Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][N+]1(C)CCOCC1.[CH:10]([C:12]1[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:11].[O-]S([O-])=O.[Na+].[Na+].[OH2:34]>CC(C)=O.C1COCC1.O=[Os](=O)(=O)=O>[OH:34][CH:10]([C:12]1[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][OH:2]
Reactant: CO[N+]1(C)CCOCC1
Reactant: O
Reactant: C=Cc1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)n1c(C(O)CO)cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
4-Methoxy-4-methylmorpholin-4-ium (1.5 g, 12.8 mmol), water (10 mL), and OsO4 (250 mg, 1 mmol) in water (10 mL) were added to a mixture of tert-butyl 2-vinyl-1H-indole-1-carboxylate (2.60 g, 10.7 mmol) in acetone (15 mL) and THF (15 mL). After being stirred at room temperature for 16 hours, saturated Na2SO3 was added, and the resulting mixture was stirred for 30 minutes. The insoluble material was filtered off. The filtrate was extracted with ethyl acetate (2×100 mL), washed with brine, dried, and concentrated to give tert-butyl 2-(1,2-dihydroxyethyl)-1H-indole-1-carboxylate (2.0 g, 69% yield) as an oil.
Reaction SMILES: CO[CH:3](O)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:17].CC(N([C@H]1CCNC[C@H]1O)C(=O)[O-])(C)C.[C:34]([O:38][C:39](=[O:48])[NH:40][C@H:41]1[CH2:46][CH2:45][NH:44][CH2:43][C@H:42]1[OH:47])([CH3:37])([CH3:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[OH:47][C@H:42]1[C@@H:41]([NH:40][C:39](=[O:48])[O:38][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:46][CH2:45][N:44]([CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[N:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:17])[CH2:43]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC[C@H]1O
Reactant: COc1cnc2ccc(=O)n(CC(O)OC)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)N(C(=O)[O-])[C@H]1CCNC[C@H]1O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C3)c2c1
Temperature: 25 °C

Procedure:
[7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde methyl hemiacetal (200 mg, 0.7992 mmol) and 1,1-dimethylethyl[(3R,4S)-3-hydroxy-4-piperidinyl]carbamate (for a synthesis see WO2004058144, Example 5(c), cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester Enantiomer 1) (173 mg, 1 eq.) were stirred in chloroform (10 ml) plus MeOH (0.5 ml) under argon for 2 h. Sodium triacetoxyborohydride (508 mg, 3 eq.) was added in one portion and the mixture was stirred at rt over the weekend, then quenched by addition of saturated aqueous sodium hydrogen cabonate (20 ml) and extracted with 20% v:v MeOH in DCM (3×200 ml). The organic extractes were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica, eluted with 0-20% (2M ammonia in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give 1,1-dimethylethyl ((3R,4S)-3-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-4-piperidinyl)carbamate (263 mg) as an off-white foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: O=P([O-])([O-])O
Reactant: Nc1c(F)c(CC2CC2)nc(C=O)c1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1c(F)c(CC2CC2)nc(C(=O)O)c1Cl
