Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[BH4-].[Na+]>>[CH2:23]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC=O
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCNCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 57.7 %

Procedure:
Using a method similar to Example 201, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol), hexanal (75 mg, 0.750 mmol), and NaBH4 (38 mg, 1.00 mmol) gives the title compound (110 mg) as a colorless glass. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.15 (d, 1H), 7.21-7.14 (m, 2H), 6.90 (m, 2H), 6.05 (br. s, 2H), 3.01 (m, 1H), 2.90-2.79 (m, 2H), 2.69-2.55 (m, 3H), 2.50-2.42 (m, 1H), 1.84-1.64 (m, 4H), 1.49 (m, 2H), 1.29 (m, 6H), 0.89 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[CH3:9])[N:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[O:16][CH3:17].[OH-].[Na+].Cl>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[CH3:9])[N:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[O:16][CH3:17]
Reactant: COC(=O)c1nc(C(C)(F)F)cc(N)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(N)cc(C(C)(F)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of methyl 4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinate (0.229 g, 0.930 mmol) in THF (2.325 ml) and MeOH (2.325 ml) was added a 2 N solution of sodium hydroxide (1.395 ml, 2.79 mmol). The reaction mixture was stirred at room temperature (LC monitoring). After 4 h, the reaction mixture was acidified with a 2 N solution of HCl (2 mL) and then concentrated (rotavap). The resulting white solid was dissolved into DMF and a few drops of water and was purified by preparative HPLC (reverse phase, C18 column) to afford 4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinic acid (188 mg, 0.810 mmol, 87% yield) as an orange oil. EIMS m/z 208; 1H NMR (400 MHz, CDCl3) δ 6.86 (s, 1H), 6.71 (dd, J=17.6, 10.9 Hz, 1H), 5.98 (dd, J=17.6, 1.0 Hz, 1H), 5.42 (dd, J=10.9, 1.0 Hz, 1H), 4.45 (s, 2H), 3.97 (s, 3H), 3.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.94, 152.06, 148.02, 143.34, 141.60, 136.73, 118.02, 108.63, 61.49, 52.84.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=1.[Li+].CC([N-]C(C)C)C.CN([CH:27]=[O:28])C>C1COCC1>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[C:10]=1[CH:27]=[O:28]
Reactant: Fc1cccc(I)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cccc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
Buthyllithium (1.6 M, 60 ml, 0.113 mol) is added to an ice cooled solution of diisopropyl-amine (17.6 ml, 0.124 mol) in THF (200 ml). The solution is stirred at 0° C. for 30 minutes and is cooled to −78° C. 1-Fluoro-3-iodo-benzene (25 g, 0.113 mol) in THF (20 ml) is slowly added to the preformed LDA mixture. The resulting solution is stirred for another hour after which DMF (9.55 ml, 0.124 mol) is added and stirring is continued for another 30 minutes at −78° C. The reaction is quenched first with acetic acid (20 ml) followed by water (200 ml). The mixture is extracted with ether. The organic layer is washed with a 2N HCl solution, brine, is dried over MgSO4 and evaporated to afford the desired compound (28.3 g).
Reaction SMILES: [CH3:1][CH:2]([CH:10]=[CH2:11])[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>CN(C)C1C=CN=CC=1>[O:17]=[C:13]([CH3:12])[CH2:14][C:15]([O:9][C:6]([CH3:7])([CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:10]=[CH2:11])[CH3:8])=[O:16]
Reactant: C=CC(C)CCCC(C)(C)O
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(C)=O
Temperature: 55 °C
Yield: 95 %

Procedure:
A mixture of dihydromyrcenol (37.88 g, 0.240 mol) and 4-dimethylaminopyridine (0.16 g, 1.30 mmol) in a 100 mL three-necked round-bottomed flask fitted with a condenser, argon inlet, addition funnel, magnetic stirrer and internal thermometer is heated to 50-60° C. Diketene (20.16 g, 0.240 mol) is added dropwise in the course of 15 min. The mixture has a slight exotherm and turned from yellow to red during this time. After stirring an additional hour at 50° C., the mixture is cooled to room temperature. At this point, NMR analysis indicates the reaction is complete. Purification of the product mixture by flash chromatography (elution with dichloromethane) yields the desired product in 95% yield as a nearly colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH3:18])=[N:12][NH:13]2.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1.Cl>O>[NH2:33][C:23]1[N:22]=[C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[C:11]([CH3:18])=[N:12][NH:13]4)=[C:2]([F:1])[CH:3]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Cc1n[nH]c2cccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Solvent: O
Product: Cc1n[nH]c2cccc(Oc3ccc(Nc4cc(-c5ccncc5)nc(N)n4)cc3F)c12

