidin-4-yl)-1H-benzo[d]imidazol-6-amine (4.62 mmol, 1 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.62 mmol, 1.558 g) and potassium carbonate (9.25 mmol, 1.278 g) were combined and stirred in acetonitrile (25 mL) at room temperature for 3 days. The reaction mixture was concentrated at reduced pressure, taken up in dichloromethane, washed with water and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (784 mg). MS (ESI) m/z 473.2 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15](=[NH:18])[NH:16][OH:17])[CH:12]=2)[C:7]1=[O:19])[CH3:2].[C:21](OC(=O)C)(=O)[CH3:22]>>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]3[N:18]=[C:21]([CH3:22])[O:17][N:16]=3)[CH:12]=2)[C:7]1=[O:19])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN1Cc2cc(C(=N)NO)ccc2C1=O
Product: CCOC(=O)CN1Cc2cc(-c3noc(C)n3)ccc2C1=O

Procedure:
The compound of example 66b (1 g; 3.8 mmol) in acetic anhydride (20 ml) was heated at 120° C. for 4 h. It was concentrated and purified using flash chromatography (silica gel, 5% CH3CN in dichloromethane) to obtain the title compound. Yield, 0.6 g (55%); mp, 155° C.; MS (ESI−): 286 (M−1), analysis: C14H13N3O4 requires C, 58.53; H, 4.56; N, 14.63; found: C, 58.13; H, 4.79; N, 14.14%.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([N:11]=[C:12]=[O:13])=[CH:3][C:2]=1[C:14]([F:17])([F:16])[F:15].[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1.Cl>O1CCCC1.C(N(CC)CC)C>[F:17][C:14]([F:15])([F:16])[C:2]1[CH:3]=[C:4]([NH:11][C:12]([C:23]2[C:22]3[C:26](=[CH:27][C:19]([Cl:18])=[CH:20][CH:21]=3)[NH:25][C:24]=2[OH:28])=[O:13])[CH:5]=[C:6]([C:7]([F:10])([F:8])[F:9])[CH:1]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.7 %

Procedure:
Under argon atmosphere, 3,5-bis(trifluoromethyl)isocyanate (255 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL). A solution of 6-chloro-oxindole (184 mg, 1.1 mmol) in tetrahydrofuran (5 ml) and triethylamine (0.3 mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (172.2 mg, 40.7%) as a pink solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[C:29]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1)(=[O:31])[CH3:30]
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-[(Piperidin-4-yl)carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (140 mg) obtained in Example 228 is suspended in dichloromethane (10 ml), and thereto are added acetyl chloride (30 μl) and triethylamine (74 μl) under ice-cooling, and the mixture is stirred at room temperature for 6 hours. The reaction solution is diluted with chloroform, washed successively with water, 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is dissolved in ethyl acetate, and treated with activated carbon. The resulting residue is recrystallized from ethyl acetate to give the title compound (38 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:16]([C:29](Cl)=[O:30])[CH2:15][CH2:14]2>O>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:29]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:30])[CH3:2]
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)Cl)CC2
Reactant: CCN(CC)CCN
Solvent: O
Product: CCN(CC)CCNC(=O)N1CCc2cc(OC)c(OC)cc2C1c1ccccc1
Temperature: 25 °C

