Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=[O:25])[CH:21]=[CH:22][O:23][C:24]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[NH4+].[NH4+]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=[O:25])[CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(=O)ccoc4c3O2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(c3O2)OCCC4=O)cc1

Procedure:
0.50 g (1.28 mmole) of [(2R)-7-oxo-2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-2-yl]methyl 4-methylbenzenesulfonate in methanol was added to a round bottom flask containing 0.40 g of 10% palladium on carbon under a stream of nitrogen, ammonium carbonate was then added and the heterogeneous mixture was heated to reflux for 2.5 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuum and the residue column chromatographed on silica gel with 0.5% methanol/methylene chloride as eluant to give 0.30 g (61%) of the (R)-enantiomer of the title compound as a white foam. 1H (CDCl3) doublet 7.8 δ (2H); doublet 7.5 δ (1H); doublet 7.4 δ (2H); doublet 6.6 δ (1H); triplet 4.6 δ (2H); multiplet 4-4.5 δ (5H); triplet 2.8 δ (2H); singlet 2.5 δ (3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].FC(F)(F)C[O:24][C:25](=O)[NH:26][C:27]1[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:32]([C:30]1[CH:31]=[C:27]([NH:26][C:25]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[O:24])[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1noc2cc(Oc3ccc(F)cc3CN)ccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(C)noc3c2)cc1
Temperature: 75 °C
Yield: 77.5 %

Procedure:
5-Fluoro-2-(3-methyl-benzo[d]isoxazol-6-yloxy)-benzylamine (9v) (60 mg, 0.22 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trifluoro-ethyl ester (12v) (89 mg, 0.22 mmol) and diisopropylethylamine (0.058 mL, 0.33 mmol) were combined in DMF (2 mL) and heated at 75° C. for 3 hours. The reaction was cooled and concentrated in vacuo and purified by column chromatography (silica, 30 to 40% EtOAc/hexanes) to provide compound (10v) (90 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.02-6.88 (m, 5H), 6.15 (s, 1H), 5.99 (s, 1H), 5.28 (t, J=7.6 Hz, 1H), 4.36 (d, J=5.5 Hz, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 1.31 (s, 9H); MS (ESI+) m/z 528 (M+H) detected; HPLC (5 to 95%) 3.49 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2=[O:22])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:39]=[C:38]([O:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]([C:45]#[N:46])=[CH:36][N:35]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[C:45]([C:37]1[C:38]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:39][C:34]([NH:33][C:32]([N:7]2[C:6]3[C:11](=[CH:12][C:13]([CH2:14][N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]4=[O:22])=[C:4]([CH:3]([O:23][CH3:24])[O:2][CH3:1])[N:5]=3)[CH2:10][CH2:9][CH2:8]2)=[O:31])=[N:35][CH:36]=1)#[N:46]
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: COCCOc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 90 °C

Procedure:
A mixture of 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 1.03 g, 3.08 mmol), phenyl(5-cyano-4-(2-methoxyethoxyl)pyridin-2-yl)carbamate (intermediate 108, 2.19 g, 6.16 mmol) and DMAP (753 mg, 6.16 mmol) in DMA (15 ml) was heated at 90° C. for 3.5 h. The cooled reaction mixture was partitioned between EtOAc and, the organic layer dried over MgSO4 and evaporated. The residue was purified by reversed phase chromatography (RP 4) and the product containing fractions were partitioned between saturated aqueous NaHCO3 and EtOAc, the organic layer dried over MgSO4 and vaporated. The residue was then triturated with a mixture of DCM, Et2O and heptane to give the title compound as a white solid. (UPLC-MS 7) tR 0.80; ESI-MS 554.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:28][O:29][CH3:30])[C:9]([C:11]3[S:12][C:13]4[C:19]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=4[N:15]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:30][O:29][CH2:28][N:8]1[C:6]2=[N:7][C:2]([CH:34]3[CH2:35][NH:31][CH2:32][CH2:33]3)=[CH:3][CH:4]=[C:5]2[N:10]=[C:9]1[C:11]1[S:12][C:13]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=2[N:15]=1
Reactant: C1CCNC1
Reactant: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(Cl)nc21
Product: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(C3CCNC3)nc21
Temperature: 130 °C
Yield: 74 %

