Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:18][C:17](=O)[C:16]3[C:15]4[C:14]([C:20]([O:22]C)=O)=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.NN.C1C2NC3C=CC=C4C(=O)[NH:41][N:42]=C(C=2C=34)CC1>>[CH:1]1([C:4]([N:6]2[CH2:7][C:8]3[NH:9][C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[C:20](=[O:22])[NH:41][N:42]=[C:17]([C:16]=3[C:15]=45)[CH2:18]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C(=O)C1CC1)C3
Reactant: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Agent: NN
Solvent: O
Product: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32

Procedure:
Compound 47 was prepared from methyl 2-(cyclopropanecarbonyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate according to the the procedure similar to that for Compound 1. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.0 (s, 1H), 7.47-7.53 (m, 2H), 7.17 (dd, 1H, J=7.2, 7.8 Hz), 4.89 (s, 2H), 4.35 (s, 2H), 2.08-2.11 (m, 1H), and 0.78-0.79 (m, 4H). MS (ESI) m/e [M+1]+ 295.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]C)=[O:17])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(NNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NNc1cccc(C(=O)O)c1
Temperature: 0 °C

Procedure:
The 4.68 g of unpurified 1-tert-butoxycarbonyl-2-(3-methoxycarbonylphenyl)hydrazine was dissolved in 75 ml of 1,4-dioxane, and 25 ml of aqueous 3N potassium hydroxide solution was added to the solution, followed by heating the mixture to reflux for one hour. The reaction mixture was cooled to 0° C., and about 25 ml of 3N hydrochloric acid was added to make the reaction mixture acidic. The mixture was subjected to salting out and the resultant was extracted with ethyl acetate (2×50 ml). The organic layers were combined, dried and concentrated to obtain 4.40 g of unpurified captioned compound.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1.[CH3:21][O:22][C:23](=[O:46])[CH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:21][O:22][C:23](=[O:46])[CH2:24][CH:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[CH:20]=[CH:19][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][N:3]=3)=[CH:35][CH:36]=2)[CH2:29][CH2:30]1
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)c1ccc(Br)nc1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 80 °C

Procedure:
To 200 mg (1 mmol) 6-Bromo-N-(6-trifluoromethyl-pyridin-3-yl)-nicotinamide, 217 mg (1 mmol) {4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester in DME (20 mL), Dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloromethane adduct (37 mg, 5 mol %), and saturated sodium carbonate aqueous solution (2 mL) were added and the mixture stirred at 80° C. over night under N2. Evaporated to dryness and purified by passing over small plug of silica gel (30% ethyl acetate in hexanes) to afford (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester: M+1=498.1. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.06 (s, 4H) 1.12-1.20 (m, 2H) 1.45-1.57 (m, 2H) 1.81 (d, J=8.59 Hz, 4H) 2.25 (d, J=6.57 Hz, 2H) 2.50-2.57 (m, 1H) 3.60 (s, 2H) 7.39 (d, J=8.34 Hz, 2H) 7.94 (d, J=8.84 Hz, 1H) 8.07-8.15 (m, 2H) 8.35-8.43 (m, 1H) 8.50 (d, J=8.59 Hz, 1H) 9.10 (s, 1H) 9.20 (d, J=2.02 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH2:32]([N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH2:44]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:44][C:40]2[N:39]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:43]=[CH:42][N:41]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3nccn3Cc3ccccc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 1-benzyl-1H-imidazol-2-ylmethyl chloride. The crude product is purified by column chromatography eluting with 2% MeOH/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:3]
Reactant: BrCCCc1ccccc1
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCCCc1ccccc1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (obtained in Example 23(4)) (4.1 mg), 1-bromo-3-phenylpropane (7 mg), and potassium carbonate (4 mg) in N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. The mixture was taken up in ethyl acetate, washed twice with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a colorless gummy oil of 1-{(2S,3R)-2-hydroxy-5-[2-(3-phenylpropoxy)phenyl]-3-pentyl}imidazole-4-carboxamide (4.9 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34][CH:33]=1>>[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]4[CH2:25][CH2:26][CH2:27][CH2:28][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:34][CH:33]=1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3c2CCCC3)cc1=O
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4c3CCCC4)cc2=O)nc1
Yield: 38 %