Procedure:
60 mg (0.23 mmol) of 3-fluoro-4-[(3-methyl-1H-indazol-4-yl)oxy]phenylamine (from example III) and 48 mg (0.23 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) are suspended in 4 ml of water, and 0.02 ml of concentrated hydrochloric acid is added. The reaction mixture is heated at reflux overnight, resulting in the formation of a brown precipitate. This is filtered off, washed repeatedly with water and dried under high vacuum. This gives 65 mg (65% of theory) of the product as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:26][O:27][NH2:28]>>[CH3:26][O:27][N:28]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:21][CH2:22][CH2:23][CH3:24])[CH3:19]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Reactant: CON
Agent: Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NOC

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime in about a 7.9 to 1 mixture of E and Z isomers as light brown crystals after recrystallization from aqueous methanol, mp 157-159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:35])[C:30]=1[O:31][CH2:32][CH2:33][OH:34])[CH:26]=O.S(=O)(O)[O-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][C:19]([F:21])=[CH:18][CH:17]=3)[NH:1][CH:26]2[C:25]2[CH:28]=[C:29]([CH3:35])[C:30]([O:31][CH2:32][CH2:33][OH:34])=[C:23]([CH3:22])[CH:24]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2ccc(F)cc2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(C)c1ccc(N2C(=O)c3ccc(F)cc3NC2c2cc(C)c(OCCO)c(C)c2)cc1
Temperature: 120 °C
Yield: 7.4 %

Procedure:
A mixture of 2-amino-N-(4-sec-butyl-phenyl)-4-fluoro-benzamide (0.920 g, 3.21 mmol), 3,5-dimethyl-4-(2-hydroxy-ethoxy)-benzaldehyde (0.627 g, 3.21 mmol), sodium bisulfite (0.640 g, 3.53 mmol), and p-toluenesulfonic acid (60 mg, 0.32 mmol) in N,N-dimethylacetamide (20 mL) was heated at 120° C. for 16 hours. The solvent was evaporated in vacuo and water was added to the flask. The precipitate was filtered off and washed with water. The solid was triturated with ether and filtered off to give 3-(4-sec-butyl-phenyl)-7-fluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-2,3-dihydro-1H-quinazolin-4-one (P) (0.11 g). The filtrate was evaporated under vacuum to give second crop of (1.02 g). The combined yield: 1.13 g (quantitative).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1)(=[O:28])=[O:27]>>[CH2:38]([O:37][C:35]([CH:31]1[CH2:30][N:29]([S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:27])=[O:28])[CH2:34][CH2:33][N:32]1[C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:36])[CH3:39]
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 9 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl 1-(2-naphthylsulphonyl)piperazine-3-carboxylate to give 2-ethoxycarbonyl-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine as a glassy solid in 9% yield;
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(OCc2ccccc2)ccc(C=O)c1[N+](=O)[O-]
Reaction time: 16 h
Yield: 97.4 %

