Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:15][NH2:16]>>[NH:15]([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH2:16]
Reactant: NN
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)NN

Procedure:
To a stirred solution of methyl (tert-butyloxycarbonyl)glycinate (8.54 g, 45.1 mmol) was added hydrazine hydrate (4.4 mL, 90.5 mmol) and the reaction was heated under reflux for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (100 mL) and water (100 mL). The phases were separated, the aqueous phase evaporated in vacuo to low volume and extracted with 5% methanol/dichloromethane (2×100 mL) The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give the product as a white crystalline solid, 5.27 g (62%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[S:30][C:31]=2[CH3:37])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1sc(-c2ccc(F)cc2)nc1CCO
Product: Cc1sc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
Intermediate 48 was prepared from 224 mg of N-(Boc)-L-Tyrosine methyl ester and 180 mg of Intermediate 11 to yield 149 mg (51% overall yield) of the title compound as a solid: 1H NMR (DMSO-d6, 400 MHz) δ7.82 (dd, 2H, J=8.6, 5.5), 7.23 (t, 2H, J=8.7), 7.08 (d, 2H, J=8.4), 6.8 (d, 2H, J=8.5), 4.56 (br s, 1H), 4.19 (t, 2H, J=6.5), 3.56 (m, 1H), 3.03 (t, 2H, J=6.6), 2.95 (m, 1H), 2.79 (dd, 1H, J=14.5, 7.5), 2.37 (s, 3H); low resolution MS (ES+)m/e 400.9 (MH+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[CH3:34]>>[CH3:34][C:33]1[CH:32]=[CH:31][C:30]([S:35](=[O:37])(=[O:36])[NH2:38])=[CH:29][C:28]=1[NH:27][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:25])[F:26])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(S(N)(=O)=O)cc1N
Product: Cc1ccc(S(N)(=O)=O)cc1NC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-4-methyl-benzenesulfonamide [CAS-No. 6274-28-8; commercially available] according to general procedure II. Yellow solid. MS (ISP) 542.1 [(M−H−]; mp 310° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCCCCC(=O)C=Cc1ccc(C)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)C=Cc1ccc(C)o1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
IX (1.65 g, 0.008 mole) was dissolved in absolute ethanol (200 ml), and the solution was cooled to 0°C. Sodium tetrahydroborate (0.70 g, 0.0185 mole) was added in one portion with stirring. The turbid solution was stirred at 0°-5°C for 15 minutes and then at room temperature for 20 hours. The solution was concentrated to 1/4 of the volume by distillation from a water bath (40°C) under reduced pressure (50 mm Hg). The residual solution was cooled to 10°C, and then cold water (800 ml) and N sodium hydroxide (25 ml) were added successively with stirring. The stirring was continued for 15 minutes at room temperature and then the pH of the emulsion was adjusted to 7.8 by addition of 3N acetic acid. The reaction mixture was extracted with two 150-ml portions of ether. The combined organic extracts were washed with water (100 ml) and dried over magnesium sulfate. The ethereal solution was evaporated to dryness from a water bath (60°C) under reduced pressure, at last under 15 mm Hg. The residual oil (1.67 g) was purified by distillation under nitrogen. 1.13 g (68%) of X were hereby obtained as a yellow liquid, b0.2 97°-99°C, nD20 1.5166.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]3[O:18][C:17](=[O:19])[N:16]([C:20]4[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=4)[CH2:15]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]3[O:18][C:17](=[O:19])[N:16]([C:20]4[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=4)[CH2:15]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N2C[C@H](CN3CCC(Cc4ccc(F)cc4)CC3)OC2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1O[C@@H](CN2CCC(Cc3ccc(F)cc3)CC2)CN1c1ccc(O)cc1
Reaction time: 1 h

