Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1(Cl)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:18].[Cl-].[NH4+]>CO.[Zn]>[O:18]=[C:3]1[CH2:2][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
106.1 g zinc dust was added to a mixture of 62.5 g tert-butyl 1,1-dichloro-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate and 500 ml saturated ammonium chloride in methanol. The mixture was stirred for 1 hr and 20 min at room temperature and filtered through Celite. The filtrate was evaporated, 1 N hydrochloric acid/ethyl acetate was added thereto, and the organic layer was recovered. The extract was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography to give 38.9 g of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate.
Reaction SMILES: [C:1]([CH:3]([C:5]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][N:6]=1)[CH3:4])#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH:3]([C:5]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][N:6]=1)[CH3:4]
Reactant: CC(C#N)c1nsc(NC(=O)OC(C)(C)C)n1
Agent: [Ni]
Solvent: CO
Product: CC(CN)c1nsc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl [3-(1-cyanoethyl)-1,2,4-thiadiazol-5-yl]carbamate (0.65 mmol) was dissolved in MeOH (15 mL) and a catalytic amount of Raney-Ni (50% in H2O) was added. The reaction mixture was stirred at room temperature for 3 h under H2 (50 psi). The reaction mixture was filtered through a pad of CELITE and the solvent was removed under reduced pressure. Purification using preparative LCMS afforded the tert-butyl [3-(2-amino-1-methylethyl)-1,2,4-thiadiazol-5-yl]carbamate.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:19]=2)=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]([CH3:12])[C:7]=1[C:8]([F:11])([F:10])[F:9])#[N:2].[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)#[N:33].C1(OP(OC2C=CC=CC=2)(OC2C=CC=CC=2)=O)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:16]([O:15][C:13]([C:5]1[N:6]([CH3:12])[C:7]([C:8]([F:9])([F:10])[F:11])=[C:3]([C:1]#[N:2])[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:32]#[N:33])=[CH:20][CH:19]=1)=[O:14])[CH3:17]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(C(F)(F)F)n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)c(C(F)(F)F)n1C

Procedure:
Prepare the title compound in a manner analogous to the procedure described in Scheme IIIa. For example, place ethyl 4-cyano-1-methyl-5-(trifluoromethyl)-3-{4-[(trifluoromethyl)sulfonyloxy]phenyl}pyrrole-2-carboxylate (11.0 mmol, prepared in example E-277), 2-cyano-phenyl boronic acid (1.5 mmol), palladium (II) acetate (0.12 mmol), triphenylphosphate (0.24 mmol), and tribasic potassium phosphate (3.6 mmol) in a round bottom flask and add dioxane. Heat reaction to reflux for 18 hours, remove the heat and wash with water while extracting with ethyl acetate. Dry organics with sodium sulfate, filter, and concentrate in vacuo. Purify the residue via radial chromatography eluting with methylene chloride, ethyl acetate and hexane to provide the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH3:6])=[C:2]=[S:3].CN(C)C=O.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>O>[CH2:4]([NH:1][C:2](=[S:3])[NH:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:5][CH3:6]
Reactant: COC(=O)c1ccsc1N
Reactant: CCCN=C=S
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=S)Nc1sccc1C(=O)OC
Temperature: 132.5 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
In a sulfonation flask, 2.02 g (0.02 mol) of 1-isothiocynatopropane are added dropwise to 30 ml dimethylformamide and 3.0 g (0.019 mol) of methyl 2-aminothiophene-3-carboxylate. The reaction mixture is then stirred at 130-135° C. for 12 hours and after cooling added to 120 ml of water. The resulting mixture is then extracted three times with ethylacetate and the separated organic phase dried over sodium sulfate. The solvent is then removed in a water-jet vacuum, giving the crude product as a dark oil, which is purified by column chromatography over silica gel (eluant: tert.butylmethylether/hexane=2:3). 2.0 g of methyl 2-(3-propylthioureido)thiophene-3-carboxylate are obtained in the form of a yellow powder having a melting point of 122-124° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:15][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:17][CH:18]=1)#[N:21]
Reactant: COCCNCc1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl bromoacetate (1.64 mL, 11.1 mmol) was added into a mixture of 4-{[(2-methoxyethyl)amino]methyl}benzonitrile (958 mg, 5.04 mmol) and K2CO3 (3.06 g, 22.2 mmol) in ACN (20 mL). The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, and then washed with water and brine, dried (MgSO4) and concentrated under vacuum. The residue was purified by flash chromatography (silica, cHex/EtOAc) to give the title compound as a colorless oil. LC/MS (Method B): 305.1 (M+H)+. HPLC (Method A) Rt 3.09 min (Purity: 91.1%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (103 mg, 0.55 mmol) (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded the title compound (81 mg, 47%) which was obtained as a light yellow solid. MS: m/e=343.3 [M+H]+.
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:24][O:25][CH2:26][CH3:27])([O:20][O:21][CH2:22][CH3:23])=[O:19])[OH:17])=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].[H][H]>CO.[Pd]>[CH2:22]([O:21][O:20][P:18]([CH:16]([OH:17])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[NH2:1])=[CH:11][CH:12]=1)([O:24][O:25][CH2:26][CH3:27])=[O:19])[CH3:23]
Reactant: CCOOP(=O)(OOCC)C(O)c1ccc(C=C(N=[N+]=[N-])C(=O)OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOOP(=O)(OOCC)C(O)c1ccc(CC(N)C(=O)OC)cc1
Yield: 85.6 %

