Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N[C@H](C)CSC1NC2C=CC=CC=2N=1.SC1NC2C=CC=CC=2N=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:58][C@@H:59]1[C@H:63]([O:64]C(=O)C)[C@@H:62]([CH2:68][O:69]C(=O)C)[O:61][C@H:60]1[N:73]1[C:95]2[N:94]=[C:93]([Cl:96])[N:92]=[C:77]([NH:78][C@H:79]([CH3:91])[CH2:80][S:81][C:82]3[NH:83][C:84]4[CH:90]=[CH:89][CH:88]=[CH:87][C:85]=4[N:86]=3)[C:76]=2[N:75]=[CH:74]1)(=O)C>N.ClCCl>[N:83]1[C:84]2[CH:90]=[CH:89][CH:88]=[CH:87][C:85]=2[NH:86][C:82]=1[S:81][CH2:80][C@H:79]([NH:78][C:77]1[C:76]2[N:75]=[CH:74][N:73]([C:95]=2[N:94]=[C:93]([Cl:96])[N:92]=1)[C@@H:60]1[O:61][C@H:62]([CH2:68][OH:69])[C@@H:63]([OH:64])[C@H:59]1[OH:58])[CH3:91]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nc5ccccc5[nH]4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@@H](N)CSc1nc2ccccc2[nH]1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](CSc1nc2ccccc2[nH]1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 51 %

Procedure:
The title compound was prepared according to method A as described in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzimidazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (1.75 g, 10 mmol) and 2-mercaptobenzimidazole (1.5 g, 10 mmol) followed by acidic hydrolysis] (0.63 g, 2.20 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.0 g, 2.2 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzimidazolyl)thio-2-propyl]-2-chloroadenosine in methanolic ammonia (200 ml) (previously saturated at -10° C.) to provide the title N-[(R)-1-(2-benzimidazolyl)thio-2-propyl]-2-chloroadenosine (0.52 g, 51%) mp 213°-215° C. after column chromatography and trituration with dichloromethane; 1H NMR (DMSO-d6) δ 1.38 (3H, d, --CHCH3), 3.95 (1H, q, H-4), 4.12 (1 H, br q, H-3'), 4.42-4.70 (2H, m, --CHCH3 and H-2'), 5.07 (1H, br, 5'-OH), 5.22, 5.50 (2H, 2 br, 2'- and 3'-OH), 5.82 (1H, d, H-1'), 7.04-7.57 (4H, 2m, Ar-H) 8.42 (1H, s, H-2), 8.73 (1H, d, --NH). HPLC retention time 13.7 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O.O.CC(O)C.C([O-])([O-])=O.[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.O>[Br:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]3[CH2:7][CH2:6][N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][C:9]3=[N:10][C:11]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(Br)ccc2n1CCOS(C)(=O)=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cc(Br)ccc32)C1
Temperature: 105 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
2-(5-Bromo-2-((tert-butoxycarbonylamino)methyl)-1H-benzo[d]imidazol-1-yl)ethyl methanesulfonate (883 mg, crude, 1.76 mmol estimated) was stirred in TFA (10 mL) for 1 h and then concentrated. Water/i-PrOH (32 mL/8 mL) and K2CO3 (2.31 g, 16.7 mmol) were added, and the mixture was heated at 105° C. for 2 h and then cooled to room temperature. Di-tert-butyl dicarbonate (812 mg, 3.73 mmol) was added, and the reaction mixture was stirred for 48 h and then diluted with water. The solid was filtered off and dried under vacuum to provide the title compound (549 mg, 89%) as a brown solid: ESI MS m/z 352 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:10]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=Cc1cccc(NC(=O)c2ccc(Cl)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-chloro-N-(3-formyl-phenyl)-benzamide (2.1 g, 8.09 mmol), ethyl isonipecotate (1.53 g, 9.55 mmol) in DCM (45 mL) is treated with sodium triacetoxy borohydride (2.5 g, 11.2 mmol) in 5 portions over 20 min. and the reaction mixture is stirred for 18 h at RT. Aq. sat. NaHCO3 (20 mL) is added and the mixture is stirred for 30 min. The phases are separated and the aqueous phase is extracted twice with DCM (50 ml). The combined organic phases are dried over MgSO4 and evaporated. The title compound is obtained as a colorless solid (3.24 g, 98%); LC-MS A: tR=0.72 min; [M+H]+=401.01.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCCc2ccc(O)cc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)C(=O)CCCC2