Procedure:
A solution of 1 g of (5S)-(−)-5-[4-(4-fluorobenzyl)-1-piperidinylmethyl]-3-(4-methoxyphenyl)-oxazolidin-2-one [obtainable by reaction of (5R)-(−)-5-(methanesulfonyloxymethyl)-3-p-methoxyphenyloxazolidin-2-one with 4- (4-fluorobenzyl)piperidine hydrochloride] in 25ml of dichloromethane is mixed with equimolar amounts of boron tribromide and stirred for 1 hour. Usual work-up gives (5S)-(−)-5-[4-(4-fluorobenzyl)-1-piperidinylmethyl]-3-(4-hydroxyphenyl)-oxazolidin-2-one,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][O:38][CH3:39])[N:31]=[CH:30][N:29]=[C:28]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][N:29]=3)[CH:42]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COc1cc(NC(=O)Oc2ccccc2)ccc1C(F)(F)F
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(OC)c4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react with phenyl 3-methoxy-4-(trifluoromethyl)phenylcarbamate described in Example 190B (140 mg, 0.45 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (103 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with dichloromethane to give 52 mg. 1H (DMSO-d6) 9.30 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 7.60 (m, 2H), 7.50 (s, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.00 (m, 2H), 4.35 (m, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 3.70 (m, 2H), 3.40 (m, 3H). LCMS (ESI) m/z 559 (M+H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])/[CH:9]=2)=[N:5][N:4]=[N:3]1.[Cl:35][C:36]1[S:40][C:39]([S:41](/[N:44]=[C:45]2\[CH:46]=[C:47](Cl)[C:48](=[O:55])[C:49]3[C:54]\2=[CH:53][CH:52]=[CH:51][CH:50]=3)(=[O:43])=[O:42])=[CH:38][CH:37]=1.SC1N=CNN=1>>[NH:4]1[CH:1]=[N:2][C:6]([S:7][C:47]2[C:48](=[O:55])[C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)/[C:45](=[N:44]/[S:41]([C:39]3[S:40][C:36]([Cl:35])=[CH:37][CH:38]=3)(=[O:43])=[O:42])/[CH:46]=2)=[N:5]1.[CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:21])=[O:22])/[CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)s2)c2ccccc21
Agent: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Agent: Sc1nc[nH]n1
Product: O=C1C(Sc2nc[nH]n2)=C/C(=N\S(=O)(=O)c2ccc(Cl)s2)c2ccccc21

Procedure:
(E)-N-(3-(1H-1,2,4-triazol-3-ylthio)-4-oxonaphthalen-1(4H)-ylidene)-5-chlorothiophene-2-sulfonamide (13ah) was prepared according to the procedure for 13x except using 12d and 3-mercapto-1,2,4-triazole, affording 69.2 mg (79.2%) title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH3:21])[CH2:2][CH2:3][CH3:4].[H][H]>CO.[Pd]>[CH2:1]([O:5][C:6]1[C:7]([CH3:21])=[CH:8][C:9]([OH:13])=[C:10]([CH3:12])[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C)c(OCc2ccccc2)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCOc1cc(C)c(O)cc1C

Procedure:
A solution of 11.2 g (39.5 mmol) of 1 butoxy-2,5-dimethyl-4-(phenylmethoxy)benzene (Example L) in 100 mL of methanol containing 1 g of 20% palladium on carbon is shaken under three atmospheres of hydrogen for 1 hour. The catalyst is removed and the solvent evaporated in vacuo to afford 7.6 g of the title compound; mp 43°-45° C.
Reaction SMILES: C([O:8][C:9](=[O:25])[CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C1C=CC=CC=1>C(O)C>[C:18]([N:11]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:10][C:9]([OH:25])=[O:8])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N(CC(=O)OCc1ccccc1)C1CCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.4 %

Procedure:
Boc-N-(cyclohexyl)glycine benzyl ester (14.0 g, 40 mmol) was dissolved in 240 mL anhydrous ethanol, flushed with dry nitrogen and combined carefully under inert atmosphere with 1.5 g of 10% palladium on carbon. Using a Parr apparatus the nitrogen atmosphere was replaced with hydrogen (43 P.S.I.) and the mixture was shaken over 24 hours at room temperature. The mixture was purged with nitrogen and the catalyst and solids were removed by filtration through a pad of celite. The filtrate was concentrated by rotary evaporation and the residue was taken up in 300 mL of ethyl acetate. The ethyl acetate layer was extracted with 150 mL of 1N sodium hydroxide solution. The basic solution was acidified in an ice bath to pH 3 with 1N hydrochloric acid solution. The acid solution was extracted with ethyl acetate (3×100 mL). This solution was washed with saturated sodium chloride solution and concentrated in vacuo to a colorless oil which was further dried under high vacuum. The resulting glass/solid was triturated with hexane, which after filtration and drying provided the title compound (8.89 g) as a colorless powder. M.P. 103-104 C (uncorr.) Anal. (C13H23NO4) C, H, N; C: calcd., 60.68; found, 60.77 H; calcd., 9.01; found, 9.20. N: calcd., 5.44; found, 5.44.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][CH:25]4[CH2:27][O:26]4)[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[O:32][CH2:33][CH2:34][NH2:35]>>[C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][N:35]([CH2:17][C:16]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:34][CH2:33][O:32][C:31]4[CH:36]=[CH:37][CH:38]=[CH:39][C:30]=4[O:29][CH3:28])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccccc2c2c(OCC3CO3)cccc21
Reactant: COc1ccccc1OCCN
Product: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2c1c1ccccc1n2S(=O)(=O)c1ccccc1