Procedure:
A total of 3.4 g (9.2 mmol) of 38 in 100 mL MeOH was hydrogenated at 40 psi H2 over 300 mg 10% Pd.C. Hydrogen was replenished at t=15, 60, 135, 210 and 255 minutes and 300 mg additional 10% Pd, C was added at t=135 and 255 minutes and the reaction terminated at t=6 hours. The mixture was filtered through celite and rotovapped (30° C.) to yield 39 as a clear colorless oil (2.97 g, 95%). The oil crystallized from ether yielding white crystals, mp 94°-100° C. (soften 77° C.). 1H NMR (250 MHz, DMSO-d6) δ: 7.34 (d, 2H, J=7.5 Hz, aromatic), 7.15 (d, 2H, J=7.5 Hz, aromatic), 6.16 (br s, 1H, OH) , 4.89 (d,1H, J=13.0 Hz, PCH), 3.93 (m, 4H, OCH2), 3.59 (m, 1H, Hα), 3.57 (s, 3H, CO2CH3), 2.87 (dd, 1H, J=13.4, 6.7 Hz, Hβ), 2.76 (dd, 1H, J=13.4, 7.2 Hz, Hβ) , 1.17 (t, 3H, J=7.0 Hz, CH3), 1.13 (t, 3H, J=7.0 Hz, CH3), mp 94°-100° C.; FABMS m/z 346.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:38][CH:37]=2)[NH2:35])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([NH:35][S:2]([CH3:1])(=[O:4])=[O:3])[C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:40][CH:41]=2)[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NS(C)(=O)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (12 μL, 0.16 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (49 mg, 0.08 mmol) and triethylamine (24 μL, 0.17 mmol) in dichloromethane (4 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture concentrated in vacuo to afford N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}methanesulfonamide which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:11]([CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Product: COC(=O)CCc1ccc(Oc2ccc(CN(Cc3ccccc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76C and 2-fluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)O.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=C(C)C=1>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1F
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 350 mg (1.97 mmol) of the compound from Example 8 and 470 mg (1.97 mmol) of the compound from Example 84A in analogy to the synthesis of the compound from Example 101. 191 mg (24% of theory) of the target compound were obtained.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH:38]([OH:40])[CH:37]([OH:41])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH:38]([OH:40])[CH:37]([OH:41])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CC(O)C(O)C1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CC(O)C(O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-(4-amino-butyl)-pyrrolidine-3,4-diol by the procedure analogous to Example 8. HPLC ret. time: minutes. 1H NMR (400 MHz, CD3OD) δ 7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][N:30]6[C:35](=[O:36])[CH:34]=[CH:33][CH:32]=[N:31]6)[CH:27]=5)[N:22](C(OC(C)(C)C)=O)[N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>O1CCOCC1.CO>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][N:30]6[C:35](=[O:36])[CH:34]=[CH:33][CH:32]=[N:31]6)[CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(Cn3ncccc3=O)ccc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5ncccc5=O)cc34)nn2)cc1)N1CCOCC1

