Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11](=[O:46])[C@H:12]([CH2:27][C:28]1[CH:35]=[C:33]([I:34])[C:32]([O:36][C:37]2[CH:44]=[C:42]([I:43])[C:41]([OH:45])=[C:39]([I:40])[CH:38]=2)=[C:30]([I:31])[CH:29]=1)[NH:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19]>>[CH3:9][O:10][C:11](=[O:46])[C@H:12]([CH2:27][C:28]1[CH:35]=[C:33]([I:34])[C:32]([O:36][C:37]2[CH:44]=[C:42]([I:43])[C:41]([OH:45])=[C:39]([I:40])[CH:38]=2)=[C:30]([I:31])[CH:29]=1)[NH:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:22][CH2:21]1)=[O:19]
Reactant: O=C1CCCC(=O)O1
Reactant: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CCCC(=O)N1CCNCC1
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CCCC(=O)N1CCN(C(=O)CCCC(=O)O)CC1

Procedure:
This material was prepared using the procedure outlined in Intermediate Preparation 1, step 6 except glutaric anhydride was reacted with N-(4-piperazinocarbonylbutyryl)thyroxine methyl ester hydromide from step 4. This compound was purified by column chromatography (SiO2).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3N=N[N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].C(OC1N(CCOCC2C=CN=CC=2)C2C(C)=C(C)N3N=NN=C3C=2N=1)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[N:29][CH:28]=[N:27][CH:26]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCC#Cc1cncnc1
Agent: CCOc1nc2c(c(C)c(C)n3nnnc23)n1CCOCc1ccncc1
Solvent: Cc1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCC#Cc1cncnc1
Yield: 14.6 %

Procedure:
The method described in Part D of Example 109 was used with the following modification. The reaction was carried out in refluxing toluene, and 8-ethoxymethyl-5,6-dimethyl-7-[2-(3-pyrimidin-5-ylprop-2-ynyloxy)ethyl]-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine (6.20 g, 15.3 mmol) was used in lieu of 8-ethoxy-5,6-dimethyl-7-[2-(pyridin-4-ylmethoxy)ethyl]-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine. The crude product was purified by column chromatography on silica gel (200 g, eluting with 95:5 dichloromethane:methanol) to provide 0.852 g of 2-(ethoxymethyl)-6,7-dimethyl-1-{2-[(3-pyrimidin-5-ylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 122–124° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.O=[CH:11][CH2:12][C:13]1([C:29](OCC)=[O:30])[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:14]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:9][C@@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:20])[CH2:14]3)[C:29]2=[O:30])[CH2:4][CH2:5]1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a suspension of cis-4-aminocyclohexanol hydrochloride (Available from Sijia Medchem Lab, China) (13.8 g, 0.0910 mol) and 1-benzyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (31.0 g, 0.0930 mol) in 1,2-dichloroethane (250 mL) was added triethylamine (23.3 mL, 0.167 mol) at room temperature. The mixture was stirred at 40° C. overnight. Sodium triacetoxyborohydride (Aldrich, cat #: 316393) (49.3 g, 0.232 mol) was added to the above mixture and stirred at r.t. for 1 h. LC/MS data indicated that the starting material was consumed, and an intermediate product with m/e: 433.2 (M+H)+ was observed.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)COB([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]([OH:34])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])=[CH:26][CH:27]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(-c3ccccc3O)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 100 °C
Yield: 21.6 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (900 mg, 3.27 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (360 mg, 0.49 mmol) was purged with N2. To this mixture was added 4′-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-2-ol (922 mg, 3.27 mmol) in toluene (5.0 mL) and EtOH (15.0 mL), followed by 2 N aqueous potassium carbonate solution (6.0 mL, 12 mmol). The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and poured into 1 N aqueous citric acid (15 mL). The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase chromatography (C-18 column, 10-40% MeCN/water) to give the title compound (258 mg, 22% yield) as a solid. MS (ES+) 365.0 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 8.18 (s, 1H), 7.82 (s, 1H), 7.68 (d, 2H), 7.50 (d, 2H), 7.36 (d, 1H), 7.19 (dt, 1H), 6.97-6.92 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[C:6](=[O:21])[NH:5]2.[SH:22][C:23]1[CH:24]=[C:25]([C:29]2([C:35]#[N:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>CN1C(=O)CCC1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:21]=[C:6]1[NH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:22][C:23]3[CH:24]=[C:25]([C:29]4([C:35]#[N:36])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:26]=[CH:27][CH:28]=3)[CH:3]=2)[N:8]2[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Reactant: O=c1[nH]c2cc(Br)ccc2n2c(-c3ccccc3)nnc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CC1(c2cccc(Sc3ccc4c(c3)[nH]c(=O)c3nnc(-c5ccccc5)n34)c2)CCOCC1
Temperature: 130 °C