Procedure:
4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (155 g, 786 mmol) was dissolved in DMF (1500 mL) and the stirred solution was treated with potassium carbonate (217 g, 1.57 mol) followed by benzyl bromide (161 g, 0.94 mol). After stirring for 16 h the reaction mixture was concentrated under reduced pressure and separated between water (2 L) and EtOAc (2 L). The organic layer was washed with brine (3×2 L), dried (sodium sulfate) and concentrated under reduced pressure. The resulting solids were triturated with Et2O (1 L) to give the title compound (220 g, 97%): 1H NMR (DMSO-d6) δ: 9.77 (1H, s), 7.87 (1H, d), 7.58 (1H, d), 7.51 (1H, m), 7.49 (1H, m), 7.39 (3H, m), 5.36 (2H, s), 3.05 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:27]1([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2-c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(-c2ccccc2)c2c(c1O)c1ccccc1n2-c1ccccc1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A mixture of 1-bromo-4-hydroxy-9-phenyl-9H-beta-carboline-3-carboxylic acid ethyl ester (91 mg, 0.221 mmol), phenyltributyltin (98 mg, 0.265 mmol), and Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) in DMF (1 mL) was stirred at 130° C. for 40 min. The mixture was then diluted with EtOAc, washed with water and saturated NaCl aqueous solution, respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column to give a white solid, the desired title compound. The title compound, ESI MS (m/z): 409 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: CCOC(=O)Cc1cccc(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1cccc(OCOC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Ethyl 2-(3-(methoxymethoxy)phenyl)acetate (8.06 g, 35.9 mmol) in DMF (50 mL) was added NaH (1.74 g, 43.5 mmol) and iodomethane (6.37 g, 44.9 mmol) at 0° C. The reaction mixture was stirred for 1 hrs at 0° C. then diluted with H2O (250 mL) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:10) as eluant.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:26]2[CH2:25][CH2:24][N:23]([CH:22]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:28][CH2:27]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
Methyl 4-fluoro-3-nitrobenzoate Compound 3a (1.0 g, 5.02 mmol) (prepared as described in Nicolaou, et al., Bioorg. Med. Chem., 1998, 1185), 1-[bis(4-fluorophenyl)methyl]piperazine Compound 3b (1.59 g, 5.52 mmol) and potassium carbonate (0.76 g, 5.52 mmol) were dissolved in N,N-Dimethylformamide (15 mL) and heated to about 80° C. for about 5 h then cooled to rt. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (2×50 mL) and water (2×50 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-nitro-benzoic acid methyl ester Compound 3c (2.4 g) as a yellow foam. MS m/z 468 (M+H). A mixture of the nitro substituted methyl ester Compound 3c (2.4 g, 5.13 mmol) and tin (II) chloride dihydrate (11.60 g, 51.34 mmol) was stirred in DMF (50 mL) for about 1 h. The reaction was diluted with ethyl acetate (100 mL), washed with brine (2×100 mL) and water (3×150 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 3-amino-4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-benzoic acid methyl ester Compound 3d (1.88 g) as a yellow foam. MS m/z 438 (M+H). A mixture of the amino substituted methyl ester Compound 3d (1.88 g, 4.30 mmol) and phenyl isocyanate Compound 3e (0.51 g, 4.30 mmol) was stirred in diethyl ether (50 mL) for about 18 h. The precipitate was collected by filtration, then washed with ether and hexane to provide Compound 11 (1.80 g) as an off-white solid. MS m/z 559 (M+H). A solution of Compound 11 (0.45 g, 0.81 mmol) and LiAlH4 in THF (1.0 M, 1 mL, 1.0 mmol) in THF (10 mL) was stirred for about 18 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×75 mL), dried over Na2SO4, filtered and concentrated in vacuo to give Compound 10 (0.31 g) as a white solid. MS m/z 529 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:16]2[O:15][C:14]([CH3:18])([CH3:17])[O:13][C:12]=2[C:11]([C:19]([C:41]2[C:51]3[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=3[C:49]([C:57]([O:59]C)=[O:58])=[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=23)([C:21]2[C:31]3[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]=3[C:29]([C:37]([O:39]C)=[O:38])=[C:23]3[O:24][C:25]([CH3:28])([CH3:27])[O:26][C:22]=23)[OH:20])=[C:10]2[C:6]=1[O:7][C:8]([CH3:62])([CH3:61])[O:9]2)=[O:4].[OH-].[Na+].O>CO.CO.O>[C:37]([C:29]1[C:23]2[O:24][C:25]([CH3:27])([CH3:28])[O:26][C:22]=2[C:21]([C:19]([C:11]2[C:12]3[O:13][C:14]([CH3:18])([CH3:17])[O:15][C:16]=3[C:5]([C:3]([OH:4])=[O:2])=[C:6]3[O:7][C:8]([CH3:61])([CH3:62])[O:9][C:10]=23)([C:41]2[C:51]3[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=3[C:49]([C:57]([OH:59])=[O:58])=[C:43]3[O:44][C:45]([CH3:47])([CH3:48])[O:46][C:42]=23)[OH:20])=[C:31]2[C:30]=1[O:34][C:33]([CH3:36])([CH3:35])[O:32]2)([OH:39])=[O:38]
Reactant: COC(=O)c1c2c(c(C(O)(c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c(c2C(=O)O)OC(C)(C)O3)O1
Reaction time: 12 h