Procedure:
Using the method described in Example 66, 3-cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 39) and 6-amino-nicotinic acid methyl ester afforded 6-{3-cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester as an off-white solid (153 mg, 38%); ES+-HRMS m/e calcd for C29H32N4O5 [M+H+] 517.2446 found 517.2442. 1H-NMR (300 MHz, CDCl3) δ ppm 1.06-1.31 (m, 2H), 1.31-1.99 (m, 1H), 2.11-2.42 (m, 2H), 2.55 (br s, 2H), 2.81 (br s, 2H), 3.93 (s, 3H), 5.64 (t, J=7.4 Hz, 1H), 5.93 (s, 1H), 6.83 (d, J=7.7 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 7.15 (t, J=7.7 Hz, 1H), 7.94 (s, 1H), 8.29 (s, 2H), 8.87 (s, 1H), 9.25 (br s, 1H).
Reaction SMILES: C([O:8][C@H:9]([CH3:59])[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([OH:8])[CH3:59])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Product: C[C@H](O)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting (S)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-propionamide (Example 182, step 4) for (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:25]2
Reactant: COc1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(OC)cc4C3)c(F)c21
Yield: 31.6 %

Procedure:
135 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 104 mg of 5-methoxyisoindoline, 121 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 63 mg of the target compound.
Reaction SMILES: [CH3:1][N:2]1[C:9](=O)[CH:6]2[CH:7]([CH3:8])[CH:5]2[C:3]1=O.[H-].COCCO[Al+]O[CH2:19][CH2:20]OC.[Na+].[H-].[OH-].[Na+].[ClH:27]>C1C=CC=CC=1>[ClH:27].[CH3:1][N:2]1[CH2:9][CH:6]2[C:5]([C:20]3[CH:19]=[CH:7][CH:6]=[CH:5][CH:3]=3)([CH:7]2[CH3:8])[CH2:3]1
Reactant: COCCO[Al+]OCCOC
Reactant: CC1C2C(=O)N(C)C(=O)C12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1C2CN(C)CC12c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of N, 3-dimethylcyclopropane-1,2-dicarboximide (U.S. Pat. No. 3,166,571, Ex. 2) in benzene is added sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution) for several minutes. This solution is stirred at ambient temperature for several hours, refluxed for one hour, and then cooled and combined with sodium hydroxide and worked-up and converted to the hydrochloride as described in Example 11 to give the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][N:21]([CH3:32])[C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:36])[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][N:21]([CH3:32])[C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CI
Reactant: CN(CCCN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)cn1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCN(C)C(=O)c1ccc(N(C)C(=O)OC(C)(C)C)cn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
The compound (170 mg, 0.372 mmol) obtained in Example 6a was dissolved in tetrahydrofuran (4 mL), sodium hydride (55%; 20 mg, 0.447 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. Methyl iodide (35 μL, 0.558 mmol) was added, and then the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate (×3), and the organic layer was washed with saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (178 mg; yield, 100%) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[C:7]([CH3:9])[CH3:8])[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[NH4+].[Cl-]>CCOCC>[CH:7]([C:5]1[CH:6]=[C:2]([CH3:1])[CH2:3][CH:4]=1)([CH3:9])[CH3:8]
Reactant: CC1=CC(=C(C)C)C=C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CC1=CC(C(C)C)=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 24 g (0.2 mol) of 3,6,6-trimethylfulvene in 100 mL of ether was added at 78° C. under argon atmosphere to a solution of 7.59 g (0.2 mol) of lithium aluminium hydride in 200 mL of ether. The reaction mixture was allowed to warm to room temperature, stirred for 2 h and then treated with a 10% aq. solution of NH4Cl. The organic phase was collected, washed with water, dried with MgSO4 and concentrated. The residue was distilled at 63° C./50 mmHg. Yield 15.88 g (65%).The desired title compound was characterized by 1H-NR
Reaction SMILES: [O:1]=[C:2]([NH:28][O:29]C1CCCCO1)[CH:3]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:29][NH:28][C:2]([CH:3]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7])=[O:1]
Reactant: CCCCC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCCCC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a solution of the title compound of Example 11f (500 mg, 0.96 mmol) in methanol (20 mL) was added p-toluenesulfonic acid, monohydrate (40 mg, 0.21 mmol). After stirring at room temperature for 2 hours, the solution was concentrated. Purification by chromatography (6:94 MeOH/CHCl3) yielded the title compound as a light beige solid (170 mg, 40%): Anal. Calcd. for C20H24N2O5S2.0.5 H2O: C, 53.91; H, 5.66; N, 6.29; S, 14.39. Found: C, 53.98; H, 5.44; N, 6.20; S, 14.47.
Reaction SMILES: ClC(C[C@@H](O)C)C[C@@H:4]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[K+].[CH2:33]([OH:35])[CH3:34]>>[CH2:19]([O:18][C:17]([NH:16][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=1)[C@@H:34]1[O:35][CH2:33]1)=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](O)CC(Cl)C[C@H](Cc1ccc2ccccc2c1)NC(=O)OCc1ccccc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)[C@H]1CO1)OCc1ccccc1

