Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>N1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: NCc1ccccn1
Solvent: c1ccncc1
Product: O=C(NCc1ccccn1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a flask containing 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (300 mg, 0.95 mmol) dissolved in pyridine (4 mL) was added 2-aminomethyl pyridine (106 μl, 1.02 mmol). The reaction was allowed to stir under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. Solvent was removed and water was added to the flask. A solid crashed out of solution that was collected by filtration. The product was purified by column chromatography (SiO2, 5% methanol in dichloromethane). The solid was taken up in 3% ammonia in methanol solution (8 mL) and allowed to reflux at 60° C. for three hours. The reaction was neutralized with 1 N HCl solution and extracted with Ethyl Acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (106 mg, 32% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 9.3 (t, 1H), 8.65 (s, 1H), 8.5 (d, 1H), 8.1 (m, 2H), 8.0 (d, 1H), 7.75 (t, 1H), 7.65 (d, 1H), 7.4 (m, 3H), 7.25 (t, 1H), 4.6 (d, 2H), ES-MS m/z 368 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25](=O)[NH2:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:25]#[N:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[C:8]([S:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(N)=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C#N)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A suspension of 3-butyl-4-[[4-[1-carbamoyl-1-phenylmethoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 3, Step A) in phosphorus oxychloride (25-30 equivalents) is stirred at 0° C. under N2 as triethylamine (2.2 equivalents) is added dropwise over about 1 hours. After the addition is complete, the mixture is gradually warmed to room temperature and then heated to reflux for about 45 minutes or until TLC indicates complete reaction. The cooled mixture is concentrated in vacuo, and the residue is partitioned between ice-water and an organic solvent, such as ether, ethyl acetate, or toluene. The organic phase is washed with dilute NaOH and then with H2O. The organic solution is dried over MgSO4, filtered, and concentrated to give the title compound, which is used directly or may be purified by chromatography on silica gel.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH:26]([OH:28])[CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.FC(F)(F)S(O[CH2:42][C:43]([F:46])([F:45])[F:44])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:28][CH:26]1[CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][CH2:22][N:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:42][C:43]([F:46])([F:45])[F:44])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[N:20]=2)[CH2:27]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)CC(O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
A suspension of tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (150 mg, 0.32 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.48 mmol), and K2CO3 (87 mg, 0.64 mmol) in DMF (10 mL) was stirred at room temperature for 18 hours, which was monitored by LCMS. After completion of the reaction, the reaction mixture was quenched with EtOAc (100 mL), washed with brine (50 mL), dried over MgSO4, concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/EtOAc (1/1) as eluting solvents to afford tert-butyl(±)-6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (82 mg, 46.5%). MS (ESI) m/z: 559 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]=2[C:23]#[N:24])[CH2:3]1.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27].C(NC(C)C)(C)C>ClCCl>[C:25]([N:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]=2[C:23]#[N:24])[CH2:3]1)(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)Cl
Reactant: CCOCCn1c(=O)c(C#N)c(NC2CNC2)c2ccccc21
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C=CC(=O)N1CC(Nc2c(C#N)c(=O)n(CCOCC)c3ccccc23)C1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(Azetidin-3-ylamino)-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (1 eq, 0.050 g, 0.16 mmole) in dichloromethane at −10° C. was added acryloyl chloride (1.1 eq, 0.005 g, 0.055 mmole) followed by the addition of diisopropylamine (1.5 eq, 0.031 g, 0.075 mmole, 0.05mL). The resulting solution stirred at −10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was, evaporated and the residue was purified by flash chromatography to afford 4-(1-Acryloyl-azetidin-3-ylamino)-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.008 g, 28% calc M+H 367, obs M+H 367).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:26])[C@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[OH:27]O>C1COCC1.O>[CH2:19]([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:26])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OO
Reactant: C=CC[C@@H](CCCCCCC)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](CCCCCCC)C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of 8.69 g (0.024 mol) of the product from Example 3 in 425 mL of THF/H2O (3:1), cooled to 0 degrees, was added 10.8 mL (0.097 mol) of 30% hydrogen peroxide solution followed by 2.03 g (0.049 mol) of LiOH--H2O. The resulting solution was stirred at 0° C. for 1.5 h and then quenched with a solution of 15.4 g of sodium sulfite in 100 mL of H2O. The reaction mixture was then acidified to pH 3 with aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.33 g (90%) of the desired product as a colorless oil. CI Mass Spec: 199 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[I:30])[CH2:5][C@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:7](=O)[NH:8][CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[NH4+].C[N:37](C)C=O>O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][C@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]2[NH:37][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:8]=2)[CH:27]=[CH:28][C:29]=1[I:30]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)C(=O)NCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)c1ncc(-c2ccccc2)[nH]1
Yield: 38 %

