Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:33][CH2:34][C@:35]1([CH3:48])[C@H:39]([CH:40]=C)[O:38][C@H:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:36]1)[CH2:10][C:11]([O:13][C@@H:14]([C@@H:29]([CH3:32])[CH:30]=C)/[C:15](/[CH3:28])=[CH:16]/[CH2:17][O:18]CC1C=CC(OC)=CC=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[C:55](C(C)(C)C)[C:54]=1[OH:64])(C)(C)C.[C:65]1(C)C=CC=CC=1>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[Si:1]([O:8][CH:9]1[CH2:10][C:11](=[O:12])[O:13][C@H:14](/[C:15](/[CH3:28])=[CH:16]/[CH2:17][O:18][CH2:59][C:57]2[CH:58]=[CH:53][C:54]([O:64][CH3:65])=[CH:55][CH:56]=2)[C@@H:29]([CH3:32])[CH:30]=[CH:40][C@@H:39]2[O:38][C@H:37]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[O:36][C@:35]2([CH3:48])[CH2:34][CH2:33]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CCC(CC(=O)O[C@H](/C(C)=C/COCc1ccc(OC)cc1)[C@@H](C)C=C)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccccc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: COc1ccc(COC/C=C(\C)[C@H]2OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]3(C)O[C@@H](c4ccccc4)O[C@H]3/C=C/[C@@H]2C)cc1
Product: COc1ccc(COC/C=C(\C)[C@H]2OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]3(C)O[C@@H](c4ccccc4)O[C@H]3C=C[C@@H]2C)cc1
Temperature: 25 °C

Procedure:
(1S,2E)-4-[(4-methoxybenzyl)oxy]-2-methyl-1-[(1S)-1-methylprop-2-en-1-yl]but-2-en-1-yl 3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(2S,4R,5S)-4-methyl-2-phenyl-5-vinyl-1,3-dioxolan-4-yl]pentanoate (1.10 g, 1.63 mmol) and 2,6-di-tert-butyl-4-methylphenol (35.9 mg, 0.16 mmol) were dissolved in anhydrous toluene under Ar atmosphere. The reaction solution was heated to reflux for one hour. An anhydrous toluene (330 ml) solution of the second generation Hoveyda-Grubbs catalyst; [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(O-isopropoxyphenylmethylene)ruthenium (102 mg, 0.16 mmol) was added to the reaction solution. After the reaction solution was heated to reflux for five hours, it was cooled to room temperature. The reaction solution was filtered with silica gel (Fuji Silysia, commercial name Chromatorex, NH, 200-350 mesh) and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=8:1) to obtain the title compound (486.1 mg) as a white solid. This was obtained as a colorless needle by recrystallization (hexane:ethyl acetate).
Reaction SMILES: [C:1]([N:11]([C@@H:13]([CH3:21])[C:14]1[CH:19]=[CH:18][C:17](N)=[CH:16][CH:15]=1)[CH3:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N([O-])=[O:23].[Na+].C1(C)C=CC=CC=1>S(=O)(=O)(O)O.O>[C:1]([N:11]([C@@H:13]([CH3:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:23])=[CH:16][CH:15]=1)[CH3:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=N[O-]
Reactant: C[C@@H](c1ccc(N)cc1)N(C)C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](c1ccc(O)cc1)N(C)C(=O)OCc1ccccc1
Temperature: 82.5 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
The above (S)-(-)-N-carbobenzyloxy-N-methyl-4-amino-α-methylbenzylamine (6.0 gm, assume 21 mmol) was dissolved in 2N sulfuric acid (63 mL) and cooled in an ice salt bath. A solution of sodium nitrite (1.6 gm, 23 mmol) in water (25 mL) was added over 15 min at 0-5° C. and the reaction stirred for another 0.5 hr. Toluene (100 mL) was then added and the reaction was rapidly heated to 80-85° C. on a steam bath. The reaction turned very dark and after 10 min was poured onto ice and extracted with 2 portions of ether. The ether layers were each washed with brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography using 20-30% ethyl acetate/hexanes to give 3.5 gm (58%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[CH2:27][CH2:26]2)=[CH:4][C:5]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:38]1([C:41]2[O:42][CH:43]=[C:44]([C:46](O)=[O:47])[N:45]=2)[CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:46]([C:44]2[N:45]=[C:41]([CH:38]3[CH2:40][CH2:39]3)[O:42][CH:43]=2)=[O:47])=[C:3]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[CH2:29][CH2:30]2)[CH:4]=1
Reactant: COCCOc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2coc(C3CC3)n2)cc1C(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
5-Amino-2-(2-methoxy-ethoxy)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 8d (91.7 mg, 0.18 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1h (41.3 mg, 0.27 mmol, 150 mol %) and N,N-diisopropylethylamine (0.09 ml; 0.54 mmol; 300 mol %) were combined in N,N-dimethylformamide (4.0 ml) and HATU (102.6 mg, 0.27 mmol, 150 mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by reverse phase HPLC (methanol+0.1% formic acid/water) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-(2-methoxy-ethoxy)-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 8f (89.3 mg; 0.14 mmol, 77%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[NH2:34][C:35]1[CH:36]=[C:37]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])[CH:38]=[CH:39][CH:40]=1>CC(O)C>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][O:41][C:37]1[CH:36]=[C:35]([NH:34][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:29])([F:28])[F:30])[CH:22]=[CH:23][CH:24]=4)=[N:10][N:11]4[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)C(F)(F)F)c3)nn2c1