Procedure:
reaction of 9-benzenesulfonyl-4-oxiranylmethoxy-9H-carbazole with benzyl-[2-(2-methoxy-phenoxy]-ethyl-amine to give a 1-(9-benzenesulfonyl-9H-carbazol-4-yloxy)-3-{benzyl-[2-(2-methoxy-phenoxy)ethyl]-amino}-propan-2-ol;
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([NH:31]C(=O)C)([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][O:11]C(=O)C)(=O)C.O.[OH-].[Li+].[Cl-].[NH4+]>CO.O>[NH2:31][C:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)([CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][OH:4]
Reactant: CCCCCCCCc1ccc(CCC(CCCOC(C)=O)(CCOC(C)=O)NC(C)=O)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCCCCCCc1ccc(CCC(N)(CCO)CCCO)cc1
Yield: 98.7 %

Procedure:
To a solution of 3-acetamido-6-acetoxy-3-[2-(4-octylphenyl)ethyl]hexyl acetate (400 mg) in methanol-water (1:1) (12 ml), lithium hydroxide monohydrate (360 mg) was added at room temperature and the mixture was refluxed under heating for 4 hours. After cooling, the mixture was neutralized with ammonium chloride and the solvent was distilled away under reduced pressure. The residue obtained was extracted with chloroform, the extract was washed with water and a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away to give the subject compound (290 mg) as a yellowish oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:16]([NH:17][C:18](=[O:26])[C:19]([N:21]([CH2:23][CH2:24]O)[CH3:22])=[O:20])[C:11]2=[CH:10][C:9]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:27](=[O:32])[C:28]([CH3:29])([CH3:31])[CH3:30])=[C:16]([N:17]3[CH2:24][CH2:23][N:21]([CH3:22])[C:19](=[O:20])[C:18]3=[O:26])[C:11]2=[CH:10][C:9]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1
Reactant: CN(CCO)C(=O)C(=O)Nc1c(C(=O)C(C)(C)C)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(c2c(C(=O)C(C)(C)C)oc3nc(-c4ccccc4Cl)c(-c4ccc(Cl)cc4)cc23)C(=O)C1=O
Temperature: 0 °C

Procedure:
A 10 mL rb flask was charged with a solution of 0.075 g (0.13 mmol) of the product of Step A and 0.052 g (0.2 mmol) triphenylphosphine in 2 mL THF. The reaction mixture was stirred at 0° C. and 39 μL of diisopropylazodicarboxylate was added dropwise. The reaction mixture was stirred an additional 1 h at room temperature, then evaporated to dryness. The residue was purified on a silica gel flash chromatographic column eluted with 0–75% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 550.0 (M+1), 551.9 (M+3); Rt=3.95 min.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[S:17][CH:18]1[CH2:23][CH2:22][N:21]([O:24][CH3:25])[CH2:20][CH2:19]1.[C:26](=[O:28])=[O:27].[Cl-].[NH4+]>O1CCCC1>[CH3:25][O:24][N:21]1[CH2:22][CH2:23][CH:18]([S:17][C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:26]([OH:28])=[O:27])[CH:8]=3)[N:12]([CH3:16])[CH:11]=2)[CH2:19][CH2:20]1
Reactant: CON1CCC(Sc2cn(C)c3ccc(Br)cc23)CC1
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CON1CCC(Sc2cn(C)c3ccc(C(=O)O)cc23)CC1
Reaction time: 1 h