Procedure:
To 10 parts by volume of 2-diethylaminoethylamine is added 3.0 parts of 6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarbonyl chloride. An exothermic reaction ensues. The mixture is heated over a steam bath for approximately 30 minutes. (Alternatively, the mixture is maintained at room temperature overnight.) The reaction mixture is then poured into water and extracted with ethyl ether. The ether layer is dried over anhydrous calcium sulfate and evaporated to dryness. The solid thus obtained is crystallized from a mixture of ethyl ether and n-hexane to afford N-(2-diethylaminoethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide, melting at about 97°-98°C.
Reaction SMILES: [CH3:1]C1C=CC([N+]([O-])=O)=CC=1O.C(Br)C=C.[CH2:16]([C:19]1[C:24]([OH:25])=[C:23](Cl)[CH:22]=[CH:21][C:20]=1[N:27]1[C:31](=[O:32])[C:30]2[CH2:33][CH2:34][CH2:35][CH2:36][C:29]=2[C:28]1=[O:37])[CH:17]=[CH2:18].ClC1C=CC([N+]([O-])=O)=CC=1O>>[CH2:16]([C:19]1[C:24]([OH:25])=[C:23]([CH3:1])[CH:22]=[CH:21][C:20]=1[N:27]1[C:31](=[O:32])[C:30]2[CH2:33][CH2:34][CH2:35][CH2:36][C:29]=2[C:28]1=[O:37])[CH:17]=[CH2:18]
Reactant: C=CCc1c(N2C(=O)C3=C(CCCC3)C2=O)ccc(Cl)c1O
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Solvent: C=CCBr
Product: C=CCc1c(N2C(=O)C3=C(CCCC3)C2=O)ccc(C)c1O

Procedure:
N-(2-allyl-3-hydroxy-4-methylphenyl)-3,4,5,6-tetrahydrophthalimide (5A) was prepared, as yellow crystals, m.p.: 141°-143° C., from 2-methyl-5-nitrophenol and allyl bromide by the procedures described in Example 3 for preparing 3D from 2-chloro-5-nitrophenol and allyl bromide.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.[OH-].[Na+:17].[CH3:18][O:19][C:20]1[CH:38]=[CH:37][C:23]([CH2:24][O:25][C:26](SC2C=C(C)C=C(C)N=2)=[O:27])=[CH:22][CH:21]=1.O1CCOCC1>O.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:38]=[CH:37][C:23]([CH2:24][O:25][C:26]([NH:1][C@@H:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]23)=[O:27])=[CH:22][CH:21]=1.[Na+:17]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: COc1ccc(COC(=O)Sc2cc(C)cc(C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COC(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CO)CS[C@H]23)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In 50 ml of water is suspended 2.30 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid and the suspension is adjusted to pH 8.5 with 1N-aqueous sodium hydroxide solution, whereupon a clear solution is obtained. To this solution are added 4.56 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyridine and 50 ml of dioxane and the mixture is stirred at room temperature for 7 hours. The reaction mixture is diluted with water and ethyl acetate and the water layer is separated and concentrated under reduced pressure. The residue is subjected to XAD-II (500 ml) column chromatography and after the column is washed with water, elution is carried out with 10% (v/v) ethanol. The eluate is concentrated under reduced pressure and freeze-dried to give 1.63 g of sodium 7β-(p-methoxybenzyloxycarbonylamino)-3-hydroxymethyl-3-cephem-4-carboxylate as colorless powders.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:25][OH:26])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[N:11][C:10]1=2.[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:26][CH2:25][C@@:3]23[C@@H:2]([OH:1])[C@@H:6]([O:7][CH2:8]2)[C@H:5]([N:9]2[CH:17]=[N:16][C:15]4[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])=[N:11][C:10]2=4)[O:4]3)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:32]2[CH:49]=[CH:50][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:39][CH:38]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]c(NC(=O)C(C)C)nc54)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound 51 (440 mg, 1.21 mmol) and 4,4′-dimethoxytrityl chloride (573 mg, 1.69 mmol) was dissolved in anhydrous pyridine (7 cm3) and was stirred at room temperature for 4 h. The mixture was evaporated under reduced pressure to give an oil. Extraction was performed in a system of dichloromethane/water (1:1, v/v, 40 cm3). The organic phase was separated and concentrated to give a solution in a minimal volume of dichloromethane containing 0.5% of pyridine (v/v) which was applied to a silica gel column equilibrated by the same solvent. The product was eluted in gradient concentrations of methanol (0.6-2%, v/v) in dichloromethane containing 0.5% of pyridine (v/v) to give compound 52 as a white solid material (695 mg, 86%). δH (CDCl3) 12.17 (1H, br s, NHCO), 10.09 (1H, br s, NH), 7.87 (1H, s, 8-H), 7.42-6.72 (13H, m, DMT), 5.69 (1H, s, 1′-H), 4.59 (1H, s, 2′-H), 4.50 (1H, s, 3′-H), 3.98 (1H, d, J 8.1, 1″-Ha), 3.69-3.39 (9H, m, DMT, 5′-H, 1″-Hb), 2.72 (1H, m, CHCO), 1.17 (6H, d, J 6.8, CH3CH). δC (CDCl3) 179.8 (COCH), 158.8, 144.5, 135.6, 135.5, 130.1, 128.1, 127.7, 126.9, 113.2 (DMT), 155.8, 147.9, 147.5, 137.0, 120.8 (guanine), 87.6, 86.4, 86.1 (C-1′, C-4′, DMT), 79.7 (C-3′), 72.6, 71.4 (C-2′, C-5′), 59.8 (C-1″), 55.2 (DMT), 36.1 (COCH), 19.1, 18.8 (CH3CH). FAB-MS m/z 668 [M+H]+.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].Cl.C(N=C=NCCCN(C)C)C.Cl>O1CCCC1.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[N:15]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:3]
Reactant: Cc1ccccc1N
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccn(-c2ccccc2C)c1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 18.6 %

