Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[N-:18]=[N+:19]=[N-:20].[Na+]>O>[N:18]([C:15]1[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnc2nc(C)ccc2c1N=[N+]=[N-]
Reaction time: 20 h

Procedure:
3-Carbethoxy-4-chloro-7-methyl-1,8-naphthyridine (0.8 g; 0.03 M) was dissolved in dry D.M.F. (5 ml) at ambient temperatures and NaN3 (0.5 g; 0.007 M) added. This mixture was stirred for 20 hr. at ambient temperatures and then poured into a large volume (1 l) of H2O. The product (0.64 g; 83%), m.p. 114°-115° C. (dec.), was filtered off, washed with H2O and dried over P2O5 in vacuo (Found: N, 27.49; C, 55.59; H, 4.50%. C12H11N5O2 requires: N, 27.24; C, 56.03; H, 4.28%), νmax (KBr) 3080, 2900, 2142, 1708, 1600, 1550, 1472, 1375, 1268, 1210, 1194, 1050, 1038, 806 cm-1, δ [(CD3)2SO] 1.38 (t), 4.40 (q), (CH3CH2), 2.68 (s), (CH3), 7.5 (d), 8.5 (d), 9.14 (s) (heterocyclic protons), m/e 257 (M+ ; 65%) 229 (M+ --N2 ; 32%), 212 (M+ --OC2H5 ; 15%), 201 (52%), 133 (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19](OC(C)(C)C)=O)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[C:30]1([CH2:36]C=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH3-]C#N.[Na+]>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(CCc3ccccc3)C1)O2

Procedure:
(±)-(E)-3-{1′-(2-Phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester was synthesized starting from Intermediate 5 (339 mg, 1.00 mmol), according to the procedure described in Example 40, Step A, using phenylacetaldehyde (0.13 ml, 1.2 mmol) and NaBH3CN (63 mg, 1.2 mmol). The product was obtained as a yellow solid (320 mg).
Reaction SMILES: [CH:1]([CH2:3][N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])=O.[F:19][C:20]([F:35])([F:34])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O.ClCCCl.C(O)(=O)C>[CH:7]1([C:5]([N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:3][CH2:1][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:34])([F:19])[F:35])[CH2:33][CH2:32]2)=[O:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CCN(C(=O)C1CCCCC1)c1ccccn1
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: O=C(C1CCCCC1)N(CCN1CCN(c2ccccc2OC(F)(F)F)CC1)c1ccccn1
Reaction time: 4 h
Yield: 51.1 %

Procedure:
A mixture comprising 0.459 g of Compound 1B, 0.445 g of 1-(2-trifluoromethoxyphenyl)piperaine (prepared as described by D. Clarke et al, in European Patent EP 711 757, 1996), 0.634 g sodium triacetoxyborohydride, 0.23 mL of glacial acetic acid and 15 mL of 1,2-dichloroethane was stirred for 4 h, under a nitrogen atmosphere. The resultant solution was then kept overnight at room temperature, followed by the addition of 10 mL of water, and alkalinization with a 20% aqueous Na2CO3 solution. This was followed by separation of phases, with the isolated aqueous phase being extracted with 2×20 mL dichloromethane, and with the collected organic phases being dried over anhydrous sodium sulphate. This was followed by the removal of solvents, via vacuum evaporation to dryness. The obtained product residue was purified by flash chromatography (ethyl acetate—petroleum ether gradient 90:10 to 10:0). This was followed by evaporation of the solvents, affording 0.44 g of the title compound (yield 51%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([NH:10][NH2:11])=O)=[C:5]([CH3:7])[N:6]=1.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:1][C:2]1[S:3][C:4]([C:8]2[N:14]([CH3:13])[C:15]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[N:11][N:10]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)NN)s1
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Product: C=CCCCc1nnc(-c2sc(C)nc2C)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.17 g yield starting from 2,4-dimethyl-1,3-thiazole-5-carbohydrazide (0.50 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.51 g). MS (m/z): 263 [MH]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:12]