Procedure:
A solution of butyllithium (7.1 ml, 2.5M in hexane) is added dropwise to 5-bromo-3-[(1-methoxypiperidin-4-yl)thio]-1-methyl-1H-indole (4.5 g, prepared in Example 59) in tetrahydrofuran (45 ml) at -78° C. After 1 hour at this temperature, a stream of CO2 is passed into the solution. After the temperature has risen to 0° C., a solution of ammonium chloride is added. The reaction mixture is concentrated, taken up with ether and washed with water. The organic phase is dried over sodium sulfate and concentrated. The 3-[(1-methoxypiperidin-4-yl)thio]-1-methyl-1H-indole-5-carboxylic acid obtained (1.4 g) is crystallized from a small volume of isopropyl ether.
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[C@@H:17]1[S:39][C@H:38]([CH2:40][O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:28]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:18]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C.[NH:50]1[CH:57]=[CH:56][C:54]([NH2:55])=[N:53][C:51]1=[O:52].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C.C(OCC)(=O)C>[C:20]([O:19][C@@H:18]1[C@H:28]([O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@@H:38]([CH2:40][O:41][C:42](=[O:49])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[S:39][C@H:17]1[N:50]1[CH:57]=[CH:56][C:54]([NH2:55])=[N:53][C:51]1=[O:52])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CC(=O)O[C@@H]1S[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ccn([C@@H]2S[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
0.44 mL of N,O-bis(trimethylsilyl)acetamide was added to a suspension of 208 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranose and 67 mg of cytosine in 2.0 mL of acetonitrile, and the obtained mixture was then stirred at 60° C. for 1 hour. Thereafter, 0.22 mL of trimethylsilyl trifluoromethanesulfonate was added to the reaction mixture, and the obtained mixture was then stirred at 80° C. for 4 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was then washed with a saturated sodium hydrogen carbonate aqueous solution. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0 to 4/1), so as to obtain 70 mg of 1-(2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranosyl)cytosine in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]4[N:24]=[C:23]([O:25][CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)[CH:22]=[CH:21][CH:20]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([O:25][CH:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)[N:24]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1Cc1cccc(OC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl 4-[(6-{[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]methyl}pyridin-2-yl)oxy]piperidine-1-carboxylate (679 mg, 1.23 mmol) was dissolved in DCM (5 ml) and TFA (1 ml) added. The reaction was stirred at rt. for 40 minutes. DCM (150 ml) and sat. Na2CO3 (aq) (150 ml) were added, the phases separated and the aqueous phase extracted with DCM (150 ml). The combined organics were dried through a phase separator and evaporated in vacuo to yield the title compound as a colorless oil. Yield: 550 mg (99%). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.63 (m, 2H), 7.55 (dd, 1H, J=8.0 Hz, J=7.4 Hz), 7.48 (s, 1H), 7.42 (m, 2H), 6.95 (d, 1H, J=7.2 Hz), 6.61 (d, 1H, J=8.2 Hz), 5.20 (s, 2H), 4.90 (m, 1H), 3.01 (m, 2H), 2.61 (m, 2H), 1.87 (m, 2H), 1.60-1.46 (m, 3H). 13C NMR (400 MHz, CDCl3) δ 163.2, 157.9, 157.1, 151.6, 151.4, 149.3, 139.8, 135.8, 131.8, 129.6, 127.8, 123.1, 121.0, 115.0, 111.3, 71.9, 50.2, 44.4, 32.6. MS (ESI+) 453.00 (M+1H+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl[C:24]([O:26][CH2:27]C(C)C)=[O:25].[N+](=C)=[N-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:24]([O:26][CH3:27])=[O:25])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: C=[N+]=[N-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)CC1CCCN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 35 (10 g, 46.46 mmol) in dry THF were added drop wise N-methyl morpholine (6.4 mL, 58.1 mmol) and isobutyl chloroformate (6.7 mL, 65.1 mmol) at −30° C. The reaction mixture was stirred at same temperature for one hour and diazomethane solution (prepared in situ) was added at −30° C. The resulting mixture was allowed to stir at rt overnight. Excess diazomethane was quenched with acetic acid (15 mL) and evaporated under reduced pressure. The residue was dissolved in ether and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The residue was dissolved in methanol (100 mL) and Ag2O (5.5 g) was added portion-wise at ice-cold conditions, and then allowed to stir at rt for 2 hours. Chloroform was added, filtered through Celite® reagent and washed with methanol. The filtrate was concentrated and the crude material was purified by chromatography on silica-gel (230-400 mesh) eluting with 1-5% of ethyl acetate-hexane to get light yellow liquid compound 36.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[C:3]1=[O:15].[CH:16]([C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1)=[O:17]>>[OH:17][CH:16]([C:10]1[S:11][C:5]2[N:4]([CH:12]([CH3:13])[CH3:14])[C:3](=[O:15])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=1)[C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: CC(C)n1c(=O)n(C)c(=O)c2ccsc21
Product: CC(C)n1c(=O)n(C)c(=O)c2cc(C(O)c3nc4ccccc4n3C)sc21

Procedure:
Prepared from 3-Methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione and 2-formyl-1-methylbenzimidazole following the method of Example 1 step d.