Procedure:
7a (108 mg, 0.32 mmol) and 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (7b, 86 mg, 0.38 mmol) were dissolved in NMP (3.2 mL) and degassed with N2 for 20 minutes. iPr2NEt (0.12 mL, 0.70 mmol) was added, followed by Pd2dba3 (15 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.03 mmol). The reaction was sealed and heated overnight at 130° C., and then cooled to room temperature and diluted with EtOAc and water. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (25-100% EtOAc in hexanes, followed by 10% MeOH in EtOAc) to give the desired product, 7c.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].Cl.[CH2:11]([N:18]([CH2:22][CH2:23]Cl)[CH2:19][CH2:20]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[CH2:11]([N:18]1[CH2:22][CH2:23][C:7]([C:8]#[N:9])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCc1ccccn1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Product: N#CC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Combine 2-pyridylacetonitrile (5.9 g, 50 mmol), N-benzyl-N,N-bis-(2-chloroethyl)amine hydrochloride (13.4 g, 50 mmol), and hexadecyltributyphosphonium bromide (1.3 g, 2.5 mmol) and a 50% aqueous sodium hydroxide solution (75 mL). Heat to 100° C. After 1 hour, cool the reaction mixture to ambient temperature and repeatedly extract with diethyl ether. Extract the combined organic layers twice with an aqueous 10% hydrochloric acid solution (350 mL). combine the aqueous layers and neutralize with an aqueous 50% sodium hydroxide solution. Again extract three times with diethyl ether, combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give 1-benzyl-4-cyano-4-(pyridin-2-yl)-piperidine: Rf =0.56 (silica gel, 9/1 dichloromethane/methanol). Elemental Analysis calculated for C18 H19N3 : C, 77.95; H, 6.90; N, 15.15. Found: C, 78.20; H, 6.97; N, 15.04.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1Br)[CH:10]([NH:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[Cu][C:31]#[N:32].N>CN1C(=O)CCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:31]#[N:32])[CH:10]([NH:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1Br)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[N-(5-acetamido-6-bromoindan-1-yl)amino]-2-fluorobenzoate (0.420 g, 0.90 mmol) in NMP (10 ml) was added copper(I) cyanide (0.137 g, 1.53 mmol). The reaction mixture was placed in an oil-bath preheated to 145° C. and stirred at this temperature for 2 hours. The reaction mixture was allowed to cool to room temperature, then poured into a mixture of aqueous ammonia (d=0.88, 5 ml) and ice (˜15 ml) and the resulting brown mixture was stirred at room temperature for ˜5 min. The brown solid was collected by filtration washed with water, then suspended in dichloromethane (60 ml). The mixture was stirred at room temperature for 5 min, dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography, on elution with 40% ethyl acetate in hexane, afforded a solid that was triturated with diethyl ether/hexane. The desired compound was obtained as a white solid: 0.202 g, (55%) m.p. 172-173° C.; 1H-NMR (250 MHz, CDCl3, TMS) 1.57 (s (obscured by water peak), 9H, C(CH3)3), 2.27 (s, 3H, COCH3), 1.96, 2.65 (2×m, 2H, indanyl 2-H), 3.00 (m, 2H, indanyl 3-H), 4.30 (d, J=8.40 Hz, 1H, N-H), 4.99 (q, J=7.80 Hz, 1H, indanyl 1-H), 6.38 (m, 2H, 3,5-H), 7.52, 8.33, 7.62 (3×s, each 1H, indanyl 4-H, 7-H, CONH), 7.74 (t, J=8.60 Hz, 1H, 6-H); MS (ESI m/z) 432 {M+Na)+, 100%}; Found: C, 67.44; H, 5.88; N, 10.25; F, 4.63; C23H24FN3O3 requires C, 67.47; H, 5.91; N, 10.26%; F, 4.64%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[C:16]([CH:17]2[CH2:19][CH2:18]2)=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:20])(=O)C.O>CO>[Cl:20][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]2[CH2:18][CH2:19]2)[C:11]=1[OH:10]
Reactant: CC(=O)Oc1c(Cl)cccc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1c(Cl)cccc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
Potassium carbonate (21.3 g, 154 mmol) was added to a solution of 2-chloro-6-cyclopropylphenyl acetate (16.3 g, 77 mmol) in methanol (80 ml) at once and the mixture was stirred at room temperature for 90 minutes. After water (240 ml) was added to the reaction mixture, the resulting mixture was concentrated by an evaporator to remove most of methanol. The obtained mixture was cooled to 0° C. and 4M hydrochloric acid was added thereto to make pH to 2 or lower such that the temperature of the mixture did not exceed 25° C. This was extracted with a 10% ethyl acetate-90% hexane (V/V) solvent mixture. The organic layer was combined and washed with a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate (90 g). After the solid was removed by filtration, the filtrate was concentrated to obtain a pale brown oil. This oil was purified by silica gel column chromatography (use of 120 g of Wakogel C-100E) to obtain 10.1 g of 2-chloro-6-cyclopropylphenol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[NH2:10])([O-])=O>C(O)C.C1COCC1.[Pd]>[C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:8]([NH2:11])[C:9]([NH2:10])=[C:4]([NH2:1])[CH:5]=1
Reactant: Nc1c([N+](=O)[O-])cc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(-c2ccccc2)cc(N)c1N
Temperature: 23 °C
Reaction time: 26 h
Yield: 81.2 %