Reactant: Clc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (1.3 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in chlorobenzene (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.38 g of 6-bromo-1-(4-chlorophenyl)-1-hexanone.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][N:15]=3)[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[C:18]([CH:17]=[CH:16][N:15]=3)[C:20]([OH:22])=[O:21])[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccnn2-c2cc(C(=O)O)ccn2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccnc(-n2nccc2-c2cccc(O)c2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-[5-(3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid (160 mg, 0.54 mmol) in CH2Cl2 (5 mL) was added 1 M BBr3 in CH2Cl2 (5 mL) at 0° C., then stirred at 45° C. overnight. The reaction mixture was cooled, concentrated and dissolved with EtOAc, then washed with water and brine. The organic phase was dried, concentrated and purified by prep-HPLC to give the title compound (54 mg, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 6.60-6.65 (3H, m), 6.71 (1H, dd, J=8.4, 2.0 Hz), 7.11 (1H, t, J=8.0 Hz), 7.78-7.82 (2H, m), 8.04 (1H, s), 8.48 (1H, d, J=5.2 Hz), 9.46 (1H, s), 13.93 (1H, br s). [M+H] Calc'd for C15H11N3O3, 282. Found, 282.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:43][CH2:44][C:45]([O:47]C(C)(C)C)=[O:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:43][CH2:44][C:45]([OH:47])=[O:46])=[O:31])=[CH:33][CH:34]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-1-(4-Chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid, 302.1 mg, 0.585 mmol) was dissolved in DCM (6 ml). N-Methylmorpholine (190 μl, 1.728 mmol) and tert-butyl glycinate hydrochloride (133.4 mg, 0.80 mmol) were added. After 10 minutes, TBTU (224.3 mg, 0.67 mmol) was added and the reaction mixture was stirred for 60 h. The intermediate tert-butylester of the title compound was confirmed. M/z: 626.88 (M−H). DCM (10 ml) and water (15 ml) were added and the mixture was acidified to pH of 3 using KHSO4 (2M). The organic phase was washed with water (2×15 ml). The combined aqueous phases were extracted with DCM (10 ml), dried over Na2SO4, filtered and concentrated. A solution of the residue (500 mg) in DCM (10 ml) and TFA (4 ml) was stirred overnight. The solvent was removed under reduced pressure. Toluene was added and evaporated to assist the removal of TFA. The residue was purified with preparative HPLC on a C8 column. A gradient from 20 to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (166.9 mg, 50%). H-NMR (400 MHz, DMS-d6): 3.51 (d, 2H), 4.33 (d, 1H), 4.34 (s, 1H), 4.36 (s, 1H), 4.47 (s, 2H), 5.17 (d, 1H), 6.96 (d, 2H), 7.16-7.21 (m, 2H), 7.35 (d, 4H), 7.54-7.59 (m, 2H), 7.83-7.90 (brs, 1H), 7.91-7.95 (m, 2H). M/z: 571.04 (M−H) and 572.88 (M+H).
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[I:15])[CH3:4]>C(O)C.O.[Fe]>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[I:15])[CH3:4]
Reactant: CCOc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(N)cc1I
Yield: 96.9 %

Procedure:
A suspension of iron (3.81 g, 70 mmol) and ammonium chloride (5.47 g, 102 mmol) in 80 mL of ethanol and 25 mL of water was heated to reflux. 1-Ethoxy-2-iodo-4-nitrobenzene (5.0 g, 20 mmol) was added in portions and the reaction was heated at reflux for 1 hour. The hot mixture was filtered through Celite, washed with hot ethanol. The filtrate was concentrated in vacuo and treated with ethyl acetate and water. The organic layer was extracted, washed with brine, dried over magnesium sulfate and filtered. Removal of the solvent in vacuo provided 5.1 g of (4-ethoxy-3-iodophenyl)amine as a light brown oil; 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 3H), 3.89 (q, 2H), 4.82 (bs, 2H), 6.53 (dd, 1H), 6.72 (d, 1H), 7.11 (d, 1H); MS (ES) m/z263.9 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:24]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: COc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
4-Fluoro phenylacetic acid (12.3 g, 79.79 mmoles) was dissolved in 30 ml dichloromethane. To this mixture, oxalylchloride (10.17 g, 79.79 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (10.6 g, 79.79 mmoles) was added and the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as white solid (6.1 g, 37% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 12.05(s,1H), 7.96(d, J=2.3 Hz, 1H), 7.58(dd, J=8.9, 2.4 Hz, 1H), 7.24(dt, J=5.4, 1.9 Hz, 2H), 7.09(dt, J=8.6, 2.1 Hz, 2H),6.79(d, J=8.7 Hz, 1H), 4.27(s, 2H).
