Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[CH:6][C:7]=1[C:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:11][N:10]([CH3:19])[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1.[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:11][N:10]([CH3:19])[N:9]=1)[O:20][CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2F)n1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2F)n1
Temperature: 60 °C

Procedure:
To a solution of 3-Fluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol (450 mg) in dimethylformamide (10 ml) was added cesium carbonate (2 g) and 2-chloro methyl quinoline (481 mg) and the reaction mixture was heated at 60° C. for 18 h. The reaction mixture was poured into 1N NaOH, extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated. Biotage MPLC purification eluting with methanol 2%/0.5% ammonium hydroxide/70% ethyl acetate/hexanes provided the title compound. The free base was stirred in ethyl acetate and 1.1 equivalents of succinic acid was added. The white precipitate was filtered and dried to provide the title compound as the succinate salt (280 mg). 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=8.3 Hz, 1H), 8.37 (d, J=6.2 Hz, 2H), 8.26 (s, 1H), 8.00 (m, 2H), 7.78 (t, J=7.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.61 (t, J=6.6 Hz, 1H), 7.38 (t, J=8.3, Hz, 1H), 7.10 (d, J=6.2 Hz, 2H), 7.00 (m, 2H), 5.40 (s, 2H), 3.88 (s, 3H), 2.38 (s, 4H); MS: (M+H m/z=411.1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]=[O:31])=[N:28][CH:29]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](=[O:31])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:28][CH:29]=1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1ccc(Br)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(Br)cn2)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (3.00 g) in ethanol (50 mL) were added 5-bromopyridine-2-carbaldehyde (2.10 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (280 mg) and triethylamine (560 μL), and the mixture was stirred with heating under reflux overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.89 g, yield 82%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 510 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[OH:19])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)[O-].[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[CH:33][C:32]([N+:35]#[N:36])=[C:31]([N+:37]([O-])=O)[CH:30]=1>>[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[CH:33][C:32]2=[N:35][N:36]([C:11]3[CH:12]=[C:13]([C:15]([CH3:16])([CH3:18])[CH3:17])[CH:14]=[C:9]([C:6]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=4)([CH3:8])[CH3:7])[C:10]=3[OH:19])[N:37]=[C:31]2[CH:30]=1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Reactant: N#[N+]c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Product: CC(C)(C)c1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)c2ccc(Cl)cc2)c1

Procedure:
Following the general procedure of Example 13, starting with the substituted phenol prepared in Example 5 and the diazonium salt prepared in Example 8, the title compound is prepared as a light yellow solid melting at 129-132° C. The structure is confirmed by 1Hnmr, 19Fnmr and mass spectroscopy analyses.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:36])[CH2:29][CH2:30][C:31]([O:33]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][NH2:38].[C-]#N.[Na+]>CCO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:36])[CH2:29][CH2:30][C:31]([NH:38][CH3:37])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)CCC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)CCC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Temperature: 50 °C
Yield: 83 %

Procedure:
A solution of (S)-ethyl 4-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-4-oxobutanoate (124 mg, 0.25 mmol) in a ˜33% methylamine solution in EtOH (5 mL) was treated with catalytic amount of sodium cyanide and allowed to heat at 50° C. for 3 days. The reaction mixture was then evaporated, washed with water and air dried to afford the title compound as a colorless foam (100 mg, 83%). LC/MS (Method B) 3.23 min, [M+1]+ 480.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[O:1]([CH2:8][CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccccc1
Solvent: CO
Product: CC(O)COc1ccccc1
Reaction time: 24 h

