Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23].[OH-].[K+].Cl>CO>[F:11][C:12]1[C:17]([CH:18]([OH:19])[C:10]2[C:3]3[C:2]([CH3:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23]
Reactant: Cc1ncnc2[nH]ccc12
Reactant: CC(C)CS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncnc2[nH]cc(C(O)c3c(F)ccc(NS(=O)(=O)CC(C)C)c3F)c12
Temperature: 25 °C
Reaction time: 7 h
Yield: 37.8 %

Procedure:
In a round bottom flask, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (7, 97.0 mg, 0.728 mmol) is combined with 2-methyl-propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (62, 202 mg, 0.728 mmol), potassium hydroxide (204 mg, 3.64 mmol) and 1.4 mL of methanol. The reaction is stirred at room temperature for 7 hours. The reaction is neutralized with 0.1 N aqueous hydrochloric acid and extracted 3× with ethyl acetate. The combined organic layer is washed with brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (77, 113 mg). MS (ESI) [M−H+]−=409.2.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH2:37])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[N:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.O>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH:37][C:51]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[O:52])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Reactant: O=C(Cl)N1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2)N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
100 mg C-((S)-1-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl }-pyrrolidin-2-yl)-methylamine trifluoroacetate, Diastereomer 2 (Example 226) (see scheme 3, 3.17.2) are placed in 2 ml dichloromethane. While cooling with the ice bath 38 μl triethylamine and 28 μl 4-morpholinecarbonyl chloride are added. The reaction mixture is stirred for 12 hours at ambient temperature and then mixed with water. The organic phase is dried and evaporated to dryness. 121 mg of the product are obtained as a solid. Analytical HPLC-MS (method D): RT=1.18 min.
Reaction SMILES: CC(C)CCC1NC2C(C=1)=CC=CC=2.[CH3:15][C:16](=[CH:18][CH2:19][CH2:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:17]>>[CH3:15][CH:16]([CH3:17])[CH2:18][CH2:19][CH2:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: CC(C)=CCCc1cc2ccccc2[nH]1
Agent: CC(C)CCc1cc2ccccc2[nH]1
Product: CC(C)CCCc1cc2ccccc2[nH]1

Procedure:
Refer to 28b) using 2-(2-methyl-2-penten-5-yl) indole as the starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[O:10]1CCC[CH2:11]1>>[F:8][C:4]1[C:3]2[O:9][C:11](=[O:10])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(F)c1O
Reactant: C1CCOC1
Product: O=c1[nH]c2cccc(F)c2o1
Temperature: 25 °C

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, 1,1-carbonyldiimidazole (15.6 g, 96 mmol) is added to a solution of 2-amino-6-fluorophenol 1 (4 g, 32 mmol) in 100 ml of anhydrous tetrahydrofuran at room temperature. The solution is refluxed for 1 h, cooled down to room temperature and concentrated in vacuo. The crude reaction mixture is purified by chromatography on silicagel (n-hexane/AcOEt:1/1 (v/v)) to afford 7-fluoro-1,3-benzoxazol-2(3H)-one 2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=[CH:4][N:3]=1.C[Si]([C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:13]1([C@H:12]2[O:11][C:10](=[O:19])[NH:9][C@@H:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)C#Cc1ccccn1
Reactant: O=C1N[C@H](c2ccnc(Br)c2)[C@@H](c2ccccc2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1N[C@H](c2ccnc(C#Cc3ccccn3)c2)[C@@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4R,5R)-4-(2-bromopyridin-4-yl)-5-phenyloxazolidin-2-one (20 mg, 0.063 mmol) and 2-((trimethylsilyl)ethynyl)pyridine (10.99 mg, 0.063 mmol) in dimethylformamide (300 mL) was purged with nitrogen for 30 min. The reaction was treated with triphenylphosphine (4.93 mg, 0.019 mmol), and purged 10 minutes longer. To this was added PdCl2(PPh3)2 (2.199 mg, 3.13 mmol) and copper(I) iodide (1.193 mg, 6.27 mmol). After purging 10 min longer, the reaction was treated with triethylamine (13.1 mL, 0.094 mmol) and placed in an 85° C. oil bath. To this was added tetrabutylammonium fluoride (1M in tetrahydrofuran, 68.9 mL, 0.069 mmol) dropwise. The reaction was stirred at this temperature for 1 h. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (50%-->100% EtOAc/Hex) gave 19 mg (89%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.68 (d, J=4.6, 1H), 8.60 (d, J=5.2, 1H), 7.73 (ddd, J=7.9, 7.6, 1.6, 1H), 7.59 (d, J=7.6, 1H), 7.38-7.50 (m, 5H), 7.33 (m, 3H), 7.25 (m, 1H), 5.19 (d, J=7.3, 1H), 4.88 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 158.8, 151.0, 150.3, 148.6, 143.3, 142.1, 136.7, 136.6, 129.6, 129.3, 127.9, 126.2, 125.1, 123.9, 120.9, 88.5, 87.4, 85.2, 63.6. Mass spec.: 342.0 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6](=[O:7])[C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:4]=2[O:3]1>C(O)(=O)C.O.[Fe]>[NH2:12][C:11]1[C:4]2[O:3][C:2]([CH3:1])([CH3:15])[C:6](=[O:7])[C:5]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Oc2c(N)cccc2C1=O
Yield: 68.6 %

