Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:6]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C#CCCO[Si](C)(C)C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cccc(CCCCO)c1
Yield: 64.3 %

Procedure:
A solution of {3-[4-(t-butyidimethylsilyloxy)but-1-ynyl]phenyl}acetic acid methyl ester (700 mg, 2.1 mmol) in MeOH (15 ml) was treated with 5% Pd/C (100 mg) and hydrogen gas (1 atm) for 1 hr. The catalyst was filtered, and the solvent evaporated. The residue was dissolved in THF (1 ml), and treated with tetrabutyl ammonium fluoride (2 ml of a 1N solution in THF) for 2 hr. The reaction was diluted with water and extracted with diethyl ether. The organic extracts were washed with water, dried, evaporated, and the volatile organics removed by vacuum to give the title compound as an oil (300 mg, 64%). MS (ESI) 223.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:6][N:5]=[CH:4][NH:3]1.NN>C(Cl)Cl.CCO>[NH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][CH:4]=[N:5][N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnc[nH]c1=O
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: NCc1nnc[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry of 2-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione (4 g, 15.6 mmol) in DCM/EtOH (1:1) (150 mL ) was charged with anhydrous hydrazine (1.23 mL, 39.0 mmol) and stirred at rt for 18 h. The reaction mixture was concentrated in vacuo and the off-white solid was triturated with warm CHCl3 and filtered through a fritted funnel. The solid was then triturated with hot boiling methanol (MeOH) and filtered through a fritted funnel resulting in an off-white solid. The material was triturated a second time as before and dried overnight resulting in the title compound as a white solid, which was taken on to the next step without further purification; 1H NMR (DMSO-d6, 400 MHz) δ 3.88 (s, 2H), 8.31 (2, 1H); MS (ES+): m/z 127.07 (100) [MH+], HPLC: tR=0.34 min (MicromassZQ, polar—5 min).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([OH:14])[C:8]([OH:15])=[N:7]2)=[N+:2]=[N-:3].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:16]([O-:18])=[O:17])[N:10]=[C:9]([OH:14])[C:8]([OH:15])=[N:7]2)=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])O
Reactant: [N-]=[N+]=Nc1ccc2nc(O)c(O)nc2c1
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Temperature: 24 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
2 g 6-azido-2,3-dihydroxyquinoxaline is suspended in 100 ml glacial acetic acid. To the suspension is added 16 ml fuming nitric acid at 24° C. The mixture is stirred at 24° C. for 4 h giving a precipitate of 1.9 g (78%) 6-azido-2,3-dihydroxy-7-nitroquinoxaline. IR: a peak at 2120 cm−1. NMR: two singlets (7.0 and 7.7 ppm downfield from TMS).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I:12](O)(=O)(=O)=O.S(=O)(=O)(O)O.II>O.C(O)(=O)C>[I:12][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][C:1]([OH:11])=[O:10])=[CH:9][CH:8]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C(O)CCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCc1ccc(I)cc1
Temperature: 105 °C
Yield: 460.8 %

Procedure:
Hydrocinnamic acid is iodinated to form 4-iodohydrocinnamic acid. The process is performed by mixing 201.2 g hydrocinnamic acid, 1 L acetic acid, 152 mL water, 52.8 g periodic acid, 76 mL sulfuric acid, and 144 g iodine. The mixture is heated at 105° C. for 6.5 hours. Next, 200 mL water is added, and the mixture is cooled to room temperature overnight. The solid product in the resultant mixture is filtered and washed with water, yielding 350 g unpurified 4-iodohydrocinnamic acid. Further purification is not necessary and is not conducted, and the product is used as is in the second step.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][C@H:3]1[CH:14]=[CH2:15].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:1][C:2]([CH3:16])([C@@H:3]([O:4][CH2:5][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:14]=[CH2:15])[CH2:7][OH:6]
Reactant: C=C[C@@H]1OC(c2ccccc2)OCC1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: C=C[C@H](OCc1ccccc1)C(C)(C)CO
Yield: 87.7 %