Procedure:
To phenoxy acetone (1 mole) dissolved in methanol (500 ml), is added BH4K (1 mole) portionwise at 0° C. Stirring is continued at room temperature during 24 hours. The methanol is removed in vacuo over a water-bath, the residue is taken up into water and ether. The organic phase is washed with water to neutral pH, after which the material is dried and the residual oil is distilled after removal of the solvent. B.p. = 139° C./20 mm Hg.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Na].[CH3:12][O:13][C:14](=[O:23])[C:15]([CH:18](OC)OC)=[CH:16]O.O>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]1[CH:16]=[N:9][C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:10][CH:18]=1)=[O:23]
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: N=C(N)c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2ccncc2)nc1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
To a solution of isonicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylic acid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 100° C. under nitrogen for 1 h. The reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-4-yl-pyrimidine-5-carboxylic acid methyl ester (1.2 g, 88%). MS: 216 (M+H); 1H NMR (300 MHz, CD3OD): δ 4.00 (s, 3H), 8.44 (d, 2H), 8.73 (d, 2H), 9.38 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([N+:11]([O-])=O)=[CH:4][C:3]=1[I:14].Cl.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[OH-].[K+]>[Fe].CCO>[NH2:8][C:6]1[CH:7]=[C:2]([I:1])[C:3]([I:14])=[CH:4][C:5]=1[NH2:11]
Reactant: O=[N+]([O-])c1cc(I)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CCO
Product: Nc1cc(I)c(I)cc1N
Yield: 66.4 %

Procedure:
Following a literature procedure, a sample of 1 (17.42 g, 41.5 mmol) and a magnetic stirring bar were added to a 500 mL conical flask fitted with a jacketed condenser. EtOH (95%, 150 mL) and conc. aqueous HCl (68.6 mL, 0.83 mol) were added, and the mixture was stirred and heated to boiling. Fe (18.59 g, 0.332 mol) was added in portions, resulting in foaming of the mixture and accelerated refluxing of the EtOH, which would subside within a few minutes of each addition. The reaction was heated for an additional 45 min beyond the final addition of Fe. A hot solution of EDTA (156 g, 0.411 mol, in 300 mL H2O) was added to the reaction mixture, and KOH pellets were added until the solution was alkaline to pH paper. The hot mixture was extracted twice with ethyl acetate and the extracts were combined, washed with water, followed by brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was recrystallized (EtOH/water), giving tan needles (9.92 g, 66%): mp 135-136° C.; 1H NMR (d8-THF) δ 4.21 (brs, 4H), 7.03 (s, 2H); 13C NMR (d8-THF) δ 91.1, 124.5, 137.6; Anal. Calcd for C6H6I2N2: C, 20.02; H, 1.68; N, 7.78. Found: C, 20.19; H, 1.59, 7.71.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2C([O-])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:51]3[CH2:52][C@@H:53]4[CH2:56][C@H:50]3[CH2:55][NH:54]4)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: O=C([O-])N1C[C@@H]2C[C@H]1CN2
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.0119 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in 1,2-dichloroethane (2 mL), and the mixture stirred for 30 min. Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the protected product. This was treated with 10% TFA in CH2Cl2 for 3 h. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound as a white solid. LC-MS m/z 761.1 (M+H)+, 1.46 min (ret time); mp 145-149° C. Analytical HPLC shows 99.0% purity, (ret time 10.092 min).
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=O.[NH2:17][NH:18][C:19]([NH2:21])=[S:20]>O1CCOCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:14][CH3:15])[C:3]1[N:21]=[C:19]([NH:18][NH2:17])[S:20][C:2]=1[CH2:11][CH2:10]2
Reactant: COc1cc2c(cc1OC)C(=O)C(Br)CC2
Reactant: NNC(N)=S
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)-c1nc(NN)sc1CC2