Procedure:
The ester of Example 15, tris(8-methoxycarbonyl-2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol (0.30 g, 0.34 mmol) was dissolved in MeOH (10 mL), and NaOH (0.041 g, 1.02 mmol) dissolved in MeOH/H2O (2.32M NaOH solution) was added until pH reached 7. In total 0.44 mL of the basic solution was used. The MeOH was evaporated in vacuum due to solubility problems and THF (3.5 mL) was added. The reaction mixture cleared with this treatment. After 12 h the reaction mixture was turbid and a precipitate had formed. This precipitate dissolved with the addition of water (10 mL). The THF was evaporated under reduced pressure and water (10 mL) was added and the aqueous phase was extracted with ether (10 mL). The organic phase was separated and the aqueous phase was acidified (pH 3.5) with 2M HCl. A yellow precipitate was formed and the aqueous phase was extracted with ether (3×20 mL) and CH2Cl2 (30 mL). The organic phases were collected, dried (Na2SO4) and the solvent was evaporated to yield the product tris(8-carboxy-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol as a slightly tanned residue (0.25 g, 87%). The product contained a small impurity (appreciated to about 2% at the same extinction) according to HPLC (C18, ion pair (tetrabutyl-ammonium acetate) chromatography, CH3CN:H2O) with UV (254 nm) detection.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=O>C(O)(C)C>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([C:28]2[N:20]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=2)=[CH:31][CH:32]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(Br)cc3)nc2-c2ccc(Cl)cc2)cc1
Yield: 63.6 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (30 mL), 2,4′-dibromoacetophenone (720 mg, 2.58 mmol) was added. After heating the reaction mixture at 80–85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (810 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 4-(4-bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (400 mg, 64%) as a pale yellow solid: mp 145–48° C. Anal. Calc'd. for C22H16N2SO2BrCl: C, 54.17; H, 3.31; N, 5.74; S, 6.57. Found: C, 54.41; H, 3.33; N, 5.50; S, 6.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:25][C:26]4[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=4)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:37][CH:38]=4)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(C(=O)Nc4ccc(C(=O)O)cc4)C3)nc3scnc23)cc1OC
Reaction time: 24 h
Yield: 59.8 %

Procedure:
To a stirred solution of tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxamido)benzoate (105 mg, 0.18 mmol) in 10 mL of dichloromethane was added trifluoroacetic acid (5 mL) in one portion at room temperature. Then the reaction mixture was stirred at this temperature for 24 hours. The solvent was evaporated at 37° C. at reduced pressure and the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% acetonitrile/70% water (0.1% TFA V/V) initially, and then proceed to 60% acetonitrile/40% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxamido)benzoic acid (56 mg, 59%) as a white solid. 1H NMR (300 MHz, DMSO): δ 10.42 (s, 1H), 9.64 (s, 1H), 8.84 (s, 1H), 7.92-7.73 (m, 6H), 7.48 (brs, 1H), 6.93 (d, 1H, J=9.0 Hz), 3.92-3.36 (m, 11H), 2.29-2.21 (m, 2H). LC-MS: 521 [M+H]+, tR=1.38 min. HPLC: 99.34% at 214 nm, 99.25% at 254 nm, tR=4.75 min.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[NH3:14]>O1CCCC1>[NH2:14][S:2]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1ncsc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 28.9 g of methyl 5-(chlorosulfonyl)-4-thiazolecarboxylate in 150 ml tetrahydrofuran was cooled to 0° and 6.6 ml of liquid ammonia was added dropwise at 0°-10°. The suspension was allowed to warm to ambient temperature and stirred 1 hour. The reaction mixture was filtered, the ammonium chloride washed with tetrahydrofuran, and the solvent evaporated from the filtrate. The residual solid was slurried in hexane, collected and dried to give 25.0 g of the title compound, m.p. 138°-140°. IR: 3.01 and 3.1μ (SO2NH2) and 5.8μ (C=O).