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (3 g, 19.5 mmol) in tetrahydrofuran (30 mL) and N,N-dimethylformamide (10 mL) was added 2-methylaniline (2.09 g, 19.5 mmol), and the mixture was stirred at room temperature for 7 hr. 4-Dimethylaminopyridine (119 mg, 0.974 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.48 g, 23.4 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 17 hr. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=1/1) to give the title compound (882 mg, 19%) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Si:28]([O:45][C@H:46]([CH3:59])[CH2:47][CH2:48][CH2:49][CH2:50][O:51][C:52]1([CH3:58])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOCC>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[N:55]1[CH2:56][CH2:57][C:52]([O:51][CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]([O:45][Si:28]([C:41]([CH3:42])([CH3:44])[CH3:43])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:59])([CH3:58])[CH2:53][CH2:54]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Reactant: C[C@H](CCCCOC1(C)CCNCC1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)n2n1
Temperature: 70 °C
Yield: 80.1 %

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.25 g, 10.73 mmol) in NMP (80 mL) was treated with (R)-4-((5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidine (6.33 g, 13.95 mmol) and Hunig's Base (5.62 mL, 32.2 mmol), and the mixture was heated (70° C. oil bath) for 16 hrs. At this point LCMS indicates completion of reaction. Mixture was then cooled, diluted with Et2O (200 mL) and washed with water (100 mL) and brine (50 mL), then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by Biotage (5-15%) EtOAc Hexane to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (7, 8.59 mmol, 80% yield) as viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J=8.0, 1.5 Hz, 4H), 7.47-7.28 (m, 6H), 7.01 (s, 1H), 5.82 (br. s., 1H), 4.50-4.38 (m, 2H), 4.31-4.07 (m, 2H), 3.94-3.77 (m, 1H), 3.41-3.24 (m, 3H), 2.61 (s, 3H), 1.88 (br. s., 2H), 1.67 (br. s., 1H), 1.54 (br. s., 1H), 1.51-1.39 (m, 5H), 1.30 (s, 3H), 1.26-1.23 (m, 6H), 1.22 (s, 9H), 1.08 (s, 3H), 1.06 (s, 9H). 4 missing piperidine hydrogens. LCMS (M+H)=816.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([S:26][CH3:27])[C@H:14]([C:16]([O:18]CC1C=CC=CC=1)=[O:17])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([S:26][CH3:27])[C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS[C@H]([C@@H](C)C(=O)OCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CS[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (4.4 g, 11.2 mmol) and Pd(OH)2 on carbon(ca.20 wt %, 2.0 g) in EtOH (50 mL) was stirred at room temperature under H2 atmosphere. After being stirred at room temperature for 14 hr, the mixture was filtrated through a pad of celite and washed with MeOH. The filtrate and washings were combined and concentrated in vacuo to give a crude gum, which was purified by flush column chromatography (hexane:AcOEt=1:1) to give (2S)-2-[(R,2S)-2-carboxy-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a gum (3.39 g, 98%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][C@@H:7]([CH2:9][OH:10])[C@H:6]([CH2:11][OH:12])[O:5]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C>CN(C)C=O>[CH2:14]([O:12][CH2:11][C@@H:6]1[O:5][C:4]([CH3:13])([CH3:3])[O:8][C@H:7]1[CH2:9][OH:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)O[C@@H](CO)[C@H](CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H](CO)[C@H](COCc2ccccc2)O1
Reaction time: 1 h
Yield: 73.2 %