Procedure:
A solution of tert-butyl 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-[(6-oxopyridazin-1(6H)-yl)methyl]-1H-indazole-1-carboxylate (202 mg; 0.32 mmol; 1.00 eq.) and HCl (6.00 mL of a 4 N solution in dioxane; 24 mmol; 76 eq.) in MeOH (4 mL) was stirred at RT for 3 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound as a white solid. HPLC (Condition A): Rt 2.67 min (purity 98.1%). MS (ESI+): 483.3, MS (ESI−): 481.3.
Reaction SMILES: IC.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:7]2.[C:26](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:26][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:8][CH2:7]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1c2ccc(OC)cc2CCN1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 100.5 %

Procedure:
Iodomethane (3.04 mL, 48.85 mmol) was added to a solution of 1-ethyl 2-tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (7.85 g, 24.43 mmol) and cesium carbonate (10.35 g, 31.75 mmol) in DMF (50 mL) at room temperature, and the mixture was stirred for 2.5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with 0.1% aqueous sodium thiosulfate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-ethyl 2-tert-butyl 6-methoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (8.23 g, 24.54 mmol, 100%) as a colorless oil.
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[O:24][C:25]1[C:26]([O:28][C@H:29]([C@H:32]([CH2:34][OH:35])[OH:33])[C:30]=1[OH:31])=[O:27])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:27]=[C:26]1[O:28][C@H:29]([C@H:32]([CH2:34][OH:35])[OH:33])[C:30]([OH:31])=[C:25]1[OH:24]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC2=C(O)[C@@H]([C@@H](O)CO)OC2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 0.5 h
Yield: 179.8 %

Procedure:
2-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)ascorbic acid (300 mg, 0.6 mmol) was dissolved in methanol (10 ml), and to the solution was added a solution in which potassium carbonate (600 mg) had been dissolved in water (9 ml). The mixture was stirred for 30 minutes. The reaction solution was neutralized with AMBERLITE® IR-120 (H+), and filtered to remove the resin. The filtrate was washed successively with methanol and 50% aqueous methanol solution. The filtrate and the washing solution were combined, and concentrated, and then water was added thereto, followed by freeze-drying to obtain 2-O-β-D-glucopyranosyl)ascorbic acid as amorphous crystals (190 mg, yield: 100%). PMR (δ ppm, D2O); 3.1-3.3 (4H, m), 3.4-3.5 (3H, m), 3.58(1H d) , 3.80(1H, t), 4.61(1H, d), 4.66(1H, d). FABMS(−) m/z: 337.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[C:11]=2[Br:15])[CH:6]1[CH2:17][C:18]([OH:20])=O)=[O:4].BrC1C(F)=CC=C2C=1CCN(C(=O)CNC(OC(C)(C)C)=O)C2CC(O)=O>O1CCOCC1.Cl>[Br:15][C:11]1[C:10]([F:16])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:18](=[O:20])[CH:17]=[C:6]12
Reactant: NCC(=O)N1CCc2c(ccc(F)c2Br)C1CC(=O)O
Agent: CC(C)(C)OC(=O)NCC(=O)N1CCc2c(ccc(F)c2Br)C1CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(2-(2-aminoacetyl)-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic Acid (HCl Salt). To a stirred solution of 2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (58.45 g, 131 mmol) in dioxane (600 mL), 4N HCl in dioxane (328 mL, 1313 mmol) was added and the reaction mixture was stirred at RT for 24 h. The solvent was evaporated under reduced pressure and the HCl salt was dried under high vacuo overnight to yield the title compound as yellow foam (54.6 g). UPLC-MS: MS 345.2/347.2 (M+H+); UPLC rt 0.56 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17].[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[CH3:18][O:8][C:4]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1Oc1c(N)n(C)[nH]c1=O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccccc1Oc1c(OC)nn(C)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.3 %