Procedure:
0.1 g 5-Chloro-3-methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridine (0.22 mmol) was dissolved in pyrrolidine (5 ml) in an autoclave and heated to 130° C. for 16 h. The residue was triturated in water whereupon a precipitate formed, which was isolated and dried in vacuo. 0.08 g 3-methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-5-pyrrolidin-4-yl-3H-imidazo[4,5-b]pyridine (74%) were obtained as a yellow solid; M.p.: 120–130° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[NH2:17][CH2:18][CH2:19][C@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:21]([OH:23])=[O:22].[BH3-]C#N.[Na+]>C1COCC1.O>[CH2:28]([O:27][C:25]([NH:24][C@@H:20]([CH2:19][CH2:18][NH:17][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1([CH3:16])[CH3:1])[C:21]([OH:23])=[O:22])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)C(C)(C)C1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a 0° C. solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (1.76 g, 7.74 mmol) and (S)-4-amino-2-(benzyloxycarbonylamino)butanoic acid (1.95 g, 7.74 mmol) in THF (20 mL) and water (3 mL) was added NaCNBH3 (0.48 g, 7.7 mmol). This mixture was stirred at 60° C. for 2 days. The reaction was then evaporated to a solid to give the crude (2S)-2-(benzyloxycarbonylamino)-4-(1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-ylamino)butanoic acid. This material was taken on directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>C1COCC1>[CH2:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:17]2[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:31]2=[O:32])[CH2:19][CH2:20]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cccc(C(NC2CCN(Cc3ccccc3)CC2)c2ccccc2N)c1
Solvent: C1CCOC1
Product: COc1cccc(C2c3ccccc3NC(=O)N2C2CCN(Cc3ccccc3)CC2)c1
Yield: 98.5 %

Procedure:
To a solution of 2.65 g (6.60 mmol) of α-(2-aminophenyl)-N-(benzylpiperidin-4-yl)-3-methoxybenzylamine in 53 ml of THF, 1.50 g (9.24 mmol) of carbonyldiimidazole were added and stirred under reflux-heating for 3 hours. After allowed to stand cool, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (1% methanol/chloroform) to give 2.8 g (6.5 mmol) of the title compound as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[Br:28]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:16]([CH2:26][Br:28])[O:15][CH2:14]2)([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(Cl)c2)CO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C(=O)Nc1cccc(Cl)c1)N1COC(CBr)=C(c2ccccc2)C1=O
Temperature: 65 °C
Yield: 8.5 %

Procedure:
A mixture of N-(3-chlorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.0 g), N-bromosuccinimide (0.45 g), azobis-isobutyronitrile (10 mg) in carbon tetrachloride was heated at 65° C. for 2 hours. A second addition of N-bromosuccinimide (0.1 g) was made and the solution heated at 65° C. for a further 2 hours. The solution was then allowed to cool and the solvent removed under reduced pressure to give a brown residue, which was purified by dry column chromatography on silica, eluting with ethyl acetate/dichloromethane to give N-(3-chlorophenyl)-2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 8, 0.1 g) as a white solid, m.p. 89.8-90.8° C.
Reaction SMILES: C1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[N:8]2)C=CC=CC=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O.CCCCCC.C(OCC)C>[C:18]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[N:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCCCCCCCBr
Reactant: C1=C(c2ccccc2)N=NC1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 202.3 %

Procedure:
Sodium hydride (588 mg of a 60% dispersion in mineral oil, 13 mmol) was washed twice with hexane and covered with dimethylformamide (DMF), (45 mL). 3,3,5-Triphenyl-3H-pyrazole (3 g, 10 mmol) was added and the mixture stirred at 110° C. under a nitrogen atmosphere for 30 minutes before being cooled to room temperature. Methyl 9-bromononanoate (2.80 g, 11 mmol) in DMF (2 mL) was added dropwise, the mixture stirred at room temperature for 2 hours and then poured onto water (100 mL). The mixture was extracted with diethyl ether (3×100 mL), the extracts washed with water (3×100 mL), dried over sodium sulfate and concentrated to give an oil. Chromatography on a column of silica gel using a mixture of hexane and diethyl ether (2:1) as eluent afforded methyl 3,4,5-triphenyl-lH-pyrazol-1-nonanoate (4.72 g, 100%) as a viscous oil. (MS(CI): m/e =467 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[Br:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>>[Br:8][C:9]1[CH:10]=[C:11]([S:15]([NH:1][C:2]([CH2:5][OH:6])([CH3:7])[CH2:3][OH:4])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(N)(CO)CO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cccc(Br)c1
Yield: 56.1 %