Procedure:
By the method of Example 1, Step E, 20.0 g (0.097 mole) of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-one and 27.0 g (0.483 mole) of powdered iron were reacted in 85 mL of glacial acetic acid and 15 mL of water, yielding 11.79 g of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran-3-one, m.p. 80°-84° C. The NMR and IR spectra of this product were consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[O:16]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17]1>>[O:16]1[CH:20]=[CH:19][C:18]([CH:21]=[C:10]2[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:15])=[CH:17]1
Reactant: O=Cc1ccoc1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1ccoc1)C2=O
Yield: 80 %

Procedure:
The title compound was prepared from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 3-furaldehyde (192 mg, 2.0 mmol) according to Method A3 in 80% yield. ES-MS m/z 283 (M+H)
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:9])[CH3:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:9])[CH3:8]
Reactant: CCCCCCC/C=C\CCCCCCCC(O)CCCNC(C)=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCC/C=C\CCCCCCCC(=O)CCCNC(C)=O

Procedure:
A 0.5 g portion of N-(4-hydroxy-12(Z)-eicosenyl)-acetamide was stirred with 0.44 g of pyridinium chlorochromate in 15 ml of dichloromethane for 2 hours. This mixture was poured into 50 ml of ether and filtered through hydrous magnesium silicate. The filtrate was evaporated giving 0.24 g of the desired product as a pale yellow solid, mp 51-52° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][CH2:29][CH2:30]O)([CH3:21])[CH3:20])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:37][CH2:30][CH2:29][CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:32])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:34])[C:9]=2[CH3:33])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:35])[CH:17]=[CH:16][N:15]=1)([CH3:21])[CH3:20]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2CCCO)c1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2CCCBr)c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[3-({1-[2-(3-hydroxypropyl)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide (Example 323h) (0.4 g) dissolved in THF (10 mL) was treated with carbon tetrabromide (0.277 g) under nitrogen. The resulting mixture was cooled to 0° C. before adding triphenylphosphine (0.219 g). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated and the residue purified (SiO2 chromatography eluting with 50% DCM in ethyl acetate) to give the subtitle compound as a solid (0.135 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:5](OC)=[O:6].[NH3:21]>CO>[CH3:1][O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:6])[NH:21][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:13]2
Reactant: N
Reactant: COC(=O)c1c(C#Cc2ccccc2)ccnc1OC
Solvent: CO
Product: COc1nccc2cc(-c3ccccc3)[nH]c(=O)c12
Temperature: 115 °C

Procedure:
Methyl 2-methoxy-4-(phenylethynyl)nicotinate (100 mg, 0.37 mmol) is dissolved in 7% NH3 in MeOH (3 mL) and heated at 115° C. in a sealed tube for 24 hours. The reaction mixture is cooled to 0° C. and the cyclized product is crystallized out. The compound is collected by filtration and dried after washing with hexanes. MS m/z 253.1 (M+1).
Reaction SMILES: [ClH:1].CN.[O:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[CH2:11]([N:13](CC)CC)C>[Pd].CO>[ClH:1].[CH3:11][NH:13][CH:7]1[CH2:8][CH2:9][O:4][CH2:5][CH2:6]1
Reactant: O=C1CCOCC1
Reactant: CCN(CC)CC
Agent: [Pd]
Agent: CN
Agent: Cl
Solvent: CO
Product: CNC1CCOCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 273.3 %