Temperature: 70 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (63 mg, 0.276 mmol) and t-butanol (1.378 mL). The mixture was treated with H2O (0.459 mL), 2-methylbut-2-ene (0.3 mL, 0.276 mmol), sodium hydrogenphosphate (78 mg, 0.551 mmol), and finally sodium chlorite (74.8 mg, 0.827 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was evaporated to dryness under N2. Purification via reverse phase chromatography yielded 4-amino-3-chloro-6-(cyclopropylmethyl)-5-fluoropicolinic acid (6.2 mg, 9.5%); 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 5.00 (m, 2H), 2.70 (dd, J=7.0, 2.6 Hz, 2H), 1.17-1.02 (m, 1H), 0.60-0.48 (m, 2H), 0.27 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −139.97; ESIMS m/z 243.2 ([M−H]−).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[C:20](O)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:6][CH:7]=1)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1O[C@H](c2ccccc2)CN1c1ccc(O)cc1
Reactant: CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Oc1ccc(N2C[C@@H](c3ccccc3)OC2=O)cc1
Yield: 52 %

Procedure:
0.50 g (1.96 mM) of (5R)-3-(4-hydroxyphenyl)-5-phenyl-2-oxazolidinone synthesized in Example 2, 0.26 g of hexanoic acid and 20 ml of methylene chloride were placed in 50 ml-round bottomed flask, followed by stirring to form a solution. To the solution, 0.43 g (2.08 mM) of N,N'-dicyclohexylcarbodiimide and 0.10 g of 4-dimethylaminopyridine were added in succession, followed by stirring for 8 hours at room temperature. The precipitated N,N'-dicyclohexylurea was filtered out and the filtrate was evaporated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=20/1) and recrystallized from methanol to obtain 0.36 g of (5R)-3-(4-hexanoyloxyphenyl)-5-phenyl-2-oxazolidinone (Yield: 52.0%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=3)[C:6]2=[O:18])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[CH:51]=1>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:15]([NH:57][CH2:56][C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:17])=[CH:13][N:14]=3)[C:6]2=[O:18])[CH2:2][CH2:3]1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1cnc(N2CCN(CC3CC3)C2=O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid (0.10 g, 0.37 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (0.17 mL, 1.34 mmol), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.59 mmol). The reaction was stirred at ambient temperature for 0.5 hours, 1-Hydroxybenzotriazole (0.07 g, 0.52 mmol) was added, followed by the addition of pyridin-3-ylmethanamine (0.06 g, 0.56 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was concentrated in vacuo. The residue was diluted with dichloromethane (150 mL), washed with water (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized in dichloromethane and hexane to yield the title compound as a colorless solid in 40% yield (0.065 g): mp 190-192° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.98 (t, J=5.8 Hz 1H), 8.49 (m, 1H), 8.43-8.39 (m, 1H), 7.98 (s, 1H), 7.68-7.65 (m, 1H), 7.34-7.30 (m, 1H), 4.40 (d, J=5.8 Hz, 2H), 4.01-3.95 (m, 2H), 3.65-3.59 (m, 2H), 3.07 (d, J=7.1 Hz, 2H), 1.01-0.85 (m, 1H), 0.53-0.39 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 161.5, 161.3, 155.1, 149.3, 148.6, 140.1, 135.7, 135.3, 127.1, 123.9, 48.2, 42.5, 42.3, 9.31, 3.63; MS (ES+) m/z 358.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:18])([F:17])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[BH4-].[Na+].O.C(=O)([O-])[O-].[Na+].[Na+].[C:30](O)(=O)[CH3:31]>>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:17])([F:18])[CH:11]([F:16])[C:12]([F:14])([F:15])[F:13])[NH:5][CH2:30][CH3:31]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCNc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Temperature: 25 °C

Procedure:
To a solution of 0.28 g 3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy) aniline in 8 mL glacial acetic acid at room temperature under an atmosphere of nitrogen was slowly added 0.31 g sodium borohydride. The addition was carried out over a 1.5 hour period through a solid addition funnel between 25-34° C. with ice water cooling. The mixture was stirred at room temperature over night. Then the reaction mixture was added to 80 mL water and the pH was carefully adjusted to 7 by adding solid sodium carbonate. The product was extracted with 80 mL ethyl acetate. The organic layer was separated, washed with brine solution, separated, and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under vacuum to give a brown oil 0.29 g. The product was chromatographed using a Michel-Miller low pressure silica gel column eluted with 9:1 heptane/ethyl acetate. Like fractions were pooled and concentrated under vacuum to give 0.19 g of a tan oil. 1H-NMR d 1.28 (t, 3H), 3.17 (q, 4H), 3.95 (bs, 1H), 4.94-5.21 (md, 1H), 6.59 (d, 1H). Anal. calcd C11H8Cl2F7N: C, 35.31; H, 2.16; N, 3.74. Found: C, 35.32; H, 2.14; N, 3.74.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:39]([NH:41][C@H:42]([C:48]([NH:50][C@H:51]([C:57]([NH:59][C@H:60]([C:63]([NH:65][C@H:66]([C:72]([NH:74][C@H:75]([C:79]([N:81]1[CH2:118][CH2:117][CH2:116][C@H:82]1[C:83]([NH:85][C@H:86]([C:91]([NH:93][C@H:94]([C:98]([NH:100][C@H:101]([C:105]([NH:107][C@H:108]([C:113]([OH:115])=[O:114])[CH2:109][CH:110]([CH3:112])[CH3:111])=[O:106])[C@@H:102]([CH3:104])[OH:103])=[O:99])[CH:95]([CH3:97])[CH3:96])=[O:92])[CH2:87][CH:88]([CH3:90])[CH3:89])=[O:84])=[O:80])[C@@H:76]([CH3:78])[OH:77])=[O:73])[CH2:67][CH2:68][C:69](=[O:71])[NH2:70])=[O:64])[CH2:61][OH:62])=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[OH:46])=[O:40])[CH2:37][OH:38])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].[OH:119]O>C(O)(=O)C.[Pt]>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:39]([NH:41][C@H:42]([C:48]([NH:50][C@H:51]([C:57]([NH:59][C@H:60]([C:63]([NH:65][C@H:66]([C:72]([NH:74][C@H:75]([C:79]([N:81]1[CH2:118][CH2:117][CH2:116][C@H:82]1[C:83]([NH:85][C@H:86]([C:91]([NH:93][C@H:94]([C:98]([NH:100][C@H:101]([C:105]([NH:107][C@H:108]([C:113]([OH:115])=[O:114])[CH2:109][CH:110]([CH3:112])[CH3:111])=[O:106])[C@@H:102]([CH3:104])[OH:103])=[O:99])[CH:95]([CH3:96])[CH3:97])=[O:92])[CH2:87][CH:88]([CH3:90])[CH3:89])=[O:84])=[O:80])[C@@H:76]([CH3:78])[OH:77])=[O:73])[CH2:67][CH2:68][C:69](=[O:71])[NH2:70])=[O:64])[CH2:61][OH:62])=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])=[O:49])[CH2:43][CH2:44][C:45](=[O:46])[OH:47])=[O:40])[CH2:37][OH:38])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:27])[CH2:22][CH2:23][S:24]([CH3:25])=[O:119])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4]
Reactant: OO
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN)C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)[C@@H](C)O)C(C)C)[C@@H](C)O)[C@@H](C)O
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CCS(C)=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 mg of the peptide obtained in Example I is dissolved in 20 ml glacial acetic acid, after which 0.08 ml 30% hydrogen peroxide is added. The mixture is stirred for about 1 hour at room temperature, after which 300 mg platinum Black in glacial acetic acid is added to the mixture and the whole is stirred for about a further 15 minutes.