Procedure:
Following the general procedure for the reductive ring opening of benzylidene-type acetals of 1,3-diols of Description 9, 9.5 g (43.5 mmol) of (4S)-5,5-dimethyl-2-phenyl-4-vinyl-1,3-dioxane (7c) was reacted with 25.0 mL (19.9 g, 140.0 mmol) of diisobutylaluminum hydride [(iBu)2AlH, DIBAL(H)] in 150 mL of anhydrous dichloromethane (DCM). After acidic aqueous work-up, the crude material was purified by silica gel column using mixtures of methyl tert-butyl ether (MTBE) and hexane (Hxn) as eluent (MTBE/Hxn=1:9→MTBE/Hxn=1:6→MTBE/Hxn=1:3) to provide 8.4 g (88% yield) of the title compound (7) as a colorless liquid. Rf=0.45 (Et2O/Hxn=1:1). 1H NMR (400 MHz, CHCl3): δ=0.91 (s, 3H), 0.92 (s, 3H), 2.82 (t, J=5.9 Hz, 1H), 3.38 (dd, J=10.8, 6.0 Hz, 1H), 3.55 (dd, J=10.8, 6.0 Hz, 1H), 3.64 (d, J=8.0 Hz, 1H), 4.31 (d, J=12.0 Hz, 1H), 4.62 (d, J=11.6 Hz, 1H), 5.22-5.28 (m, 1H), 5.36-5.40 (m, 1H), 5.81 (ddd, J=17.2, 10.4, 8.4 Hz, 1H), 7.27-7.38 (m, 5H) ppm. MS (ESI) m/z: 221.1 (M+H)+, 243.1 (M+Na)+. The analytical data for the compound was consistent with the proposed structure and with the data given in the literature (Ito et al., Synthesis 1993, 137-140; and Mandel et al., Org. Lett. 2004, 6(26), 4801-4803).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[CH:5]=[C:4]([NH2:11])[N:3]=1.CC([O-])=O.[K+]>O1CCCC1.CO.[Pd]>[C:8]([C:7]1[CH:2]=[N:3][C:4]([NH2:11])=[CH:5][C:6]=1[NH2:10])#[N:9]
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cnc(N)cc1N
Yield: 69.1 %

Procedure:
A solution of (II) (15.1 g, 0.071 mol), KOAc (7.0 g, 0.071 mol) and 5% Pd/C (4 g) in THF (tetrahydrofuran) (130 mL) and MeOH (methanol) (70 mL) was hydrogenated (55 psi/20° C.) for 7 days. The resulting solution was filtered over Celite, washing with THF/MeOH, then the solvents were removed under reduced pressure. The residue was dissolved in dilute HCl, then the solution neutralised with 40% NaOH and excess Na2CO3 to give 3-cyano-4,6-diaminopyridine (III) (6.58 g, 69%): mp (water) 197-198° C. [Metzger R., Oberdorfer J., Schwager C., Thielecke W., Boldt P., Liebigs Ann. Chem., 1980;946-953 record mp (benzene) 205° C⟧
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[C:17]([CH:21]=1)[C:18](O)=[O:19]>O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[C:17]([CH:21]=1)[CH2:18][OH:19]
Reactant: O=C(O)c1cc(Cl)ccc1Sc1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cc(Cl)ccc1Sc1cccs1