Procedure:
To a solution of 80 mg (309 μmol) 3,5-dinitrobiphenyl-4-amine in a mixture of 34 mL ethanol and 10 mL THF were added 6.6 mg palladium on charcoal (10%) and the mixture was stirred under an atmosphere of hydrogen for 26 hours at 23° C. After filtration and removal of the solvent the residue was purified by chromatography to yield 50 mg (81%) of the title compound.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:9]1[S:10][C:6]([CH3:5])=[CH:7][CH:8]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(C=O)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc(C)s1)CC(=O)O
Yield: 60.8 %

Procedure:
Sodium ethylate (6.5 g, 95 mmol) was added under vigorous stirring to a solution of 5-methylthiophene-2-carbaldehyde (10 g, 79 mmol) and diethyl succinate (27.6 g, 158 mmol) in ethanol (300 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 200 mL of 10% HCl and 300 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 200 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 400 mL of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions containing the target product were collected and evaporated in vacuum to give 12.3 g (48 mmol, 61%) of 3-(ethoxycarbonyl)-4-(5-methyl-2-thienyl)but-3-enoic acid as a light-brown oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][CH3:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([N:24]([C:2]2[O:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH3:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN[C@@H]1CCN(Cc2ccccc2)C1
Reactant: Clc1ccc2nc(Cl)oc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(c1nc2ccc(Cl)cc2o1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g (2.6 mmol) 2,6-dichloro benzoxazole, 0.68 g (3.58 mmol) ((R)-1-benzyl-pyrrolidin-3-yl)-methyl-amine and 0.4 g (4 mmol) NEt3 in 12 mL DCM was stirred over night at room temperature. DCM was added and the mixture was washed with NaHCO3 aq., dried with MgSO4 and evaporated to dryness to yield the title compound as yellow oil which was used in the consecutive step without further purification. (MH+) 342.1
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23]C(=O)C)=[O:16])[N:13]=[C:12]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[S:11]1.FC(F)OC1C=CC=CC=1C1N(C(C2C(F)=CC(F)=CC=2F)=O)N=C(C2C=NC(C)=CC=2)S1.[Li+].[OH-].Cl>C1COCC1.CO>[F:34][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[O:16])[N:13]=[C:12]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[S:11]1
Reactant: CC(=O)Oc1ccccc1C(=O)N1N=C(c2ccc(C)nc2)SC1c1ccccc1OC(F)F
Agent: Cc1ccc(C2=NN(C(=O)c3c(F)cc(F)cc3F)C(c3ccccc3OC(F)F)S2)cn1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C2=NN(C(=O)c3ccccc3O)C(c3ccccc3OC(F)F)S2)cn1

Procedure:
(2-(2-(Difluoromethoxy)phenyl)-5-(6-methylpyridin-3-yl)-1,3,4-thiadiazol-3(2H)-yl)(2-acetoxyphenyl)methanone (0.02 mmol) prepared in a similar manner as described in experiment 11 for [2-(2-difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone, is dissolved in THF/MeOH (1 mL/0.5 mL) and treated with aqueous LiOH (1 M) (0.5 mL) at room temperature for 30 minutes. Aqueous HCl (3 M) is added to adjust the pH to 5-6. Solvent is removed and the residue is purified by preparative HPLC (20-100% MeCN/H2O) to yield [2-(2-difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2-hydroxy-phenyl)-methanone: 1H NMR (400 MHz, CDCl3) 9.02 (d, J=2.0 Hz, 1H), 8.41 (d, J=8.6 Hz, 1H), 8.23 (dd, J1=8.2 Hz, J2=2.2 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.65 (s, 1H), 7.62 (dd, J1=7.8 Hz, J2=1.3 Hz, 1H), 7.45-7.53 (m, 5H), 6.97-7.01 (m, 2H), 2.79 (s, 3H); LC/MS (ES+): (M+1) 442.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1([O:25][C@H:24]([CH2:26][O:27]CC2C=CC=CC=2)[C@@H:15]([O:16]CC2C=CC=CC=2)[C@@H:6]1[O:7]CC1C=CC=CC=1)[CH2:4][OH:5]>CO.C(O)(=O)C.[Pd]>[OH:1][CH2:2][C:3]1([O:25][C@H:24]([CH2:26][OH:27])[C@@H:15]([OH:16])[C@@H:6]1[OH:7])[CH2:4][OH:5]
Reactant: OCC1(CO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1OC(CO)(CO)[C@@H](O)[C@@H]1O