Reaction SMILES: [C:1]1([C:7]2([CH2:17][CH:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH3:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C(Cl)[Cl:41]>>[ClH:41].[C:33]([N:9]1[CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([CH2:17][CH:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH3:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:35])[CH3:34]
Reactant: ClCCl
Reactant: CC(CC1(c2ccccc2)CNCc2ccccc21)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1Cc2ccccc2C(CC(C)N2CCN(c3ccc(F)cc3)CC2)(c2ccccc2)C1
Product: Cl

Procedure:
To a solution of 4-phenyl-4-{2-[4-(p-fluorophenyl)piperazin-1-yl]propyl}-1,2,3,4-tetrahydroisoquinoline (1.2 g) in methylene chloride (30 ml) was added acetic anhydride (0.33 ml) with ice-cooling and stirring and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness and the residue was purified by silica gel column chromatography (ethyl acetate-methanol=10:1) and treated with hydrochloric acid to provide the title compound (1.2 g) as white crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][OH:20])[CH:14]=[CH:15][CH:16]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][O:20][S:30]([CH3:29])(=[O:32])=[O:31])[CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(OC(c2cccc(SCCO)c2)c2nc3ccccc3s2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(OC(c2cccc(SCCOS(C)(=O)=O)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{3-[benzothiazol-2-yl(1-methyl piperidin-4-yloxy)-methyl]phenylsulfanyl}ethanol (400 mg) in dichloromethane (5 mL) is added methanesulfonylchloride (1.25 molar equivalent) in dichloromethane (1.5 mL) and triethylamine (1.5 molar equivalent). The reaction mixture is stirred overnight at room temperature. Volatiles are removed under reduced pressure to dryness. Water is added and the aqueous phase is extracted by diethylether. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (dichloromethane/methanol from 98/2) to afford methanesulfonic acid 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl ester that will be used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[F:20][C:21]1([F:33])[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30](Cl)=[O:31])[C:23]=2[O:22]1>C1COCC1.CCOC(C)=O>[F:33][C:21]1([F:20])[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30](/[N:12]=[C:6]3\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\3[CH2:4][CH2:3][O:2][CH3:1])=[O:31])[C:23]=2[O:22]1
Reactant: O=C(Cl)c1cccc2c1OC(F)(F)O2
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.6 %

Procedure:
To the product of Example 126A (0.20 g, 1.1 mmol) in 30 mL THF was added Et3N (0.37 mL, 2.7 mmol) followed by 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (Lancaster, 0.29 g, 1.3 mmol). This mixture was stirred at ambient temperature for 17 hours then was warmed to reflux and allowed to stir for an additional 4 hours. The mixture was then cooled to ambient temperature and additional 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (73 mg, 0.33 mmol) and Et3N (0.37 mL, 2.7 mmol) were added. This mixture was warmed to reflux at which temperature it stirred for 2 hours. The mixture was then cooled to ambient temperature, diluted with 10 mL EtOAc and washed with 5 mL saturated, aqueous NH4Cl. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 50% hexanes:EtOAc) to afford the title compound (0.22 g, 0.59 mmol, 55% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.32 (s, 3H), 3.83 (t, J=5.1 Hz, 2H), 4.44 (t, J=5.1 Hz, 2H), 7.12 (d, J=4.4 Hz, 1H), 7.14 (s, 1H), 7.89 (dd, J=6.6, 2.9 Hz, 1H); MS (DCI/NH3) m/z 371 (M+H)+; Anal. calculated for C16H16F2N2O4S: C, 51.89; H, 4.35; N, 7.56. Found: C, 52.27; H, 4.24; N, 7.53.
Reaction SMILES: [C:1]1([C:7]2[C:8](O[C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[C:1]1([C:7]2[C:8](=[O:9])[N:23]=[N:24][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1C=C(c2ccccc2)C(=O)N=N1
Yield: 33.9 %

Procedure:
Phenylmaleic anhydride (20 g, 115 mmol), sodium acetate trihydrate (1875 g, 138 mmol), hydrazine monohydrate (6.68 ml, 133 mmol) and 40% aqueous acetic acid (400 ml) were heated at reflux for 15 h then allowed to cool. The reaction mixture was left to cool in the fridge for 1 h. The solid produced was filtered and washed with water and diethyl ether before drying in a vacuum oven at 40° C. to give the required product (7.26 g). 1H NMR (250 MHz, DMSO) δ 3.43 (2H, broad peak), 7.17 (1H, s), 7.44 (3H, m), 7.81 (2H, m); MS (ES+) m/e 189 [MH+].