Procedure:
A mixture of 5-amino-4-(2-methoxyphenoxy)-1-methyl-1,2-dihydro-3H-pyrazol-3-one (Preparation 69) (300 mg), caesium carbonate (1.25 g) and iodomethane (200 mg) in dry dimethylformamide (5 ml) was stirred under a nitrogen atmosphere for 24 hours at room temperature. The reaction mixture was partitioned between ethyl acetate (7×25 ml) and water (40 ml) and the combined organic extracts were dried (magnesium sulfate) and concentrated under vacuum. The residue was purified by chromatography on a Biotage Flash™ 40s silica cartridge (40 g silica) using neat ethyl acetate and then 1% methanol/dichloromethane as eluants to give the title compound as a brown solid (90 mg), Rf 0.57 (10% methanol/dichloromethane).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O>>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]1[O:10][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: Nc1ccccc1O
Reactant: Nc1ccccc1C(=O)O
Product: Nc1ccccc1-c1nc2ccccc2o1
Temperature: 0 °C
Yield: 48 %

Procedure:
The reaction of 13.71 g (0.10 mole) of anthranilic acid with 10.91 g (0.10 mole) of ortho-aminophenol was carried out in 100 ml of polyphosphoric acid at 200° C. After 10 hours from the start of the reaction, the reaction mixture was poured into ice water and the precipitate was filtered and dried. The solid thus obtained was purified by column chromatography and concentrated to give 10.28 g (0.048 mole, 49%) of ortho-aminophenylbenzoxazole.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[OH:15].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:22]=[N:23][OH:24]>>[F:17][C:18]([F:32])([F:33])[C:19]1[CH:20]=[C:21](/[CH:22]=[N:23]/[O:24][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:16])=[C:5]([OH:15])[CH:6]=2)[CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1O
Reactant: ON=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(O)c1ccc(OCCCO/N=C/c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Yield: 12 %

Procedure:
The title compound (0.115 g, 12%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-hydroxy-benzoic acid methyl ester and 3,5-bis-trifluoromethyl-benzaldehyde oxime using a procedure similar to step 1 of example 12. mp=181.9-183.4° C.; mass spectrum −ESI, (M−H) m/z 450. 1H NMR (400 MHz, DMSO-d6); 613.60 (bs, 1H), 11.50 (bs, 1H), 8.48 (s, 1H), 8.23 (s, 2H), 8.13 (s, 1H), 7.66 (d, 1H), 6.47 (m, 2H), 4.33 (t, 2H), 4.12 (t, 2H), 2.12 (m, 2H). Elemental analysis: Calcd. for C19H15F6NO5: C, 50.56; H, 3.35; N, 3.1, Found: C, 50.25; H, 3.32; N, 2.93.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C@@H:7]1([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[NH2:26][C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CO>O>[OH:9][CH:8]1[C@H:7]([N:16]2[CH:17]=[N:18][C:19]3[C:25]2=[N:24][CH:23]=[N:22][C:20]=3[NH2:21])[O:15][C@H:12]([CH2:13][OH:14])[CH:10]([OH:11])[N:26]1[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1ncccn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2ncccn2)C1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium metaperiodate (2.13 g) in water (25 ml) was added to a suspension of adenosine (2.67 g) and 2-aminopyrimidine in water (25 ml) at 15° C. The mixture was stirred at ambient temperature for five hours. To the reaction mixture was added methanol (50 ml). A precipitate was filtered off and the filtrate was evaporated in vacuo at 35° C. The residue was triturated with acetone to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]adenine (3.64 g).