Procedure:
Prepared by general procedure III from 2-amino-2-methyl-1,3-propanediol (2.71 g, 25 mmol) and commercially available 3-bromobenzenesulfonyl chloride (0.72 mL, 5 mmol) to give the title compound as a white solid (0.91 g, 12%). MS (ISN) 322.1 [(M−H)−], 324.1 [(M+2−H)−].
Reaction SMILES: N.[Br:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7][C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[CH3:16]I.O>CO.CN(C=O)C>[Br:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7][C:8](=[O:13])[N:9]([CH3:16])[S:10](=[O:11])(=[O:12])[C:5]=2[CH:4]=1
Reactant: O=C1Nc2ccc(Br)cc2S(=O)(=O)N1
Reactant: CI
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CN1C(=O)Nc2ccc(Br)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Gaseous ammonia was passed through a suspension of 7-bromo-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (760 mg, 2.7 mmol) in MeOH (8 mL) until a clear solution was obtained. The solvent was then evaporated and the residue was slurried with MeOH (5 mL) and filtered. The solid obtained was dissolved in DMF (5 mL) and treated with MeI (169 μL, 2.75 mmol). The reaction mixture was stirred at rt for 18 h, poured into water (20 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc layer was dried over Na2SO4, filtered, and concentrated to obtain compound 42a. 1H-NMR (400 MHz, CD3OD) δ (ppm): 7.86 (d, J=2.0 Hz, 1H), 7.60 (dd, J=8.7, 2.1 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 3.26 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:6]([O:7][CH3:8])=[CH:5][S:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>C(Cl)Cl>[Br:1][C:2]1[C:6]([O:7][CH3:8])=[C:5]([S:10]([Cl:9])(=[O:12])=[O:11])[S:4][CH:3]=1
Reactant: COc1cscc1Br
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1c(Br)csc1S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
To a stirred solution of 3-bromo-4-methoxythiophene (550 mg, 2.85 mmol), prepared in Step C above, in 30 mL of methylene chloride at −78° C. was added dropwise along the inside wall of the flask chlorosulfonic acid (0.48 mL, 7.21 mmol). The mixture was stirred at −78° C. for 10 min, continued at room temperature for 1 h, and filtered through a 1-in silica gel pad, rinsing with methylene chloride. The filtrate was concentrated in vacuuo to give 270 mg of 4-bromo-3-methoxy-2-thiophene sulfonylchloride (33%) as a light yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OC(C)(C)C)=O)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>CN(C)C=O>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:26]1([S:32]([N:1]2[C:9]3[C:4](=[C:5]([O:10][CH2:11][C@@H:12]4[CH2:16][CH2:15][CH2:14][NH:13]4)[CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc2[nH]ncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1ncc2c(OC[C@@H]3CCCN3)cccc21
Reaction time: 0.17 h

Procedure:
A solution of t-butyl (2S)-2-[(1H-indazol-4-yloxy)methyl]pyrrolidine-1-carboxylate (0.317 g, 1.0 mmol) in dimethylformamide is treated with sodium hydride (0.08 g, 2.0 mmol, 60% in mineral oil) at room temperature, stirred for 10 min, treated with benzenesulfonyl chloride (0.264 g, 1.5 mmol), stirred for 18 h under nitrogen at room temperature, quenched with water and diluted with ether. The organic phase is separated, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a white foam residue. The residue is purified by chromatography (silica gel, EtOAc:hexanes, 15:85) to give a white solid. This solid is dissolved in trifluoroacetic acid at 0° C., stirred at room temperature for 90 min and concentrated in vacuo. The resultant residue is triturated under ether to afford the title compound as a white solid, 300 mg, mp 218-219° C., identified by NMR and mass spectral analyses.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17]>CCOCC>[N:8]1([C:6]([NH2:5])=[O:7])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: CCOCC
Product: NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 14.4 %

Procedure:
Chlorosulfonyl isocyanate (1.20 g, 8.4 mmole) was added to a mixture of 2-oxindole (0.94 g, 7.1 mmole) in ether (30 ml) and the reaction was stirred at room temperature for 20 hours. The ether was removed under vacuum and the residue was treated with water (10 ml) and 1N HCl (10 ml). Ethyl acetate (125 ml) was added and the mixture was stirred for one hour. The ethyl acetate phase was separated, washed with 1N HCl (1×50 ml), brine (2×100 ml) and dried (MgSO4). Concentration afforded 0.97 g (77%) of crude product. Recrystallization from ethanol gave 0.18 g of the title product, m.p. 177°-179° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]1[C@@H:11]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])[O:10][C@@H:9]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:8]1)(=[O:5])[CH3:4]>C(O)(C)C>[C:3]([O:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[O:10][C@@H:9]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:8]1)(=[O:5])[CH3:4]
Reactant: COC(=O)C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)CC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O