Temperature: 52.5 °C
Reaction time: 7 h
Yield: 72.4 %

Procedure:
A mixture of 3-hydroxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (7.02 g), potassium carbonate (8.25 g) and iodomethane (7.4 ml) in N,N-dimethylformamide (70 ml) was stirred at 50-55° C. for 7 hours. The resulting mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-methoxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (5.49 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:4]=1.N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>C(Cl)Cl>[C:19]([C:5]1[CH:4]=[C:3]([NH:2][C:30](=[O:31])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])[N:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[N:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)NCC3)n1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3c(c2)C(=O)NCC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinolin-1-one hydrochloride (0.5 g, 1.76 mmol) in CH2Cl2 (25 mL) were added pyridine (0.22 mL) and trichloroethyl chloroformate (0.27 mL) at 0° C. and the mixture was stirred overnight at RT. LCMS showed the reaction was incomplete. Pyridine (0.25 mL) and TROC-Cl (0.25 mL) were added and then the mixture stirred at RT for 2 hours. The reaction mixture was diluted with CH2Cl2, the organic layer was washed with 3M HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in EtOAc and hexane was added. The solid was filtered to obtain 2,2,2-trichloroethyl 3-tert-butyl-1-(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-ylcarbamate (0.46 g, 57% yield). MS (ESI) m/z: 458.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:27]([CH2:23][CH2:24][CH2:25][CH3:26])[C:28]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: CCCCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Yield: 58.4 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with n-butyl isocyanate (2.14 mL, 19.02 mmol) in DMA afforded crude product. Recrystallization from chloroform provided 1.40 g of the title compound as a solid, mp 147-148° C.
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].BrN1C(=[O:24])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClC1C=CC=CC=1>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([OH:24])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CN1c2ccccc2CCc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: Clc1ccccc1
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 50 °C
Yield: 51.9 %

Procedure:
6.60 g (0.030 mols) of (I) are dissolved in 45 ml of chlorobenzene, the mixture is heated to 50° C. under stirring. The resulting solution is added under stirring with 5.6 g (0.0315 mols) of N-bromosuccinimide then with 0.49 g (0.003 mols) of azobisisobutyronitrile, stirring for 1 hour while heating at 75-80° C. The mixture is then is cooled to 40° C., added with 30 ml of water and stirred at 40° C. for 30 minutes, then heated to 80° C. for 3 hours. After decanting for 30 minutes, the aqueous phase is separated and re-extracted with 8 ml of chlorobenzene. The combined organic phases are washed with water (10 ml) and dried, then concentrated at 60° C. to 20 ml, adding 15 ml of hexane at this temperature. The mixture is cooled to 0-5° C. for 30 minutes and the separated solid is filtered, to obtain 3.68 g (52%) of 5-cyano-10-hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine (VI), m.p. 117-8° C., purity>98% (HPLC).