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[N:10]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[Cl:16][C:11]1[CH:12]=[C:13]([Cl:15])[N:14]=[C:9]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: NC1CCCCC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Cl)nc(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
To a solution of cyclohexanamine (1.1 mL, 9.57 mmol) in ethyl acetate (10 mL) was added 2,4,6-trichloropyrimidine (1.0 mL, 8.70 mmol) dropwise at 0° C. followed by dropwise addition of diisopropylethylamine (1.8 mL, 10.4 mmol). The reaction was warmed to ambient temperature and stirred for 3 h. Additional cyclohexanamine (0.3 mL) and diisopropylethylamine (0.5 mL) were added. After 4 h, the mixture was diluted with ethyl acetate and washed with 20% brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting oil was purified by flash chromatography on silica gel eluting with a gradient of 92:8 to 85:15 hexane/ethyl acetate to give 0.740 g (35%) of the title compound.
Reaction SMILES: CS(C)=O.C(N(CC)CC)C.[N:12]1([CH2:24][CH2:25][OH:26])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]3[O:23][CH:22]=[CH:21][C:19]3=2)[CH:14]=[N:13]1.Cl>O>[N:12]1([CH2:24][CH:25]=[O:26])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]3[O:23][CH:22]=[CH:21][C:19]3=2)[CH:14]=[N:13]1
Reactant: OCCn1ncc2ccc3occc3c21
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCn1ncc2ccc3occc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
A dimethyl sulfoxide (15 ml) solution containing 4.20 ml of triethylamine and 4.74 g of SO3-pyridine complex was added to a dimethyl sulfoxide (15 ml) solution containing 1.80 g of 2-(1H-furo[2,3-g]indazol-1-yl)ethanol, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under a reduced pressure, and the residue was purified by a silica gel column chromatography to give 0.89 g of (1H-furo[2,3-g]indazol-1-yl)acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>ClCCl>[F:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]([CH:15]2[CH2:17][CH2:16]2)=[O:19])=[CH:7][N:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(F)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)nc1)C1CC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of 5-amino-2-fluoropyridine (6.63 g, 0.059 mol) and pyridine (5.16 g, 0.065 mol) in dichloromethane (120 ml) was stirred at room temperature. Cyclopropane carboxylic acid chloride (6.2 g, 0.059 mol) was added dropwise to the reaction mixture at such a rate to maintain the temperature at 20°-30° C. After complete addition the reaction mixture was stirred at temperature for a further one hour, then washed with 5% sodium hydroxide (100 ml), water (100 ml) and dried over anhydrous magnesium sulphate. Removal of the solvent gave a dark brown solid which was purified by column chromatography (silica eluted with dichloromethane : tetrahydrofuran=9:1) to give N-(2-fluoro-5-pyridyl)cyclopropane carboxamide (7.7 g, 72%) as an orange brown solid m.p. 116°-117° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1OC(OC1C=CC=C(C(C)(C)C)C=1)=S)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1([CH:59]=[CH:60][Sn](CCCC)(CCCC)CCCC)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1[CH:60]=[CH:59][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COCCO[C@@H]1[C@H](OC(=S)Oc2cccc(C(C)(C)C)c2)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reactant: CCCC[Sn](C=Cc1ccccc1)(CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COCCO[C@@H]1[C@H](C=Cc2ccccc2)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 40 °C
Yield: 13.6 %

Procedure:
To a solution of 5′-O-(tert-butyldiphenylsilyl)-3′-O-(3-tert-butylphenoxythiocarbonyl)-2′-O-(2-methoxyethyl)-5-methyluridine (15.0 g, 20.0 mmol) in 150 mL of benzene was added PhCH═CHSnBu3 (18.7 g, 50 mmol). The resulting solution was degassed three times with argon at rt and 45° C. After AIBN (1.0 g, 6.1 mmol) was added, the resulting solution was refluxed for 2 h. Another portion of AIBN (1.0 g, 6.1 mmol) was added after cooling to about 40° C. and refluxed for 2 h. This procedure was repeated until the starting material disappeared. The solvent was evaporated and the residue was purified by flash chromatography on a silica gel column using 10:1 and 5:1 hexanes-EtOAc as eluent to give 1.74 g of 5′-O-(tert-butyldiphenylsilyl)-3′-deoxy-2′-O-(2-methoxyethyl)-3′-(2-phenylethenyl)-5-methyluridine as a white foam.