Procedure:
1.02 g of benzyl [3-chloro-2(S)-hydroxypropyl-1(S)-[(2-naphthyl)methyl]propyl]carbamate were stirred in 40 ml of ethanol with 4 ml of 0.7M potassium hydroxide solution in ethanol for 0.75 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulphate and evaporated to give a white solid which was recrystallized from ethyl acetate/n-hexane. There was obtained 0.879 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-(2-naphthyl)butane as a white solid of melting point 115°-116° C.
Reaction SMILES: F[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=1)=O.[NH2:20][OH:21].C1CCN2C(=NCCC2)CC1>C(O)C.CCOC(C)=O>[CH3:9][O:8][C:7]1[C:2]2[O:21][N:20]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: NO
Reactant: COc1cccc(C(=O)c2ccnc(SC)n2)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc2c(-c3ccnc(SC)n3)noc12
Temperature: 25 °C

Procedure:
A mixture of (2-fluoro-3-methoxy-phenyl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (1 g, 3.59 mmol) and hydroxylamine (50% in water, 1.5 mL) in ethanol was heated to reflux overnight. The resulting mixture was cooled to RT, diluted with EtOAc and then concentrated under reduced pressure. The residue was dissolved in THF and DBU (0.84 mL, 5.6 mmol) was added, the resulting mixture was heated to 150° C. in a microwave reactor for 30 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by flash chromatography (hexane/EtOAc, 95/5) to give 458 mg of 7-methoxy-3-(2-methylsulfanylpyrimidin-4-yl)-benzo[d]isoxazole.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F-].[Cs+]>>[CH2:6]([O:13][CH2:1][C@@H:2]([OH:3])[CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1ccccc1
Reactant: OC[C@H]1CO1
Agent: [Cs+]
Agent: [F-]
Product: OC[C@H](O)COCc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
A mixture of (S)-glycidol (77) (20 g, 0.27 mol), benzyl alcohol (27.9 mL, 0.27 mol) and CsF (0.82 g, 5.40 mmol) was heated with stirring at 120° C. for 16 h. Unreacted benzyl alcohol was removed using a rotary evaporator attached to a high vacuum line. The product was partitioned between EtOAc and water, and the organic extract was evaporated and chromatographed on silica. Elution with petroleum ether gave fore fractions, and then further elution with EtOAc/petroleum ether (3:7) gave (2S)-3-(benzyloxy)-1,2-propanediol (78) (9.52 g, 19%) as a viscous oil: [α]19 −3.64° (c, 6.59, CHCl3); 1H NMR (CDCl3) δ 7.38-7.28 (m, 5H), 4.56 (s, 2H), 3.92-3.87 (m, 1H), 3.71 (dd, J=11.4, 3.9 Hz, 1H), 3.64 (dd, J=11.4, 5.4 Hz, 1H), 3.61-3.57 (m, 2H), 2.60 (br, 1H), 2.22 (br, 1H). APCI MS m/z 183 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:30])[C:9]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]3[CH:26]=[C:25]([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:28]C)[CH:23]=4)[N:18]=3)[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:30])[C:9]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]3[CH:26]=[C:25]([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([OH:28])[CH:23]=4)[N:18]=3)[CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(N[C@H]3CCN(C(=O)C(=O)c4ccc(Cl)cc4)C3)cc(C)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N[C@H]2CCN(C(=O)C(=O)c3ccc(Cl)cc3)C2)nc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