Procedure:
In accordance with Flowchart G, 2,5-anhydro-2-C-(hydroxymethyl)-3,4,6-tris-O-(phenylmethyl)-D-glucitol 42 is hydrogenated in methanol/acetic acid over palladium on carbon, giving 2,5-anhydro-2-C-(hydroxymethyl)-D-glucitol 51, which is treated with copper sulfate and sulfuric acid in acetone, then neutralized, giving 2,5-anhydro-2-C-(hydroxymethyl)-21,3-O-(1-methylethylidene)-D-glucitol 52. Compound 52 is reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving 2,5-anhydro-2-C-[[(diphenoxyphosphinyl)oxy]methyl]-1,3-O-(1-methylethylidene)-D-glucitol, 6-(diphenyl phosphate) 53, which is then treated with 80% aqueous acetic acid at 80° C., giving 2,5-anhydro-2-C-[[(diphenoxyphosphinyl)oxy]methyl]-D-glucitol, 6-(diphenyl phosphate) 54. Substitution of other esterifying agents as described in Flowchart A will result in the corresponding tetraesters. Compound 53 is hydrogenated in methanol over platinum oxide, giving directly the product 2,5-anhydro-2-C-[(phosphonooxy)methyl]-D-glucitol, 6-(dihydrogen phosphate) 55. Compound 54 may be hydrogenated under the same conditions, giving 55. ##STR20##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:34][CH3:35])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:34][CH3:35])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
To a solution of methyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D83) (188 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (30.7 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E34) (14 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.07 (3H, t), 1.36 (6H, d), 2.69 (2H, m), 2.87 (2H, m), 3.59 (3H, m), 4.28 (4H, m), 4.90 (1H, m), 7.30 (2H, m), 7.37 (1H, m), 7.44 (1H, d), 7.85 (1H, s), 8.22 (1H, dd), 8.27 (1H, d), 9.98 (1H, br s), 13.19 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C27H29N3O3S requires 475. found 476.2 (M+H+).
Reaction SMILES: [ClH:1].[C:2]([NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[NH:6])#[N:3].C([OH:18])(C)C>>[ClH:1].[ClH:1].[C:2]([NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[NH:6])(=[O:18])[NH2:3]
Reactant: N#CNC(=N)NCc1ccncc1
Reactant: CC(C)O
Agent: Cl
Product: N=C(NCc1ccncc1)NC(N)=O

Procedure:
Concentrated HCl (21 ml) is added to a mixture of 1-cyano-3-(4-pyridylmethyl)guanidine (10.0 g) in 500 ml of isopropanol. A pale yellow precipitate forms. The stirred suspension is heated on a steam bath and boiled for ten minutes. The solvent is evaporated under reduced pressure and the residual solid treated with 25 ml of concentrated HCl. The solution is heated on a steam bath for several minutes and diluted with isopropanol (50 ml) and allowed to cool. The resulting solid is collected and dred in air, extracted into 900 ml of methanol, which is filtered, and concentrated on a not plate. The hot solution is diluted with ethyl acetate and concentrated further. A white precipitate forms on cooling which is collected and dried in air giving the desired amidinourea dihydrochloride, MP 208°-209.5° C. w/dec.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:20][CH:21]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(Nc2c([N+](=O)[O-])cnc3ccccc23)cc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 4-aminophenylacetic acid in N,N-dimethylformamide in the presence of triethylamine to provide N-(3-nitro-4-quinolinyl)-4-aminophenylacetic acid. This acid was reduced using the method of Example 26 to provide N-(3-amino-4-quinolinyl)-4-aminophenylacetic acid. This diamine was then reacted with formic acid using the method of Example 137 to provide 1-(4-carboxymethylphenyl)-1H-imidazo[4,5-c]quinoline. Recrystallization from methanol provided solid of m.p. 236°-240° C. Analysis: Calculated for C18H13N3O2 : %C, 71.3; %H, 4.3; %N, 13.9; Found; %C, 70.8; %H, 4.3; %N, 13.7.