Procedure:
About 0.39 g sodium borohydride was added to a cold (ice bath) stirred, mixture of 3.17 g of 3'-O-acetyl-5'-carbomethoxymethylene-5'-deoxythymidine in 95 ml isopropanol. The mixture was stirred at 0° C. under nitrogen atmosphere for half an hour, then at room temperature for an additional four and one half hours.
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5]([CH3:33])=[C:6]([C:18]([O:20][C@@H](C)CN(C)CC2C=CC=CC=2)=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.N1C=CC=CC=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:50]([O-:52])=[O:51])C=1>ClCCl>[CH3:33][C:5]1[NH:4][C:3](=[O:2])[N:8]([C:50]([OH:52])=[O:51])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([OH:20])=[O:19]
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)O[C@@H](C)CN(C)Cc2ccccc2)=C(C)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)N(C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, (S)-1-methyl-2-[methyl(phenylmethyl)amino]ethyl ester (2.20 g, 4.87 mmol) and pyridine (2.36 ml, 29.2 mmol) in dichloromethane (20 ml) in an ice bath under argon was treated dropwise, via addition funnel, with a solution of 4-nitrophenylchloroformate (1.08 g, 5.36 mmol) in dichloromethane (20 ml). The reaction was then stirred in the ice bath for 15 minutes and evaporated. The residue was coevaporated with toluene to remove pyridine. The residue was then taken up in tetrahydrofuran (50 ml) and methanol (25 ml) and treated with 3N hydrochloric acid (5.0 ml, pH 1). After stirring at ambient temperature for 1.5 hours, the reaction was quenched by pouring into cold (ice bath) saturated sodium bicarbonate. After evaporating to near dryness, the mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated sodium chloride, dried (potassium carbonate), and evaporated to give 3,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-oxo-3,5-pyrimidinedicarboxylic acid, 5[(S)-1-methyl-2-[methyl(phenylmethyl)methyl)amino)ethyl], 3-(4-nitrophenyl)ester as a brown solid (2.38 g, 83%). TLC (10% acetone/dichloromethane) two major spots, Rf =0.25 and 0.39.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:14][SiH:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1.ClCCl.C1([Pt](Cl)(Cl)C2C=CC=C2)C=CC=C1>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH:1]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCCc1ccc(Cl)cc1
Reactant: C[SiH](C)C
Agent: Cl[Pt](Cl)(C1C=CC=C1)C1C=CC=C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCC(c1ccc(Cl)cc1)[Si](C)(C)C
Yield: 79.8 %

Procedure:
About 15.9 g (0.082 Mol) of 4-(5-hexenyl)-1-chlorobenzene were dissolved in 10 ml of toluene, 0.8 ml of a 1 percent solution of dicyclopentadienylplatinum dichloride in dichloromethane (corresponding to 100 ppm of Pt) were added, and the mixture was introduced into a 100 ml bench autoclave. About 10 g (0.147 Mol) of trimethylsilane in the condensed state were added, the autoclave was sealed, and 5 MPa of nitrogen were injected. The mixture was warmed at 70° to 80° C. for 90 minutes (8 MPa, internal stirring). The mixture was then cooled, the solvent was stripped off, and the resultant residue fractionated. About 17.6 g of 4-(1-trimethylsilylhexyl)-1-chlorobenzene, corresponding to 77.1 percent of theory, were obtained at 0.1 hPa and at a boiling range of 107° to 112° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[O:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([O:5][CH:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[C:3]([OH:20])=[O:2])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A solution of rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yl)oxy]-acetic acid methyl ester (598 mg, 1.87 mmol) in ethanol (15 mL) was treated with a solution of potassium hydroxide (262 mg, 4.68 mmol) and water (2 mL) and the mixture was allowed to stir at 25° C. After 3 h, the reaction was diluted with water (10 mL) and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH 2 with 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The reaction product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol plus 1% acetic acid) to afford rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yl)oxy]-acetic acid (544 mg, 95% yield) as a clear colorless oil: EI-HRMS m/e calcd for C13H14Cl2O4 (M+) 304.0269, found 304.0259.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](B(O)O)[CH3:13].C([O-])([O-])=O.[K+].[K+].N#N>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: CCB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 24.2 %

Procedure:
2-Bromo-4-fluoro-1-nitrobenzene (21.8 g, 100 mmol), ethyl boronic acid (7.5 g, 100 mL), K2CO3 (40 g, 300 mL), dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) (6 g) in dioxane (250 mL) and H2O (80 mL) was flushed with N2 and heated at 100° C. overnight. The reaction was diluted with EtOAc and H2O and filtered through Celite®. The organic layer was separated, concentrated and purification by flash chromatography provided the title compound (4.1 g, 24.2 mmol, 24%). 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.78, 3H), 2.92 (q, J=7.78, 2H), 7.01-7.11 (m, 2H), 7.98 (dd, J=8.53 Hz, J=5.53 Hz, 1H).