Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][OH:19]>C(Cl)Cl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH:18](=[O:19])/[CH:17]=[CH:16]\[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCC/C=C\CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCC/C=C\C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
A solution of 9.5 ml of pyridine in 150 ml of methylene chloride was treated in one portion with 6.0 g of chromium trioxide. The mixture was stirred for 15 minutes at room temperature and then 1.60 g of 3Z-dodecen-1-ol in 3 ml of methylene chloride was added. After 5 minutes the reaction mixture was diluted with 200 ml of ether and then filtered through celite. The filtrate was washed three times with 100 ml of 5% aqueous sodium hydroxide, then with ice-cold 5% hydrochloric acid, saturated sodium bicarbonate and finally with brine. After drying over sodium sulfate, the solvent was evaporated giving 1.5 g of 3Z-dodecen-1-al.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]([OH:20])[CH:9]([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[CH3:24][CH:25](O)[CH3:26]>>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@@H:9]([O:21][CH:25]([CH3:26])[CH3:24])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: CC(C)O
Reactant: Cc1nc2c3c(ccn2c1C)C(O)C(O)C(c1ccccc1)N3
Product: Cc1nc2c3c(ccn2c1C)[C@H](OC(C)C)[C@H](O)[C@@H](c1ccccc1)N3

Procedure:
1 g of the title compound of melting point 168-9° C. is obtained by reaction of 3 g of 7R, 8R, 9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine with 2-propanol according to Example 1, Method a.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:10]([SH:14])[C:11](O)=[O:12]>C1(C)C=CC=CC=1>[SH:14][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:12]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)CS
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)CS)c1
Temperature: 25 °C