Reaction SMILES: FC1C=CC=CC=1COCCCCNC(C)C.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:42])=[C:23]([CH:41]=1)[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH:31]([CH3:33])[CH3:32]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:42])=[C:23]([CH:41]=1)[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH:31]([CH3:32])[CH3:33]
Reactant: CC(C)N(CCCCOCc1cc(Cl)ccc1F)C(=O)OC(C)(C)C
Agent: CC(C)NCCCCOCc1ccccc1F
Product: CC(C)NCCCCOCc1cc(Cl)ccc1F

Procedure:
The desired intermediate was prepared essentially as described for the 4-(2-fluorobenzyloxy)-N-(isopropyl)butylamine above, except that an equimolar amount of 4-(5-chloro-2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine was employed in place of the 4- (2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine employed therein.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][N:7]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:17]=[N+:18]([O-:45])[CH:19]=[C:20]([Cl:44])[C:21]=1[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:24][C:25](=[O:28])[CH2:26]O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:44][C:20]1[CH:19]=[N+:18]([O-:45])[CH:17]=[C:16]([Cl:15])[C:21]=1[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:24][C:25](=[O:28])[CH2:26][O:13][C:12]([C:9]1[CH:8]=[N:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:11][CH:10]=1)=[O:14]
Reactant: CS(=O)(=O)Nc1ncc(C(=O)O)cn1
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ncc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cn1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a suspension of 2-(methylsulfonamido)pyrimidine-5-carboxylic acid (0.130 g, 0.599 mmol) in dry DCM (5.44 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (See Scheme 21, step 6-9) (0.260 g, 0.544 mmol), EDC (0.313 g, 1.632 mmol), and DMAP (0.665 g, 0.544 mmol) were sequentially added with stirring at room temperature under nitrogen, and the mixture was stirred for 20 hours. The solvent was removed, and the crude was purified by flash chromatography on silica gel column (DCM:MeOH=97:3 to 95:5) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(methylsulfonamido)pyrimidine-5-carbonyloxy)acetoxy)ethyl)pyridine 1-oxide as a pale yellow spongy solid (0.168 g, 0.248 mmol, 45.6% yield, MS/ESI+ 677.1 [MH]+, [αD]=−47.48, c=0.5, MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][C:17]([C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH2:29])[CH:28]=1)=[CH:16]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][C:17]([C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH:29][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:28]=1)=[CH:16]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
4-Nitrobenzaldehyde (0.3 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 6 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and the mixture was stirred for 2 hours. The mixture was shaken; the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a red solid. Recrystallization from methanol gave the product (450 mg), mp 181-182° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)c2ccccc2)[C@H]1O)c1ccccc1
Yield: 39.3 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-benzoylamino-1,3-dideoxy-β-D-ribofuranuronic acid (125 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (250 mg) prepared in Example 1 with benzoyl chloride (110 mg) according to a similar manner to that of Example 17, mp. 112°-118° C. (dec.).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1.Cl>C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:2][CH:3]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:31])=[C:28]([C:35]([F:36])([F:37])[F:38])[CH:27]=1
Reactant: CCOC(=O)C(N)C(=O)c1ccccc1C
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
6.2 g (0.024 mol) of ethyl 2-amino-3-oxo-3-o-tolylpropionate hydrochloride were dissolved in methylene chloride, and 9.7 g (0.096 mol) of triethylamine were added. At 0° C., 5.4 g (0.024 mol) of 4-fluoro-2-trifluoromethylbenzoyl chloride, dissolved in methylene chloride, were added dropwise. The mixture was stirred at room temperature (RT) for 1 h, and 5% strength hydrochloric acid was then added. The organic phase was separated off, washed and dried, and the solvent was removed. Chromatographic purification (silica gel column, cyclohexane/ethyl acetate) gave 4.7 g of the title compound as colorless crystals.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2Nc2ncccc21
Agent: Cl
Solvent: C1COCCO1
Product: c1cnc2c(c1)CNc1ccccc1N2

Procedure:
Diborane dimethylsulfide complex (35 mL) was added via syringe to a suspension of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 1:1 salt with hydrochloric acid of Step A (25 g, 0.1 mole) in dioxane (230 mL) under nitrogen. The mixture was sonicated overnight at room temperature and then evaporated to dryness in vacuo. The green residue was treated with cold 2N hydrochloric acid and diethyl ether. The cold aqueous layer was basified with 50% aqueous sodium hydroxide (to pH 9) and the basic layer extracted with ethyl acetate. The organic extracts were dried over anhydrous potassium carbonate, and evaporated to dryness to yield a burgundy solid (24.35 g). This crude material was purified by trituration with diethyl ether. The solid was collected, washed and dried in vacuo. The mother liquors from different runs were combined and the mixture (18.5 g) flash chromatographed (on silica Merck-60, eluant 20% ethyl acetate in hexane) to provide additional material homogeneous by TLC (yellow solid, 11 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1C=CC=CC=1>[CH3:11][C:10]([NH:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[F:1])=[O:12]
Reactant: Nc1cc(F)ccc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(F)ccc1F
Yield: 94.2 %

Procedure:
20.5 g of 2,5-difluoroaniline was dissolved in 68 ml of benzene, and 17.8 g of acetic anhydride was dropwise added. Fifteen hours later, benzene was distilled off, and the residue was washed with ethyl ether to obtain 25.6 g of 2,5-difluoroacetanilide as white crystals. Then, this compound was dissolved in 98% sulfuric acid, and 60% nitric acid was dropwise added at a temperature of not higher than 0° C. After the dropwise addition, the mixture was stirred for three hours at room temperature, and poured on ice. Precipitated crystals were collected by filtration and dried to obtain 25.9 g of the above-identified compound as yellow crystals.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[C:11]([O:13][CH3:14])[C:9](N)=[C:8]([O:15][CH3:16])[CH:7]=1.[ClH:17]>O>[Br:5][C:6]1[CH:12]=[C:11]([O:13][CH3:14])[C:9]([Cl:17])=[C:8]([O:15][CH3:16])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Br)cc(OC)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (97 mg) in water (2.0 mL) was added dropwise to an ice-cold suspension of 4-bromo-2,6-dimethoxyaniline (232 mg) in 6.0 M hydrochloric acid (2.5 mL). After stirring in ice for 30 minutes, a solution of cupric chloride (495 mg) in concentrated hydrochloric acid (2.0 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then at 100° C. for 2 hours, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and evaporated. The residue was subjected to a column of silica gel using hexane-ethyl acetate (10:1) as an eluent to give the title compound as white powder.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[C:19]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][C@@H:24]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.C(N(CC)CC)C.C1(N(C2C=CC=CC=2)C([NH:52][S:53](Cl)(=[O:55])=[O:54])=O)C=CC=CC=1.Cl>C1COCC1>[S:53](=[O:55])(=[O:54])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[C:20]([F:21])=[C:19]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][C@@H:24]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:13][C@@H:9]1[OH:8])[NH2:52]
Reactant: O=C(NS(=O)(=O)Cl)N(c1ccccc1)c1ccccc1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O)C2)c1F
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(5-fluoro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)-oxy]cyclopentyl}methanol (190 mg, 0.36 mmol) in THF (5.40 mL) was added triethylamine (0.08 mL, 0.54 mmol) and [(diphenylamino)carbonyl]sulfamoyl chloride (186 mg, 0.54 mmol) at 0° C. under an atmosphere of Argon, and the mixture was stirred for 30 min. The reaction mixture was added 1.00 M Hydrochloric acid in (5.40 mL) at 23° C., and the resulting mixture was stirred for 16 h. The reaction mixture was quenched by addition of saturated NaHCO3 solution (80.0 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 0 to 10% methanol in DCM to afford the title compound (91.0 mg, 51%). 1H-NMR (400 MHz, CD3OD) δ: 8.01 (s, 1H), 7.25-7.13 (m, 4H), 5.72 (d, 1H, J=6.5 Hz), 5.65-5.58 (m, 1H), 4.43-4.38 (m, 1H), 4.33 (dd, 1H, J=9.7, 7.6 Hz), 4.22 (dt, 1H, J=5.0, 2.4 Hz), 4.16 (dd, 1H, J=9.7, 7.3 Hz), 3.35 (s, 3H), 3.14 (dd, 1H, J=16.6, 2.4 Hz), 3.02 (dd, 1H, J=16.6, 5.0 Hz), 2.60-2.49 (m, 1H), 2.31 (ddd, 1H, d=14.8, 6.8, 2.3 Hz), 2.12 (ddd, 1H, J=14.8, 5.0, 4.7), 2.08-1.95 (m, 2H). LC/MS: Rt=6.76, ES+ 469.3 (FA long).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH2:7][CH2:6]2.O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In methanol (100 ml), 6-methoxy-3,4-dihydroisoquinoline (10.4 g) was dissolved. To the resulting solution, water (10 ml) and then sodium borohydride (6.10 g) were added. The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, followed by washing with water. The organic layer thus separated was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=100:15), whereby the title compound (7.95 g, 76%) was obtained.