Procedure:
A solution of tert-butyl (1S)-1-(3-bromo-4-iodobenzyl)-2-oxo-2-[(2-oxo-2-phenylethyl)amino]ethylcarbamate (1.20 g, 1.63 mmol), ammonium acetate (6.30 g, 81.7 mmol) and N,N-dimethylformamide (15.1 mL) was microwave irradiated at 120° C. for 30 min. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (440 mg, 38%).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[OH-].[Na+].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O>O1CCOCC1>[Br:2][CH2:3][CH2:4][NH:5][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 183 %

Procedure:
Treat a 0° C. solution of 2-bromoethylamine hydrobromide (50 g, 0.246 mol) in dioxane (500 mL) with aqueous NaOH (1 M, 492 mL, 0.492 mol), add benzyl chloroformate (21.6 g, 0.127 mol) drop-wise, warm to RT and stir overnight. Pour the mixture into H2O, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Petroleum ether) to afford the title compound (60 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.37-7.33 (m, 5H), 5.12 (s, 2H), 3.61 (t, J=5.6 Hz, 2H), 3.47 (t, J=5.6 Hz, 2H).
Reaction SMILES: BrC(C)[C:3]#[N:4].C([NH+](CC)CC)C.[N+:13]([C:16]1[C:21]2[N:22]([CH2:25][C:26]([O-])=O)[CH:23]=[N:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[C:21]2[N:22]([CH:25]([CH3:26])[C:3]#[N:4])[CH:23]=[N:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: CC(Br)C#N
Reactant: O=C([O-])Cn1cnc2cccc([N+](=O)[O-])c21
Agent: CC[NH+](CC)CC
Product: CC(C#N)n1cnc2cccc([N+](=O)[O-])c21

Procedure:
The compound was synthesised from 4(7)-nitro-1H-benzimidazole (1.0 g, 6.1 mmol) and 2-bromopropanenitrile (0.58 mL, 6.5 mmol) according to the procedure described for the synthesis of (7-Nitro-1H-benzimidazol-1-yl)acetic acid triethylammonium salt, part A, in a is 0.14 g (11%) yield. MS (ESI) m/z: 217.16 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.01 (d, J=7.0 Hz, 3H) 6.08 (q, J=7.1 Hz, 1H) 7.48 (t, J=8.1 Hz, 1H) 8.09 (m, 1H) 8.16 (dd, J=8.0, 1.0 Hz, 1H) 8.89 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](O)=[O:21])=[CH:12]1>>[CH2:4]1[C:3]2([CH2:2][NH:1][C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:11][CH:12]=3)=[O:21])[N:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5]1
Reactant: NCC12CCCN1CCC2
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: O=C(NCC12CCCN1CCC2)c1c[nH]c2ccccc12