Procedure:
To 30 ml of abs. ether cooled to 3° is added under nitrogen 1.14 g (0.03 mole) of lithium aluminium hydride, and there is then added dropwise at 5°-10° with stirring, within half an hour, a solution of 5.4 g (0.02 mole) of 5-chloro-2-(2-thienylthio)-benzoic acid (produced according to Swiss Patent Specification No. 405,354; C.A. 66, P 2550e) in 45 ml of abs. ether. After completion of the dropwise addition, the mixture is refluxed for 16 hours; and there is thereupon slowly added dropwise at 3°-7° 5 ml of water. The occurring precipitate is filtered off with suction, and subsequently well washed with ether. The filtrate is concentrated in vacuo, and the residue is recrystallised from carbon tetrachloride to yield 5-chloro-2-(2-thienylthio)-benzyl alcohol having a melting point of 95°-96°.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:22].[OH-].[Na+]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:22]
Reactant: COCOc1c(C)cc(-c2ccc(C(=O)OC)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Product: COCOc1c(C)cc(-c2ccc(C(=O)O)cc2)cc1C
Yield: 83.7 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 4′-methoxymethoxy-3′,5′-dimethylbiphenyl-4-carboxylate (1.24 g) and aqueous sodium hydroxide (1N, 8.20 ml) and the reaction mixture was treated to afford the desired compound (0.99 g) as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].CCN(CC)CC.[CH3:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>C(Cl)Cl>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:12]2[CH2:13][CH2:14][N:15]([CH2:38][C:39]3[CH:46]=[CH:45][C:42]([CH3:43])=[CH:41][CH:40]=3)[CH2:16][CH2:17]2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:9][CH:10]=1)[CH3:30]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccc(C)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of compound 1 (0.80 g; 1.99 mmol) in CH2Cl2 (20 ml) was added Et3N (0.83 ml; 5.97 mmol) followed by p-methyl benzyl bromide (773 mg; 4.18 mmol). The reaction mixture was stirred overnight and was then was concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[S:7][CH2:6][CH2:5]1)[CH3:3].C(OC(=O)C)(=O)C.[OH-].[NH4+]>CS(C)=O>[C:2]([CH:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[S:7][CH2:6][CH2:5]1)(=[O:1])[CH3:3]
Reactant: CC(O)C1CCSc2[nH]c3ccccc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC(=O)C1CCSc2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the product (300 mg) of the above (1) in dimethylsulfoxide (5 ml) is added acetic anhydride (0.7 ml). The mixture is stirred at room temperature for 20 hours. The reaction mixture is poured into ice water, made alkaline with ammonium hydroxide and extracted with ether. The extract is washed with water, dried and evaporated to give an oil (450 mg). The oil is chromatographed on a column of silica gel and eluted with hexane-benzene (3:10) and benzene. The title compound is obtained from the latter eluate. Recrystallization from acetone-petroleum benzine gives colorless needles melting at 120.5°-122.5° C.
Reaction SMILES: C[CH:2]([CH:6]1[C:11]2=[CH:12][C:13]3[C:18]([N:10]2[CH2:9][CH2:8][CH2:7]1)=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH:20]([CH3:22])[CH3:21])[C:3]([O-:5])=[O:4].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>>[F:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12]([C:33]([C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)=[O:34])=[C:11]3[CH:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][CH2:8][CH2:9][N:10]32)=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:15]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)c1cc(F)cc2c1cc1n2CCCC1C(C)C(=O)[O-]
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1ccc3ccccc3c1)c1n2CCCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl(3-fluoro-1-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (Example 122, Step 4) and 2-naphthoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30]C(=O)C(F)(F)F)[CH:25]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:30][C:26]1[CH:25]=[C:24]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(C2(C#Cc3cccc(NC(=O)C(F)(F)F)c3)CCCC(=O)C2)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C#Cc3cccc(N)c3)CCCC(=O)C2)cc1OC1CCCC1
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To a solution of 3-(3-cyclopentyloxy4-methoxyphenyl)-3-(3-trifluoroacetamidophenylethynyl)cyclohexan-1-one (0.62 g, 1.24 mmol) in 95:5 methanol/water (10 mL) under an argon atmosphere was added potassium carbonate (0.86 g, 6.2 mmol). The mixture was refluxed for 6 h and was stired for 18 h at room temperature. The solid precipitate was collected and purified by trituration from ethyl acetate/hexanes to provide the title compound as a white solid (0.39 g, 77%), m.p. 100-102° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by hydrolysis of 9l using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]1[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7]1([CH3:14])[CH3:13])=[N+]=[N-]>C(OCC)(=O)C.O=[Pt]=O>[CH3:11][C:9]1([CH3:12])[O:10][C@@H:6]([CH2:5][CH2:4][NH2:1])[C:7]([CH3:14])([CH3:13])[O:8]1
Reactant: CC1(C)O[C@@H](CCN=[N+]=[N-])C(C)(C)O1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H](CCN)C(C)(C)O1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
Step I A suspension of (S)-5-(2-azido-ethyl)-2,2,4,4-tetramethyl-[1,3]dioxolane (1.6 g, 8 mmol) and PtO2 (0.32 g) in ethyl acetate (15 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 18 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethylamine as a colorless oil (1.3 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:39]1[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:39]1[CH:43]=[CH:42][C:41]([CH2:44][O:14][C:10]2[CH:11]=[CH:12][C:13]3[C:4]4[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]([CH3:1])=[N:15][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[CH:40]1
Reactant: Cc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Reactant: OCc1ccoc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2cnc3cc(OCc4ccoc4)ccc3c2n1CC(C)C
Reaction time: 144 h
Yield: 127.4 %

Procedure:
2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (300 mg, 1.17 mmol), triphenylphosphine (921 mg, 3.51 mmol), and 3-furanmethanol (173 mg, 1.76 mmol) were slurried in 20 mL of anhydrous THF. After 5 minutes diisopropyl azodicarboxylate (710 mg, 3.51 mmol) was added dropwise to the mixture. The resulting homogeneous solution was stirred six days. Analysis of the reaction by HPLC indicated that mostly starting material was present. Additional portions of triphenylphosphine (150 mg), 3-furanmethanol (0.5 mL) were added followed by diisopropyl azodicarboxylate (1 mL). Analysis of the reaction after 1 hour indicated that all of the 2-methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinolin-7-ol was consumed. The reaction was filtered through an acidic ion-exchange resin with methanol followed by 1M ammonia in methanol. The filtrate was concentrated to give 500 mg of 7-(furan-3-ylmethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a dark orange oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][CH2:21][OH:22])=[O:6])[CH:2]=[CH2:3].Cl.C[O-].[Na+]>CO.ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][CH2:21][OH:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A solution of (2R,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-(2-hydroxyethyl)pyrrolidine (5.0 g) and conc. hydrochloric acid (2.53 ml) in methanol (25 ml) was stirred under ice-cooling for 10 minutes and then stirred at ambient temperature for 1 hour. To the reaction mixture cooled at 0° C. was added 28% sodium methoxide in methanol solution (5.84 ml). The resulting precipitates were filtered off and the filtrate was evaporated in vacuo to give a residue. The residue was dissolved in dichloromethane (15 ml) and the solution was dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was washed with n-hexane and dried in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-hydroxyethyl)pyrrolidine (3.10 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.[CH3:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([NH2:46])[N:32]=1>>[NH2:46][C:33]1[N:32]=[C:31]([CH3:30])[C:36]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[C:8]([CH3:23])[C:6]=3[N:7]=2)=[CH:35][N:34]=1
Reactant: Cc1c(CN2CCN(C(=O)C(C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(=O)[C@H](C)O)CC3)c(C)c2n1