Procedure:
Freshly distilled 3-methoxyaniline (7.6615 g) was dissolved in toluene (35 ml) and treated with thioglycollic acid (4.75 ml). The mixture was heated under reflux, and water collected in an Dean and Stark apparatus overnight. Upon cooling to room temperature crystals formed which were collected at the pump. The title compound (which was sufficiently pure for the next reaction) was obtained as a white solid, yield 9.233 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([C:8](=[O:14])[CH:9](C)[C:10](O)=O)=[N:6][CH:7]=1.C(O)(=O)C.[Cl:20]Cl>O>[Cl:20][CH:9]([CH3:10])[C:8]([C:5]1[C:4]([F:15])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:14]
Reactant: CC(C(=O)O)C(=O)c1ncc(Cl)cc1F
Reactant: ClCl
Solvent: O
Solvent: CC(=O)O
Product: CC(Cl)C(=O)c1ncc(Cl)cc1F
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
20.8 g of 3-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3-oxopropionic acid (Example P35) are introduced into 125 ml of glacial acetic acid. 6.3 g of chlorine gas are introduced into the solution in the course of 1 hour . The mixture is then poured into 700 ml of water and extracted with tert-butyl methyl ether. The combined ethereal phases a rewashed with water and dried over magnesium sulfate, filtered and concentrated by evaporation in vacuo. The crude product is dissolved in 180 ml of tert-butyl methyl ether, 45 g of silica gel are added and the mixture is stirred for 30 minutes, in the course of which the evolution of gas observed initially comes to a halt. The silica gel is then filtered off and subsequently washed and the combined ethereal phases are concentrated to dryness in vacuo. 20.1 g of an oily crude product are obtained, which is purified over a flash chromatography column (silica gel; eluant: n-hexane/ethyl acetate 411 (v/v)). 17.0 g of the desired title compound are obtained in the form of a solid having a melting point of 29-32° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([O:15]C)(=[O:14])[CH:12]=[CH2:13].[Li+].[OH-].Cl>C(O)(=O)C.CO>[N:1]1([CH2:13][CH2:12][C:11]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (3.0 g, 22.5 mmol) and methyl acrylate (3.9 g, 45.0 mmol) in acetic acid (15 mL) was refluxed for 16 hours. Upon cooling, volatiles were removed in the rotary evaporator and the residue obtained was co-evaporated with methanol (3×20 mL) and then dissolved in methanol (15 mL). To this mixture an aqueous solution of LiOH (1.9 g, 45 mmol) was added and it was stirred at room temperature for 2 hours. Reaction mixture was acidified with conc. HCl to pH ˜3 and extracted with ethyl acetate. The organic layer was washed twice with water and brine, dried over MgSO4 and evaporated to dryness to yield 2.91 g of Compound 7 as a dark brown viscous liquid. This product was used without any further purification. The structure of Compound 7 is given below:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][S:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:32][C:31]3[C:26]([N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)=[N:27][CH:28]=[C:29]([N:33]4[CH2:34][CH2:35][S:36][CH2:37][CH2:38]4)[CH:30]=3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(N2CCSCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCSCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (117 mg, 0.43 mmol), 2-morpholino-5-thiomorpholinopyridin-3-amine (120 mg, 0.43 mmol) and a 4.0M solution of HCl in dioxane (0.11 mL, 0.43 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 7-fluoro-3-methyl-N-(2-(4-morpholinyl)-5-(4-thiomorpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=4.1, 1.0 Hz), 7.85-7.96 (2H, m), 7.75-7.84 (2H, m), 7.58 (1H, d, J=2.7 Hz), 7.40 (1H, ddd, J=7.0, 4.9, 1.8 Hz), 7.28-7.32 (1H, m), 6.74 (1H, s), 6.19 (1H, d, J=2.7 Hz), 3.93 (4H, t, J=4.7 Hz), 3.31 (4H, ddd, J=4.9, 2.7, 2.5 Hz), 3.23 (4H, br. s.), 2.63 (4H, dt, J=5.1, 2.5 Hz), 2.38 (3H, s). Mass Spectrum (ESI) m/e=517.0 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CS(C)=O.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O.C(N(CC)CC)C>C(Cl)Cl>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[O:5][CH2:1][CH2:2][O:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: BrCCCCCCCCC1OCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (11.66 g, 92 mmol) in DCM (250 mL), a solution of dimethylsulfoxide (DMSO) (13.0 mL, 183 mmol) in DCM (50 mL) was added over 15 minutes. After a further 5 minutes, a solution of 9-bromononanol (10.25 g, 45.9 mmol) in DCM (50 mL) was added dropwise over 15 minutes. The resulting reaction mixture was stirred at this temperature for 45 minutes. Triethylamine (32 mL, 230 mmol) was added, and the reaction mixture stirred at this temperature for 10 minutes. The coolant was removed and allowed to warm to RT. The reaction mixture was stirred at RT for 40 minutes and then diluted with water. The organic phase was removed and washed with 10% aqueous potassium hydrogen sulfate and dried (magnesium sulfate). The suspension was filtered and the filtrate evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([S:21](C3C=CC=CC=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li][C:32]([CH3:35])([CH3:34])C>C1COCC1>[C:34]1([S:21]([C:14]2[C:13]([C:6]([OH:30])=[O:5])=[C:12]3[C:17]([CH2:18][CH2:19][CH:10]([CH2:9][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:30])[CH3:8])[O:11]3)=[CH:16][CH:15]=2)(=[O:22])=[O:23])[CH:32]=[CH:35][CH:3]=[CH:1][CH:2]=1
Reactant: CN(CC1CC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(CC1CCc2ccc(S(=O)(=O)c3ccccc3)c(C(=O)O)c2O1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 35 %