A solution of (S)-1-(4-chlorophenyl)-2-(3-(6-methoxy-4-methylquinolin-2-ylamino)pyrrolidin-1-yl)ethane-1,2-dione (0.467 g) in dichloromethane (50 mL) was cooled to −78° C., followed by addition of a solution (6.1 mL) of 1 M boron tribromide in dichloromethane, and the mixture was stirred for 3 h while heating slowly to room temperature. To the reaction mixture was added a saturated sodium hydrogencarbonate solution to make it basic, and then the mixture was extracted with chloroform. The aqueous layer was reextracted with a mixed solution of ethyl acetate and n-butanol, then the organic layer was combined, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, chloroform/methanol) to obtain light yellow amorphous (S)-1-(4-chlorophenyl)-2-(3-(6-hydroxy-4-methylquinolin-2-ylamino)pyrrolidin-1-yl)ethane-1,2-dione (0.068 g).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C([O:17][C@@H:18]1[C@H:22]([O:23]C(=O)C2C=CC=CC=2)[C@@H:21]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[O:20][C@H:19]1[N:42]1[CH:50]=[N:49][C:48]2[C:43]1=[N:44][C:45]([Cl:52])=[N:46][C:47]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:52][C:45]1[N:46]=[C:47]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]2)[C:48]2[N:49]=[CH:50][N:42]([C:43]=2[N:44]=1)[C@@H:19]1[O:20][C@H:21]([CH2:32][OH:33])[C@@H:22]([OH:23])[C@H:18]1[OH:17]
Reactant: NN1CCCC(O)C1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCC(O)C4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 7.6 %

Procedure:
The title compound was prepared according to method A as described above by reacting 1-amino-3-hydroxypiperidine (prepared from 3-hydroxypiperidine as outlined in Example 6) (0.60 g, 5.9 mmol) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 3.94 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-(3-hydroxypiperidinyl) adenosine (0.12 g, 8%) (after column chromatography) as a foam (a mixture of diastereoisomers); 1H NMR (DMSO-d6) δ 3.52-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, m, H-2'), 5.08 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 8.43 (1H, br s, H-8), 9.45 (1H, 2 br s, N--H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:24]C(=O)OCC=C)[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.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>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=2[F:23])[NH2:24])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1nc(-c2cc(N)ccc2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluorophenyl}carbamate (11 g, 24.6 mmol) in DCM (200 mL), HOAc (3.6 g, 59.2 mmol), Pd(PPh3)2Cl2 (345 mg, 0.5 mmol) were added. Then tri-n-butyl tin hydride (8.6 g, 29.6 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by adding saturated NaHCO3 (100 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (100 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure and washed with petroleum ether (200 mL) to afford the crude product, 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluoroaniline (7.62 g, 85.3% yield), 7.4 g of which was used directly in the next step.