Procedure:
7.71 g of sodium hydride (content: 60%) (193 mmol) was added portionwise to a solution of 30.92 g of (+)-2,3-O-isopropylidene-L-threitol (191 mmol) in N,N-dimethylformamide (285 ml) under a nitrogen atmosphere and under ice-cooling over 45 minutes, and the mixture was stirred at the same temperature for one hour. 23.8 ml of benzyl bromide (200 mmol) was added to the reaction mixture over 30 minutes, and the mixture was stirred at the same temperature for three hours. 2.2 ml of acetic acid (38 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=2/1-1/1) to obtain 35.27 g of the title compound (yield: 73%).
Reaction SMILES: Cl.[CH2:2]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH2:4].C(Cl)Cl.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16]>C(N(CC)CC)C>[CH2:2]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:15](=[O:16])[CH:14]([Cl:18])[Cl:13])[CH:3]=[CH2:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C=CCNCCCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CCCC)C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ten and five-tenths grams of allyl-n-butyl amine hydrochloride was added to 100 ml. of methylene chloride followed by 14.5 g. of triethylamine. The mixture was stirred in a water bath at room temperature while 10.4 g. of dichloroacetyl chloride was added dropwise, and stirring was continued for 30 minutes after addition was complete. The mixture was washed and the solvent stripped under vacuum. Yield was 13 g., nD30 1.4603. The intermediate was used without further purification to prepare Compound No. 12 (Example VII).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]2[N:9]=[C:19]([C:18]3[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1c(Cl)cnc(N)c1N
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)cnc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Temperature: 80 °C

Procedure:
5-Chloro-4-methoxypyridin-2,3-diamine (0.500 g, 2.88 mmol) was dissolved in DMF (7 ml). Iron(III)chloride hexahydrate (0.062 g, 0.23 mmol) was added and the mixture heated to 80° C. 4-Nitrobenzaldehyde (0.434 g, 2.87 mmol) dissolved in DMF (4 ml) was added dropwise, and the reaction mixture was heated at 110° C. for 11 h with air bubbling through the solution. The DMF was removed by evaporation, the solid residue was dissolved in warm methanol and filtered through a short plug of silica gel. Following evaporation and recrystallization (methanol) the subtitle compound was isolated. Yield: 0.569 g (65%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5]Cl.[C:7](=[O:12])([O:10]C)[O:8][CH3:9]>>[C:7](=[O:10])([O:8][CH3:9])[O:12][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: ClCCCCCl
Reactant: COC(=O)OC
Product: COC(=O)OCCCCCl
Reaction time: 2 h
Yield: 13.8 %

Procedure:
The reaction conditions of Example 37 are substantially repeated employing 1,4-dichlorobutane (190.52 g, 1.5 moles), dimethyl carbonate (135.0 g, 1.5 moles) and 30.0 g of DOWEX® MWA-1 beads. After 2 hours at 150° C., distillation gives 34.5 g (13.8 percent yield based on 1,4-dichlorobutane) of 4-chlorobutyl methyl carbonate, b.p. 66° C.-67° C. (0.5 torr).