Procedure:
To a solution of (7-benzenesulfonyl-4-oxo-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (141 mg, 0.338 mmol) in THF (15 mL) cooled at −78° C. was added t-BuLi (1.7M in hexanes, 0.68 mL) dropwise. The reaction was allowed to warm to 0° C. for 3 hours, then it was quenched with CO2 (gas) and diluted with water. The volatiles were removed in vacuo and the aqueous residue was washed with Et2O and then acidified to give a white precipitate that was filtered and dried to afford 7-benzenesulfonyl-2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-chroman-8-carboxylic acid (55 mg, 35% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:6]([C:7](Cl)(Cl)Cl)=[N:5][CH2:4][CH2:3]1.[CH3:12][O-:13].[Na+].C[OH:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][NH:5][C:6]=1[C:7]([O:13][CH3:12])=[O:16]
Reactant: ClC(Cl)(Cl)C1=NCCC1(Cl)Cl
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Product: COC(=O)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
4,4-Dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole (47.4 mmol, 1.0 equiv.) was added to a solution of sodium methanolate (284.5 mmol, 6.0 equiv.) in methanol (126 ml), and the mixture was heated for 1.5 h at boiling temperature. The reaction mixture was cooled to 25° C., the solvent was concentrated under reduced pressure, the residue was taken up in diethyl ether (470 ml), and the mixture was stirred for 30 min. The resulting solid (sodium chloride) was filtered out, and the filtrate was dried over K2CO3 and concentrated under reduced pressure. The residue was taken up in DCM (600 ml), extracted with 2 N HCl (2×150 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was used in the next step without being purified further. Yield: 83%
Reaction SMILES: [CH3:1][CH:2]([C:10]([O-:12])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Li+].[CH3:15][CH:16]1N(C(N(C)C)=O)[CH2:17]1.Cl[CH2:25]/C=C\CCl>C1COCC1.O.CC(OC)(C)C>[CH3:25][O:11][C:10]([C:2]1([C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4])[CH2:17][CH:16]=[CH:15][CH2:1]1)=[O:12]
Reactant: ClC/C=C\CCl
Reactant: CC(C(=O)[O-])C(=O)OC(C)(C)C
Reactant: CC1CN1C(=O)N(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)C1(C(=O)OC(C)(C)C)CC=CC1
Temperature: 2.5 °C

Procedure:
Add a solution of t-butyl methylmalonate (129 g, 0.75 mol) in THF (385 mL) to a slurry of LiH (14.9 g, 1.875 mol) in THF (900 mL) and N,N-dimethylpropylene urea (DMPU, 155 g, 1.2 mol) over 30 minutes while maintaining the temperature at 0-5° C. Heat the reaction mixture to 65° C. and add a solution of cis-1,4-dichloro-2-butene (95%, 100 g, 0.8 mol, 1.08 eq) in THF (100 mL) over 5.5 hours, maintaining the temperature at 63-67° C. Stir the reaction for 4 hours at 65° C. A water/MTBE work-up of the reaction mixture yields 1-(methoxycarbonyl)-1-(tert-butoxycarbonyl)cyclopent-3-ene.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)=O)(C)(C)C.[CH:16]([N:19](CC)C(C)C)([CH3:18])[CH3:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CC(N)C>CN(C)C=O.C(OCC)(=O)C>[CH:16]([NH:19][C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:15])([CH3:18])[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.6 %