Procedure:
A mixture of methylamine hydrochloride (5.4 g), terahydro-4H-pyran-4-one (8 g), triethylamine (2.4 g), 5% palladium on carbon (400 mg) and methanol (56 ml) were stirred at 60° C. for 3 hours under a hydrogen atmosphere. The palladium on carbon was removed by filtration through diatomaceous earth (Celite®) and the resultant filtrate evaporated in vacuo to a cream solid. To this solid were added propan-2-ol (39 ml), methanol (10 ml) and diethyl ether (20 ml), the resultant suspension then allowed to stir at room temperature for 1 hour, the solid was collected by filtration, washed with diethyl ether (10 ml) and dried in vacuo at room temperature to give N-methyl-N-(tetrahydropyran-4-yl)amine hydrochloride (9.83 g) as a white solid; NMR Spectrum: (DMSOd6) 1.62 (m, 2H); 1.94 (m, 2H); 2.53 (m, 3H); 3.14 (m, 1H); 3.3 (m, 2H); 3.91 (m, 2H); 9.24 (s, 2H).
Reaction SMILES: [N:1]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])[C:8]([OH:12])([CH3:11])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3].CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[N:1]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])[C:8]([O:12][S:35]([CH3:34])(=[O:37])=[O:36])([CH3:11])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]
Reactant: COc1ccc(COC(=O)C2N3C(=O)[C@H](N=[N+]=[N-])[C@H]3SCC2(C)O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2N3C(=O)[C@H](N=[N+]=[N-])[C@H]3SCC2(C)OS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 94.8 %

Procedure:
A solution of p-methoxybenzyl 7α-azido-3-hydroxy-3-methyl-cepham-4-carboxylate (310 mg., 0.82 mMol) and Et3N (1.72 μl, 1.23 mMol) in anhydrous CH2Cl2 (4 ml.) is cooled in an ice bath under N2. A solution of MeSO2Cl (83 μl, 1.07 mMol) in anhydrous CH2Cl2 (1 ml.) is added dropwise with stirring over 6 min. The resulting solution is stirred 15 more min. in the cold, then diluted with ice cold CH2Cl2 (5 ml.) and washed with ice cold H2O (5 ml.), 5% HCl (5 ml.), and 5% NaHCO3 (5 ml.). The CH2Cl2 solution is dried over MgSO4, filtered, and evaporated in vacuo to provide p-methoxybenzyl 7α-azido-3-methanesulfonyloxy-3-methyl-cepham-4-carboxylate (355 mg.) as a pale yellow gum: ir (CHCl3) 4.78, 5.63, 5.78, 6.64, 7.43, 7.99, 8.48, and 11.08μ; nmr (CDCl3) δ2.03 (s, 3, CH3), 2.68 (s, 3, SO2CH3), 3.00 (d, l, J=14Hz, SCH), 3.80 (s, 3, OCH3), 3.82 (d, l, J=14Hz, SCH), 4.47 (d, l, J=1.3Hz, H7), 4.65 (s, l, H4), 4.97 (d, l, J=1.3 Hz, H6), 5.00 and 5.28 (ABq, 2, J=10.5 Hz, CH2Ar), and 6.87 and 7.33 (two d's, 4, J=9Hz, ArH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:4]([NH2:22])[CH:3]=1.[C:23](Cl)(Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:23](=[O:24])[NH:22][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(4,5-Dichloro-2-aminophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D39) (140 mg, 0.4 mmol) was dissolved in 10 ml of dichloromethane at 0° C. and phosgene (20% in toluene, 0.25 ml) and triethylamine (0.2 ml, 1.5 mmol) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous sodium bicarbonate, dried over MgSO4, filtered and evaporated The product was chromatographed on silica gel eluting with methanol-dichloromethane mixtures, and then further purified by MDAP to yield 5,6-dichloro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 22 mg, which was converted into the hydrochloride salt using 4M HCl in dioxan.
Reaction SMILES: O[CH2:2][NH:3][C:4](=O)C1C=CC=CC=1.OCNC(=O)C1C=CC=NC=1.O[CH2:24][N:25]1[C:29](=[O:30])[C:28]2=CC=CC=[C:27]2[C:26]1=[O:35].OCN1CC(=O)NC1=O.OCN1C(=O)CCC1=O>>[CH3:2][N:3]([CH2:24][N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:35])[CH3:4]
Reactant: O=C(NCO)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: O=C(NCO)c1cccnc1
Agent: O=C1CCC(=O)N1CO
Agent: O=C1CN(CO)C(=O)N1
Product: CN(C)CN1C(=O)CCC1=O

Procedure:
Materials: N-(hydroxymetyl)-benzamide (Hellman, H, Angew. Chem. 69 (1957), 470), N-(hydroxymethyl)-nicotinamide (Chechelska, B. & Urbanski, T., Roczniki Chem. 27, 396-409), N-(hydroxymethyl)-phthalimide (Buch, S. R., J. Am. Chem. Soc. 69 (1947) 254- ), N-(hydroxymethyl)-hydantoin (Konishiroku Photo Industr. Co. Ltd. Japan 6882 ('58) Aug. 20, Chemical Abstracts 54, 135h), N-hydroxymethyl succinimide (Vail, S. L. & Pierce, A. G., J. Org. Chem. 37 (1972) 393-), and the Mannich bases N-dimethylaminomethyl nicotinamide (Singh, G. et al., Indian J. Pharm. 30 (1968) 231-3) and N-dimethylaminomethyl succinimide (Boehme, H. et al., Ann. Chem. 664 (1963) 130-40) were produced in a known manner.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C:21]2=[O:33])=[CH:4]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.CO>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:33])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(OCc3ccccn3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Reaction time: 1.5 h
Yield: 77.6 %