Procedure:
1-[4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one (200 mg) was coupled to 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine via General Procedure A to yield 20 mg of 349. MS (Q1) 513.2 (M)+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:10][CH2:9][C@@H:8]([N:11]2[C:15]3=[C:16]4[S:22][CH:21]=[CH:20][C:17]4=[N:18][CH:19]=[C:14]3[N:13]=[C:12]2[C@H:23]([OH:25])[CH3:24])[CH2:7][CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]1[O:10][CH2:9][C@@H:8]([N:11]2[C:15]3=[C:16]4[S:22][CH:21]=[CH:20][C:17]4=[N:18][CH:19]=[C:14]3[N:13]=[C:12]2[C@H:23]([OH:25])[CH3:24])[CH2:7][CH2:6]1
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN=[N+]=[N-])OC1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)OC1
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A solution of (1R)-1-{1-[(3S,6R)-6-(azidomethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol (12 mg, 0.034 mmol) in methanol (0.2 mL) was added 10% palladium on carbon (5.7 mg). The resulting mixture was stirred under H2 balloon overnight. The reaction mixture was filtered through a pad of Celite and washed with methanol. The solvent was removed under reduced pressure to give the desired product (11 mg, 99%). LCMS calculated for C16H21N4O2S (M+H)+: m/z=333.1. Found: 333.1.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[CH3:9][S:10][CH2:11]Cl.C(N(CC)CC)C>>[C:1]([O:8][CH2:9][S:10][CH3:11])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6]
Reactant: CSCCl
Reactant: CCCC=CC(=O)O
Solvent: CCN(CC)CC
Product: CCCC=CC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting 2-hexenoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 75°-76° C./2 mm Hg, n20 1.4836.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:36][O:37][CH3:38])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:36][O:37][CH3:38])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2COC)cc1C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To 0.097 g (0.407 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.145 g (0.459 mmol) of the above prepared 3-chloromethyl-2-methoxymethyl-6-(4-trifluoromethyl-phenyl)-pyridine, dissolved in 2.5 ml of abs. acetonitrile, was added 0.180 g of Cs2CO3 (0.552 mmol). The reaction was stirred for 22 h at ambient temperature. Pouring onto crashed ice/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=88/12), gave 0.214 g of pure title compound as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([CH3:14])[CH:3]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[C:20]([CH:33]=1)[CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([O:6][CH2:7][C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[C:20]([CH:33]=2)[CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(Br)cc(C)c1OCC(=O)O
Reactant: CCS(=O)(=O)c1ccc(N)cc1CNC(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCS(=O)(=O)c1ccc(NC(=O)COc2c(C)cc(Br)cc2C)cc1CNC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
To a solution of 79A (100 mg, 0.386 mmol) and 28A (148 mg, 0.386 mmol) in 2 mL pyridine at −15° C., was added POCl3 (0.040 mL, 0.425 mmol), dropwise. The mixture was stirred at this temperature for 20 min, then was quenched with water. The mixture was diluted with EtOAc, washed with water (2×), 1N HCl, water, sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography to afford 222 mg (98%) of 79B as a colorless oil. MS (ESI) m/z 589.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[CH:6][C:7]=1OC.O.[NH2:13]N>O>[NH2:13][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[CH:6][CH:7]=1
Reactant: COc1cnn(C)c(=O)c1Cl
Reactant: NN
Solvent: O
Product: Cn1nccc(N)c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
9.14 g (52 mmoles) of intermediate 4b are placed in mL hydrazine monohydrate. The reaction medium is agitated for 3 h at 80° C. then diluted in 100 mL water and extracted with CH2Cl2 then with AcOEt. After drying over Na2SO4, the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2Cl2—AcOEt, gradient 100:0 to 0:100 over 50 min). 4.17 g of intermediate 4c are thus obtained in the form of an orange-like solid (yield 63%). TLC silica 60 F 254 Merck, CH2Cl2—AcOEt: 50:50, Rf=0.16.