Procedure:
To (3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (150 mg, 0.70 mmol) in N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) and 1-hydroxybenzotriazole (94 mg, 0.70 mmol) were added. The mixture was stirred at room temperature for 5 min, followed by addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.77 mmol). The mixture was then stirred for 20 min. 2-Propanamine (59 μL, 0.69 mmol) was added and the mixture was stirred overnight. The mixture was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated, and purified by preparative LCMS using pH 2 buffer to give desired boc-protected intermediate. The product fractions were concentrated and treated with 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 30 min, at which time the mixture was concentrated and dissolved in DCM/MeOH and treated with Trisamine resin (Silicycle) for 30 min. The resulting mixture was filtered and the solvents were evaporated to give the desired compound (63 mg, 58%) which was used in the next step without further purification. LCMS calc. for C8H17N2O (M+H)+: m/z=157.1. found: 157.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]([C:9]1[C:10]([CH3:19])=[N:11][O:12][C:13]=1[N:14]=[CH:15]OCC)#[N:8].[O-]CC.[Na+].[Na]>C(O)C.O>[CH3:19][C:10]1[C:9]2[C:13](=[N:14][CH:15]=[N:8][C:7]=2[NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[O:12][N:11]=1
Reactant: CCOC=Nc1onc(C)c1C#N
Reactant: CC(C)CCN
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cc1noc2ncnc(NCCC(C)C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
3-Methylbutylamine (1.74 g) was added dropwise to a solution of 4-cyano-5-ethoxymethyleneamino-3-methylisoxazole (3.6 g, prepared as described by E C Taylor and E E Garcia, J. Org. Chem., 1964, 29, 2116) in ethanol (30 ml). The mixture was stirred for ten minutes* at room temperature, treated with a solution of sodium ethoxide** (from 0.46 g sodium) in ethanol (10 ml) and refluxed*** for four hours. It was then cooled and diluted with water. The precipitate**** was dried and recrystallised from isopropanol to give 3-methyl-4(3-methylbutylamino)isoxazolo [5,4-d] pyrimidine (2.7 g, m.p. 133°), Compound no 29 of Table I.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:18]([O:21][CH:22]([C:31]1[CH:35]([OH:36])[O:34][C:33](=[O:37])[CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:20])[CH3:19]>O1CCCC1.O>[C:18]([O:21][CH:22]([C:31]1[CH:35]([O:36][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:34][C:33](=[O:37])[CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:20])[CH3:19]
Reactant: CCCCCCCCC(OC(C)=O)C1=CC(=O)OC1O
Reactant: CCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCC(OC(C)=O)C1=CC(=O)OC1OC(=O)CCCCCCC
Temperature: 0 °C

Procedure:
Octanoyl chloride (83.6 μl, 0.49 mmol), followed by triethylamine (68.2 μl, 0.49 mmol), was added to 4-(1-acetoxynonyl)-5-hydroxy-2(5H)-furanone (132.6 mg, 0.47 mmol) in tetrahydrofuran (6 ml) at 0°. Stirring was continued for 14h while the ice bath attained room temperature. The mixture was diluted with water (10 ml) and extracted with dichloromethane. Evaporation of the dried (magnesium sulfate) extract gave a yellow oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf 0.38 on evaporation gave the title compound as a colorless oil.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:25][O:26]CC2C=CC=CC=2)[CH2:16][O:17]CC2C=CC=CC=2)=[O:13])[O:5][C@@H:4]([N:35]2[C:45]3[N:44]=[C:42]([NH2:43])[NH:41][C:39](=[O:40])[C:38]=3[N:37]=[CH:36]2)[CH2:3]1>C(OCC)(=O)C.CO.C(O)(=O)C.[Pd]>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:16][OH:17])[CH2:25][OH:26])=[O:13])[O:5][C@@H:4]([N:35]2[C:45]3[N:44]=[C:42]([NH2:43])[NH:41][C:39](=[O:40])[C:38]=3[N:37]=[CH:36]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](COC(=O)CCC(=O)OC(COCc3ccccc3)COCc3ccccc3)O2)c(=O)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](COC(=O)CCC(=O)OC(CO)CO)O2)c(=O)[nH]1

Procedure:
A solution of 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dibenzyloxy-2-propyloxy carbonyl)propanoyl]guanosine (3.2 g, 5.13 mmole) in 50 ml ethyl acetate, 50 ml methanol and 10 ml acetic acid was hydrogenated with palladium black (0.6 g) under 40 psi overnight. The catalyst was filtered and washed with methanol, The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromathography. Yield: 1.64 g
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[N:14]=[CH:13][CH:12]=[C:11]([I:15])[C:7]=1[C:8](O)=[O:9].CO>ClCCl>[OH:5][C:6]1[N:14]=[CH:13][CH:12]=[C:11]([I:15])[C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)c1c(I)ccnc1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(Cl)c1c(I)ccnc1O
Temperature: 75 °C