Reaction SMILES: [CH2:1]([C:3]([OH:33])([CH2:31][CH3:32])/[CH:4]=[CH:5]/[CH2:6][CH:7]([C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:24](OC)=[O:25])[C:17](=[CH:22][CH:23]=1)[C:18](OC)=[O:19])[CH3:8])[CH3:2].[BH4-].[Li+]>>[OH:25][CH2:24][C:16]1[CH:15]=[C:14]([CH:23]=[CH:22][C:17]=1[CH2:18][OH:19])[CH2:13][O:12][C:11]1[CH:10]=[C:9]([CH:7]([CH3:8])[CH2:6]/[CH:5]=[CH:4]/[C:3]([CH2:1][CH3:2])([OH:33])[CH2:31][CH3:32])[CH:30]=[CH:29][CH:28]=1
Reactant: CCC(O)(/C=C/CC(C)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1)CC
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)(/C=C/CC(C)c1cccc(OCc2ccc(CO)c(CO)c2)c1)CC

Procedure:
In a manner similar to Example 53(e), by treating 63 mg (0.14 mmol) of dimethyl 4-[3-((E)-5-ethyl-5-hydroxy-1-methylhept-3-enyl)phenoxymethyl]phthalate (prepared in a manner similar to Example 70) with 10 mg (0.4 mmol) of lithium borohydride, a colourless oil is obtained (m=54 mg; Y=97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>>[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:20]([N:11]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:35])[N:9]=[C:10]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH:32]([CH3:33])[CH3:34])=[O:21]
Reactant: CN(C)CCN
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)NCCN(C)C)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N,N-dimethyl-1,2-ethanediamine (Aldrich) to give the title compound. LC-MS: 583.2 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH:42][CH3:43]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH3:43])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CNCCOC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: COCCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and (2-methoxyethyl)methylamine according to conditions described in general procedure C. Mp: 81-82° C.; 1H NMR (400 MHz, CDCl3) δ 1.62-1.70 (m, 6 H), 3.06-3.40 (m, 14 H), 6.05 (s, 1 H), 6.76 (d, J=12.0 Hz, 1 H), 6.99 (d, J=7.8 Hz, 1 H), 7.26-7.30 (m, 2 H), 7.47-7.56 (m, 2 H), 7.88-7.96 (m, 3 H), 8.17 (s, 2 H).
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH2:18][CH2:19][CH3:20])[O:13][CH2:14][CH2:15][CH3:16])[P:2](=[O:11])([O:7][CH2:8][CH2:9][CH3:10])[O:3][CH2:4][CH2:5][CH3:6].C=O.[CH2:24](NCC)C>CO>[C:1]([P:2](=[O:11])([O:7][CH2:8][CH2:9][CH3:10])[O:3][CH2:4][CH2:5][CH3:6])([P:12](=[O:21])([O:13][CH2:14][CH2:15][CH3:16])[O:17][CH2:18][CH2:19][CH3:20])=[CH2:24]
Reactant: CCCOP(=O)(CP(=O)(OCCC)OCCC)OCCC
Reactant: CCNCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCC)OCCC)P(=O)(OCCC)OCCC
Yield: 71.9 %

Procedure:
5.97 g (17.4 mmol) of tetra-n-propyl methylenebisphosphonate, 2.61 g (86.8 mmol) of paraformaldehyde and 1.27 g (17.4 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 46 hours. After the methanol is eliminated as described above in Example I, 4.46 g of tetra-n-propyl ethenylidenebisphosphonate is produced as a clear oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:65])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH2:53][CH2:54][CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[C:57]=3[OH:64])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:65])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH2:53][CH2:54][CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[C:57]=3[OH:64])[CH:52]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([OH:32])[CH3:31])([CH3:24])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3cc(F)cc(F)c3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3cc(F)cc(F)c3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a solution of (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(3,5-difluoro-2-hydroxyphenyl)propyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (130 mg, 0.142 mmol) in THF (3 mL) was added 1M solution of TBAF (0.712 mL, 0.712 mmol) and the resulting mixture was stirred at room temp for 16 h. Mixture was then concentrated and the residue was purified by Biotage (5-50% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(3,5-difluoro-2-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (70 mg, 0.104 mmol, 72.9% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 6.79-6.61 (m, 2H), 6.34 (s, 1H), 5.94 (br. s., 1H), 4.29-4.09 (m, 2H), 3.87 (d, J=5.4 Hz, 1H), 3.49-3.36 (m, 2H), 2.92-2.79 (m, 3H), 2.76 (br. s., 1H), 2.62 (s, 3H), 2.16-2.07 (m, 2H), 1.98 (d, J=13.2 Hz, 2H), 1.64 (d, J=4.3 Hz, 3H), 1.56-1.41 (m, 4H), 1.33 (br. s., 2H), 1.27-1.20 (m, 15H). LCMS (M+H)=675.8.