Procedure:
A solution of 400 mg (1.4 mmol) of 2-bromo-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one and thiosemicarbazide (127 mg, 1.4 mmol) in 20 ml of anhydrous dioxane was stirred at 80° C. for 24 h. The resulting yellow precipitate was filtered and washed with dioxane (10 ml). The dried precipitate was then basified with 2 M Sodium Carbonate (20 ml) solution. The formed pale brown product was filtered at the pump and washed with water. The LCMS analysis showed the formation of the required 1-(7,8-dimethoxy-4,5-dihydronaphtho[1,2-d]thiazol-2-yl)hydrazine along with 7,8-dimethoxy-4,5-dihydro-4aH-naphtho[1,2-e][1,3,4]thiadiazin-3-amine.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[CH:9][C:10](=[O:12])[CH3:11].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[C:14]1([C:13](=[O:20])[CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC(C)=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CCC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 8.1 g (0.03 mol) 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride, 180 ml triethylamine, 150 ml ethanol, 21 g of 1-butene-3-one (0.3 mol) and 30.7 g of benzaldehyde (0.29 mol) was gently stirred at 80° C. for 16 hours. Volatile components were removed by evaporation. The 1-phenyl-1,4-pentanedione thus formed was recovered by extraction and subsequent vacuum distillation.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Cl>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=3[Cl:24])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Fc1ccc(CCl)c(Cl)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1ccc(F)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (1.0 g, 3.19 mmol)/THF (40 mL) at 0° C., was added NaH (153 mg, 60 w/w % in mineral oil, 3.83 mmol, 1.2 eq.) in one portion. The resulting foaming mixture was stirred in an ice bath for 30 min, followed by addition of 2-chloro-4-fluorobenzyl chloride (572 mg, 3.19 mmol). The resulting mixture was stirred at 0° C. for 30 min then warmed to ambient overnight. The reaction failed to proceed at room temperature and it was warmed in a 60° C. oil bath for 20 h. An aliquot indicated that the reaction was over. It was quenched with aq. NH4Cl (50 mL). Volatiles were evaporated. The resulting mixture was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to a yellow oil. The oil was purified by SiO2 (Biotage 40+M cartridge, eluted by EtOAc/hexanes, gradient; 5% to 40%). The titled compound was obtained as a colorless glassy material. LC-MS: 456.12 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.77 (s, 2H), 7.46 (dd, J=8.7, 6.0 Hz, 1H), 7.17 (dd, J=8.4, 2.5 Hz, 1H), 7.03 (m, 1H), 5.68 (d, J=8.2 Hz, 1H), 4.83 (d, J=15.6, 1H), 4.36 (d, J=15.3 Hz, 1H), 4.06 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C@H:13]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:12]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:31][C:27]1[NH:28][C:29](=[O:30])[C:24]2[S:23][C:22](=[O:32])[N:21]([C@H:13]3[C@H:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][C@@H:11]([CH2:10][OH:9])[O:12]3)[C:25]=2[N:26]=1
Reactant: CS(=O)(=O)N[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)N[C@@H]1C[C@@H](CO)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 3.9 %