Procedure:
Thionyl chloride (3.81 ml, 52.2 mmol) was added to a suspension of 2-hydroxy-4-iodonicotinic acid (3.46 g, 13.1 mmol) in dichloromethane (12 mL) in a pressure vessel at room temperature. The reaction mixture was then heated at 75° C. for 3 h. An aliquot was taken and hydrolyzed with methanol. LCMS analysis showed the derived methyl ester seen as major compound. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give 2-hydroxy-4-iodonicotinoyl chloride. 2-hydroxy-4-iodonicotinoyl chloride in MeOH (100 mL) was stirred at room temperature for 2 h. Concentration in vacuo of the reaction mixture afforded methyl 2-hydroxy-4-iodonicotinate (3.64 g, 13.1 mmol, quantitative yield). MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C7H61NO3: 279.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:22]=[C:9]2[N:10]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH2:26][N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[CH2:16][NH:15][C:11]1[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:22]=[C:9]2[N:10]=1
Reactant: Nc1nc(NCC2CCCN2)nc2nc(-c3ccco3)nn12
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(NCC2CCCN2Cc2c(Cl)cccc2Cl)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Furan-2-yl-N5-pyrrolidin-2-ylmethyl-[1,2,4]-triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 2,6-dichlorobenzaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.95-7.0 (m, 3H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 2.2-3.2 (m, 8H). MS: m/z: 460[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24](=[O:27])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[CH2:29]([Mg]Cl)[CH3:30].[NH4+].[Cl-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH2:29][CH3:30])([OH:27])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(=O)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.24 mmol) prepared in example 103 in tetrahydrofuran (3 mL) at −78° C. was added a tetrahydrofuran solution of ethylmagnesium chloride (2M, 6 mL, 12 mmol). The reaction mixture was stirred at −78° C. for 0.5 h, then slowly warmed to room temperature and stirred for 2 h. The mixture was poured into saturated aqueous NH4Cl solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc:MeOH=10:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-1-hydroxy-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 100 mg, 93%)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:1][C:3]2[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(B(O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-Formylphenylboronic acid (1 eq, 2 mmol, 0.3 g) in dry DCM (7 ml) under an inert atmosphere of argon is treated with 1-methyl-piperazine (1.2 eq, 2.4 mmol, 0.266 ml) followed by acetic acid (1.2 eq, 2.4 mmol, 0.14 ml) and NaBH(OAc)3 (1.6 eq, 3.2 mmol, 0.678 mg) and the resulting mixture is stirred at room temperature for 3 hours. The reaction is quenched by addition of water and is then extracted with DCM. The organic extracts are concentrated in vacuo and the crude residue is purified by flash chromatography on silica eluting with MeOH/DCM (0 to 100% MeOH in DCM) followed by 2M NH3 in MeOH. The appropriate fractions are combined and concentrated in vacuo to afford the title compound; [M+H]+=235.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH2:17](I)[CH3:18]>Cl>[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:17][CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1NC(=S)NCC(N)=O
Reactant: CCI
Agent: Cl
Product: CCSC1=NCC(=O)N1c1cccc(Cl)c1C

Procedure:
The title compound was prepared by the procedure described in Example 6 using 12.0 g of 2-[3-(3-chloro-2-methylphenyl)-thioureido]-acetamide, and 25.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride. Crystallization from ethyl acetate afforded the title compound as a white solid, mono-hydrochloride (5.1 g), m.p. 161°-163° C. (dec.). Anal. Calcd. for. C12H13Cl N2O S . HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 47.03; H, 4.40; N, 9.09. Mass spectrum (+FAB, [M+H]+) m/z 269/271. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.05-9.85 (broad s, 2 H), 7.62 (d, 1 H), 7.39 (t, 1 H), 7.33 (d, 1 H), 4.48 (q, 2 H), 3.20 (m, 2 H), 2.15 (s, 3 H), and 1.29 ppm (t, 3 H).