Procedure:
Following the procedure of example 1, 7a-Aminomethylhexahydro-1H-pyrrolizine is reacted with indole-3-carboxylic acid to afford the title compound.
Reaction SMILES: [CH2:1](I)[CH3:2].[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([C:26]4[CH:27]=[N:28][C:29]5[C:34]([CH:35]=4)=[CH:33][C:32]([O:36][CH3:37])=[CH:31][CH:30]=5)=[O:25])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1>CN(C)C=O.[Ag]=O>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][N:15]([CH2:1][CH3:2])[C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([C:26]4[CH:27]=[N:28][C:29]5[C:34]([CH:35]=4)=[CH:33][C:32]([O:36][CH3:37])=[CH:31][CH:30]=5)=[O:25])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: CCI
Reactant: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)cc2c1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCN(Cc1ccc2c(c1)OCCO2)[C@H]1CC[C@H](COC(=O)c2cnc3ccc(OC)cc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl iodide (51 μL, 0.63 mmol, 8.0 eq) is added at room temperature to a stirred solution of 6-methoxy-quinoline-3-carboxylic acid trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethyl ester (37 mg, 0.08 mmol, 1.0 eq) in N,N-dimethylformamide (0.5 mL), followed by silver oxide (73 mg, 0.31 mmol, 4.0 eq). After 4 hours stirring at room temperature, the reaction mixture is filtered through decalite and the mother liquid is concentrated to give a residue that is purified by preparative HPLC to afford 6-methoxy-quinoline-3-carboxylic acid trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-ethyl-amino]-cyclohexylmethyl ester as an off-white lyophilizated solid (9 mg, 14% yield)
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]2[C:10]([F:20])=[CH:11][C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[N:1]1([C:6]([O:8][C:9]2[C:10]([F:20])=[CH:11][C:12]3[O:17][CH2:16][C:15](=[O:18])[N:14]([CH2:22][CH2:23][CH3:24])[C:13]=3[CH:19]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1COc2cc(F)c(OC(=O)N3CCCC3)cc2N1
Reactant: CCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN1C(=O)COc2cc(F)c(OC(=O)N3CCCC3)cc21
Yield: 74.5 %

Procedure:
A stirred mixture of 0.70 g (0.0025 mole) of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one-6-yl 1-pyrrolidinecarboxylate, 0.60 g (0.0036 mole) of 1-iodopropane, 1.1 g (0.0076 mole) of potassium carbonate, and 0.1 g (0.00038 mole) of 18-crown-6 in 50 mL of acetone was heated at reflux for five hours. The reaction mixture was cooled, filtered and the filtrate evaporated under reduced pressure leaving a residue. The residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure leaving a residue. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-heptane (50:50), to yield 0.6 g of (7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one-6-yl) 1-pyrrolidinecarboxylate as a solid 73°-75° C., Compound 4 of Table 1. The nmr ir spectra were consistent with the proposed structure.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:30][CH2:31][C:32]1[C:37]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[CH:36][C:35]([F:46])=[CH:34][N:33]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:47]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O>[Si:13]([O:30][CH2:31][C:32]1[C:37]([N:38]2[CH2:39][C@H:40]([CH3:45])[O:41][C@H:42]([CH3:44])[CH2:43]2)=[C:36]([Cl:47])[C:35]([F:46])=[CH:34][N:33]=1)([C:26]([CH3:27])([CH3:29])[CH3:28])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C[C@@H]1CN(c2cc(F)cnc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H](C)O1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of diisopropylamine (3.51 ml, 24.65 mmol) in THF (30 ml) was cooled in a dry ice-acetone bath. A solution of n-butyllithium (2.5 M in hexanes, 9.28 ml, 23.20 mmol) was added and the mixture was warmed to 0° C. and recooled in a dry ice-acetone bath. The solution was added to a second solution of (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 44, 6.94 g, 14.50 mmol) in THF (30 ml) cooled in a dry ice-acetone bath. The mixture was stirred for 45 minutes before the solution was transferred via cannula to a solution of hexachloroethane (2.79 ml, 24.65 mmol) in 60 ml THF also cooled in a dry ice-acetone bath. The mixture was allowed to warm to room temperature before being diluted with EtOAc and washed with water and brine. The combined aqueous layers were extracted again with EtOAc, which was washed with brine. Drying (MgSO4) of the combined EtOAc extracts and removal of solvent gave a gummy solid that was chromatographed on silica gel (50% hexanes in CH2Cl2 followed by gradient elution to 100% CH2Cl2) to afford product as an oil that slowly solidified (5.26 g yield). MS (ES) MH+: 513 for C28H34ClFN2O2Si.
Reaction SMILES: C(OC(=O)C)(=O)C.[OH:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)=[N:15][CH:16]=1)[CH3:10].O>CS(C)=O>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)=[N:15][CH:16]=1)(=[O:8])[CH3:10]
Reactant: CC(O)c1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reaction time: 96 h