Procedure:
To a solution of [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-(methanesulfonamido)tetrahydrofuran-2-yl]methyl benzoate (compound 33d, crude, 80 mg, 0.54 mmol) in MeOH (5 mL) was added K2CO3 (80 mg, 0.6 mmol). After being stirred at room temperature for 5 hours, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 8.0 mg of N-[(2R,3R,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-3-yl]methanesulfonamide (Example 33) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[NH2:10][OH:11]>CCO>[OH:11][N:10]=[C:8]([NH2:9])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(C#N)n1
Reactant: NO
Solvent: CCO
Product: Cc1cccc(C(N)=NO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-Methylpicolinonitrile (12 mg, 0.1 mmol) was dissolved in EtOH (0.5 mL) and treated with NH2OH (1.5 eq of a 50% aq solution). The mixture was stirred at room temperature for 12 hours then reduced to dryness to afford N′-hydroxy-6-methylpicolinimidamide (6) as a clear yellow oil, which was used without purification.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[C:6]2[CH:29]=[CH:28][CH:27]=[N:26][C:7]=2[N:8]2[C:13]=1[CH2:12][CH2:11][CH:10]([N:14]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:15])[CH2:9]2.C1COCC1.O.[Li+].[OH-].CC(O)=O>[Cl-].[Na+].O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:14]([CH3:15])[CH:10]2[CH2:11][CH2:12][C:13]3[N:8]([C:7]4[N:26]=[CH:27][CH:28]=[CH:29][C:6]=4[C:5]=3[CH2:4][C:3]([OH:30])=[O:2])[CH2:9]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1
Reactant: COC(=O)Cc1c2n(c3ncccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CN(C1CCc2c(CC(=O)O)c3cccnc3n2C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of (±)-{8-[(4-fluoro-benzenesulfonyl)-methyl-amino]6,7,8,9-tetrahydro-pyrido[3,2-b]indolizin-5-yl}-acetic acid methyl ester (28 mg) in 4 mL of 121 THF/water was added 0.2 mL of 1 N aqueous LiOH solution. After stirring for 1 h at room temperature, AcOH (0.2 mL) and 4 mL of brine were added and the mixture was extracted with 2×10 mL of EA, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography eluted with 50% EtOAc/hexane containing 5% AcOH to give 20 mg of the desired product as a white solid.
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.[CH3:12][C:13]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:17][CH2:16][CH2:15][CH:14]1[NH:18]S(C1C=CC(C)=CC=1)(=O)=O>C(COC)OC>[NH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][C:13]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)NC2CCCC2(C)NC(=O)OC(C)(C)C)cc1
Agent: [Li]
Solvent: COCCOC
Solvent: c1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)NC1(C)CCCC1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of lithium granules (7.17 g, 1195 mmol) and naphthalene (57.39 g, 448.36 mmol) in dry dimethoxyethane (1900 ml) was stirred at room temperature for 2 hours. The deep blue solution was then cooled to 0° C. and a solution of tert-butyl N-[1-methyl-2-(4-methylbenzenesulfonamido)cyclopentyl]carbamate (55.0 g, 149.45 mmol) in dry dimethoxyethane (300 ml) was added drop wise over 30 minutes. The mixture was stirred at 0° C. for 3 hours. The un-dissolved lithium was removed by filtration and 1M HCl solution (aq, 720 ml) was added to the filtrate. The organic layer was washed with further 1M HCl (aq, 2×600 ml). The combined aqueous layers were washed with diethyl ether (2×600), and then basified with 2M NaOH (aq) to give pH 12-14. The aqueous layer was then extracted with ethyl acetate (5×600 ml). The combined organics were dried over sodium sulfate and then concentrated in vacuo. This was then purified by column chromatography (silica, 0-4% methanol/DCM) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]([NH:12][C@H:13]1[C:16](=[O:17])[NH:15][C@H:14]1[CH2:18][I:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:31]([O:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])[CH:32]=[O:33]>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:10]([NH:12][C@H:13]1[C:16](=[O:17])[N:15]([CH:32]([OH:33])[C:31]([O:35][CH:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:34])[C@H:14]1[CH2:18][I:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@H]1C(=O)N[C@H]1CI)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)N[C@H]1C(=O)N(C(O)C(=O)OC(c2ccccc2)c2ccccc2)[C@H]1CI)c1ccccc1

Procedure:
A suspension of 1.02 g (2.21 mmol) of product from Example 21 in 22 ml of dry tetrahydrofuran is stirred under argon with cooling to -78° and 1.24 ml (2.44 mmol) of a 1.97M n-butyllithium in hexane solution is added. The mixture is stirred for 30 minutes at -78° while 0.66 g (2.75 mmol) of benzhydryl glyoxylate in 20 ml of toluene is dried by distilling off 12 ml of the toluene. The remaining solution is added to the reaction mixture. The resulting mixture is stirred at -78° for 1 hour and then is warmed in an ice bath to 0° for 10 minutes. The reaction is quenched by pouring into cold aqueous NaH2PO4. The mixture is extracted with ethyl acetate and the combined extracts are washed with saline. The dried solution is evaporated and the residue is taken up in carbon tetrachloride and then hexane is added to precipitate the product, 15 g (97%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH:27]=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
Sodium triacetoxyborohydride (35.7 g, 0.168 mol) was added to a mixture of crude (S)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (11.2 g, 0.056 mol), pyrrolidine (5.16 ml, 0.062 mol) and mol sieves (10 g) in dichloromethane (100 ml). Acetic acid (6.42 g, 0.112 mol) was added. The reaction mixture was stirred for 16 hours at room temperature. The precipitation was removed by filtration. The filtrate was diluted with a 1 N aqueous solution of sodium hydroxide (100 ml) and tert-butyl methyl ether (100 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×80 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane/triethylamine (1:1, 5%) as eluent, to give 9.23 g of (S)-2-((pyrrolidin-1-yl)methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.