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[C:7]1=[O:21].[NH3:37]>CO>[Cl:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:22]([N:5]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]3)[C:7]1=[O:21])[CH2:4][C:3]([NH2:37])=[O:2])(=[O:23])=[O:24])[CH:34]=[CH:33]2
Reactant: N
Reactant: COC(=O)CN([C@H]1CCCN(C2CCN(C(C)C)CC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Solvent: CO
Product: CC(C)N1CCC(N2CCC[C@H](N(CC(N)=O)S(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(S)-[(6-Chloro-naphthalene-2-sulfonyl)-(1′-isopropyl-2-oxo-[1,4′]bipiperidinyl-3-yl)-amino]-acetic acid methyl ester (the product obtained in Example 8) was dissolved in 2.0M NH3 in methanol (5.0 mL), and the mixture was stirred at room temperature for 48 hr. The solvent was removed. HPLC purification (10% to 100% acetonitrile/water) provided the title compound as a white solid. LC-MS found: (M+1)+=521.31.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(CC)CC>C(Cl)Cl>[CH3:16][C:10]1([CH3:17])[C@@H:11]([C:13]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:15])[CH2:12][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCOCC2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.3 g, 1.23 mmol) in DCM (5 ml) EDCI (0.237 g, 1.23 mmol) and HOBt (0.167 g, 1.23 mmol) were added at about 0° C., after 10 minutes morpholine (0.2 ml, 2.469 mmol) and Et3N (0.9 ml, 6.2 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by a silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 0.205 g; Yield: 53.1%; 1H NMR (300 MHz, CDCl3): δ 4.75 (d, 1H, J=8.4 Hz), 3.90-3.40 (m, 8H), 2.83-2.74 (m, 1H), 2.40-2.21 (m, 2H), 1.43 (s, 9H), 1.32 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([I:11])[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Solvent: C1CCOC1
Product: OCc1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-bromo-5-iodobenzoic acid (1.0 eq.) in THF (0.2 M) at RT was added borane-methyl sulfide complex (1.5 eq). After 3 days of stirring at RT, the reaction mixture was quenched cautiously with 2 N aq. HCl and extracted with ether. The combined organic extracts were washed with 1 N aq. NaOH, water and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:42]=[CH:43][CH:44]=1)[CH2:13][O:14][C:15]1[CH:41]=[CH:40][CH:39]=[CH:38][C:16]=1[CH2:17][C:18]1[C:19]([O:26][C@@H:27]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]2[OH:29])=[N:20][NH:21][C:22]=1[CH:23]([CH3:25])[CH3:24])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C@@H:27]1([O:26][C:19]2[C:18]([CH2:17][C:16]3[CH:38]=[CH:39][CH:40]=[CH:41][C:15]=3[O:14][CH2:13][C:12]3[CH:42]=[CH:43][CH:44]=[C:10]([CH2:9][OH:8])[CH:11]=3)=[C:22]([CH:23]([CH3:25])[CH3:24])[NH:21][N:20]=2)[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]1[OH:29]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(CO)c1
Reaction time: 15 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole (164 mg) and potassium carbonate (115 mg) in N,N-dimethylformamide (5 mL) was added 3-tert-butyldimethylsilyloxymethylbenzyl bromide (197 mg) at room temperature, and the mixture was stirred for 20 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1–5/1) to give 4-[2-(3-tert-butyldimethylsilyloxymethylbenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. To a solution of the obtained 4-[2-(3-tert-butyldimethylsilyloxymethylbenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole in tetrahydrofuran (2 mL) was added tetra-(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 0.065 mL) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (22 mg).