Procedure:
Acetic anhydride (25 ml) was added to a solution of 5-[4-[2-[5-(1-hydroxyethyl)-2-pyridyl]ethoxy]benzyl]-2,4-thiazolidinedione (8.7 g) in dimethyl sulfoxide (100 ml). The mixture was allowed to stand at room temperature for 4 days. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (100:1, v/v) gave 5-[4-[2-(5-acetyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione. This compound was recrystallized from ethanol to obtain colorless prisms, m.p. 114°-115° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[NH2:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:27][C@@H:26]1[OH:38]>N1C=CC=CC=1>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:23][CH2:24][C@H:25]2[O:29][C@@H:28]([N:30]3[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]3=[O:32])[CH2:27][C@@H:26]2[OH:38])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Reactant: N#Cc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(C(NC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
4-Cyanotrityl chloride (0.406 g, 1.34 mmol) was added to a solution of 5′-amino-2′,5′-dideoxyuridine (0.239 g, 1.05 mmol) in dry pyridine (5 mL). The reaction mixture was stirred at 40° C. for 48 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. Purification was carried out using flash column chromatography eluting the column (ISOLUTE SI) with a gradient of 0→5% CH3OH in CHCl3. The fractions with Rf=0.31 (10% CH3OH/CHCl3) afforded the title compound as a white crystalline solid (0.386 g, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=O.[CH3:19][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[CH2:19]
Reactant: C[Mg]Cl
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2Oc2c1cc(Cl)nc2F

Procedure:
To a solution of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (50 mg, 0.152 mmol) in 5 mL of dry THF at −78 C was added methylmagnesium chloride, 3.0 m solution in tetrahydrofuran (16.87 μL, 0.228 mmol) (0.07 mL) and the reaction was slowly warmed up to −30 C. Only half of conversion was detected. To this was added another batch of methylmagnesium chloride, 3.0 m solution in THF (16.87 μL, 0.228 mmol) (0.07 mL). The reaction was quenched at −30 C with sat. NH4Cl, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. It was then treated with 1 mg of PPTS in DCM at 25 C for 0.5 h. After cooling, 0.1 g of NaHCO3 was added the solvent was evaporated to dryness to give crude 7-bromo-3-chloro-1-fluoro-5-methylene-5H-chromeno[2,3-c]pyridine which was directly used in the next step.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH2:14][O:15][CH3:16])[N:3]=1.C([OH:19])C>[OH-].[Na+]>[CH3:16][O:15][CH2:14][O:13][CH2:12][C:4]1[NH:3][C:2](=[O:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: COCOCc1nc(N)c2nccnc2n1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: COCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in section d of Example 2, starting with 5.3 g (0.024 mole) of 4-amino-2-(methoxymethoxymethyl)pteridine in 250 ml of 5% aqueous sodium hydroxide. Heating time: 2 hours at 80° C. Yld: 2.2 g (41%), m.p. 161°-163° C. (ethanol).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Br:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Br:22])[CH:24]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Brc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(Br)c3)CC2)c(OC)nc1C
Yield: 65 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9]C)=O)[N:6]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].NC1SC(C2C=CC=CC=2)=C(C(OC)=O)N=1>>[Br:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:9])[N:6]=1
Reactant: COC(=O)c1nc(Br)sc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: COC(=O)c1nc(N)sc1-c1ccccc1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(Br)sc1-c1ccccc1
Yield: 20.3 %

Procedure:
2.0 g (6.7 mmol) of methyl 2-bromo-5-phenyl-4-thiazolecarboxylate and 1.61 g (10.1 mmol) of t-butyl (2-aminoethyl)carbamate were stirred under reduced pressure for 2.5 hours at 110° bath temperature, whereby the methanol formed was distilled off continuously. After chromatography on 100 g of silica gel with methylene chloride and a 4:1 mixture of methylene chloride and ethyl acetate there was obtained 0.58 g (26%) of t-butyl [2-(2-bromo-5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as a pale yellow, crystallizing oil which was used directly.