Procedure:
To a stirred solution of tert-butyl 4-[1-ethyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylate (4.952 g, 10.97 mmol) in DCM (20 mL) is added trifluoroacetic acid (4.15 mL, 54.84 mmol) over 2 minutes and the reaction stirred for 90 minutes. The reaction is diluted with MeOH and poured on to a SCX2 ion-exchange column. This is flushed with one column volume of MeOH, and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. This solution is then concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 40% MeOH in EtOAc, to give the title compound as an orange oil (2.989 g, 8.51 mmol). MS (m/z): 352 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4)c3O2)cc1
Agent: [Na+]
Product: Cc1cccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)c1

Procedure:
Treatment of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.90 g, 2.27 mmol) with sodium azide (0.44 g, 6.84 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (10%, 0.060 g) generally according to the procedure described for Example 1 afforded 0.444 g (71%) of (±)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >210° C. (dec); Anal. calcd. for C16H17NOHCl.0.2H2O: C, 68.79; H, 6.64; N, 5.01. Found: C, 68.54; H, 6.57; N, 4.9.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:3]=1[O:4][C@H:5]([CH3:27])[C:6]([NH:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH2:23][CH3:24])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@@H:12]([F:25])[C@@H:11]1[OH:26])=[O:7].[C:35]([NH:42][C@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[C:38]([O:37][C:35]([NH:42][C@H:43]([C:47]([O:26][C@@H:11]1[C@@H:10]([CH2:9][NH:8][C:6](=[O:7])[C@H:5]([O:4][C:3]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:2]=2[Cl:1])[CH3:27])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH2:23][CH3:24])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]1[F:25])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:36])([CH3:40])([CH3:41])[CH3:39]
Reactant: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H]2F)c(=O)[nH]c1=O

Procedure:
Coupling of 1-[5-[2(R)-(2,4-dichloro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil with N-Boc-L-valine in a manner analogous to that described in Example 1(A) gave 1-[3-O-[N-(tert-butoxycarbonyl)-L-valyl]-5-[2(R)-(2,4-dichloro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white solid, m.p. 110° C. (dec).
Reaction SMILES: ClC(OCC(Cl)(Cl)Cl)=O.C(N(CC)CC)C.ClC(Cl)(Cl)C[O:20][C:21](=O)[NH:22][C:23]1[C:24]([CH3:42])=[CH:25][C:26]2[O:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[C:27]=2[C:40]=1[CH3:41].[C:46]([NH2:50])([CH3:49])([CH3:48])[CH3:47]>CS(C)=O.O>[C:46]([NH:50][C:21]([NH:22][C:23]1[C:24]([CH3:42])=[CH:25][C:26]2[O:30][CH2:29][C@H:28]([C:31]3[CH:32]=[CH:33][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:35][CH:36]=3)[C:27]=2[C:40]=1[CH3:41])=[O:20])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)N
Reactant: Cc1cc2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of (+)-(3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine (1.0 g, 3.55 mmol) obtained in Reference Example 141 in THF (10 mL) was added dropwise with ice-cooling 2,2,2-trichloroethyl chloroformate (0.49 mL, 3.55 mmol), was added triethylamine (0.52 mL, 3.73 mmol) and the reaction mixture was stirred for 30 minutes, and then the reaction solution was warmed to room temperature. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The solution of the obtained 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate (1.60 g, 3.50 mmol) and tert-butylamine (779 mg, 10.65 mmol) in dimethylsulfoxide (20 mL) was stirred at 45° C. for 5 hours under an argon atmosphere. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=2:1) to obtain 1.19 g (yield: 88%) of the title compound. Melting point: 205-206° C. (ethyl acetate-hexane). [α]D20=+81.0° (c=0.51, chloroform).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20]COC)[C:5]=1[O:24][CH3:25])[CH3:2].Cl>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCOC)c1OC
Agent: Cl
Solvent: CO
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Temperature: 50 °C
Yield: 68.4 %

Procedure:
To a stirring solution of 5-(4-ethoxy-3-methoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one (100 mg, 0.292 mmol) in methanol (5 mL) was added conc. hydrochloric acid (0.5 mL) and heated to 50° C. for 1 h. The reaction mixture was concentrated under reduced pressure; the residue was basified with sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (60 mg, 68%).