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(NC(=O)C(F)(F)F)c3)nn2c1

Procedure:
N-{3-[3-(2-chloro-4-pyrimidinyl)-6-(methyloxy)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (0.26 g, 0.58 mmol) and {2-[(3-aminophenyl)oxy]ethyl}dimethylamine dihydrochloride (0.18 g, 0.70 mmol) were combined in i-PrOH (4 mL)) and microwaved for 15 min. at 160° C. The reaction mixture was concentrated to dryness to afford N-{3-[3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}phenyl)amino]-4-pyrimidinyl}-6-(methyloxy)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide as a brown solid. The solid was dissolved in THF (5 mL) and water (0.5 mL) and treated with 1N NaOH (3 mL) and stirred for 16 h at rt after which time the reaction was incomplete by LC/MS. 1N NaOH (1 mL) was added and the mixture heated at 40° C. for 2 h and then cooled to rt and diluted with DCM and water. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the title compound as crude yellow solid (320 mg, >100%), which was used as such in Step C. ES-LC/MS m/z=496 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19](=[N:21][OH:22])[NH2:20])[CH2:5][N:6]([CH3:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][C:27]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41].C(Cl)CCl>CC#N.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]1[N:20]=[C:32]([C:30]2[CH:29]=[CH:28][C:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:31]=2)[O:22][N:21]=1)[CH2:5][N:6]([CH3:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)c(Cl)c1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: ClCCCl
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)cc3Cl)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 65 (0.298 g, 0.91 mmol) and Intermediate 3 (0.79 g, 0.70 mmol) in MeCN (2 mL) was added EDC (0.188 g, 0.98 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. under microwave irradiation for 20 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.43 (1H, d, J=1.8 Hz), 8.17 (1H, dd, J=7.9, 1.9 Hz), 7.99 (1H, d, J=7.9 Hz), 7.59 (1H, s), 7.42 (1H, dd, J=8.0, 1.6 Hz), 7.37-7.21 (4H, m), 7.13 (1H, d, J=7.4 Hz), 4.22 (2H, m), 3.75 (2H, s), 3.31 (3H, s), 3.22 (2H, s), 2.41 (3H, s), 2.08 (3H, s), 1.50 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>O>[O:22]=[C:10]1[CH2:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:1][C:23](=[O:25])[CH3:24])[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12](=[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]3=[CH:15][CH:16]=2)[NH:11]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-Amino-phenyl)-3,4-dihydro-1H-benzo[h]quinolin-2-one (0.25 g, 0.87 mmol), acetic anhydride (1 ml) and anhydrous pyridine (1 ml) was stirred at ambient temperature overnight. Water was added and the precipitate was separated by filtration. Crystallization from methanol-acetonitrile afforded the title compound (0.06 g, 0.18 mmol).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1.Cl.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[N:23]([CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:30]1=[O:36])[CH2:22]2>CN(C=O)C>[O:36]=[C:30]1[CH:29]([N:23]2[CH2:22][C:21]3[C:25](=[CH:26][CH:27]=[C:19]([CH2:18][NH:17][C:11](=[O:13])[CH2:10][C:7]4[CH:6]=[CH:5][C:4]([S:3][C:2]([F:1])([F:15])[F:14])=[CH:9][CH:8]=4)[CH:20]=3)[C:24]2=[O:28])[CH2:34][CH2:33][C:32](=[O:35])[NH:31]1
Reactant: O=C(O)Cc1ccc(SC(F)(F)F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(SC(F)(F)F)cc1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
A stirred mixture of 4-(trifluoromethylthio)phenylacetic acid (0.38 g, 1.6 mmol), and CDI-(0.27 g, 1.7 mmol) in DMF (20 ml) was heated at 40° C. for 2 hrs. Then, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.5 g, 1.6 mmol) was added to the mixture and allowed to stir for 3 h. The mixture was quenched with 4% aqueous HCl (30 mL). The precipitate was filtered and washed with H2O (50 mL) and dried in vacuo, providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-2-(4-trifluoromethylsulfanyl-phenyl)-acetamide as a white solid (0.36 g, 46% yield); mp 208-210° C.; HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 6.30 (98.81%); 1H NMR (DMSO-d6) δ 1.97-2.03 (m, 1H), 2.36-2.44 (m, 1H), 2.58-2.63 (m, 1H), 2.86-2.98 (m, 1H), 3.60 (s, 2H), 4.28 (d, 1H, J=17.4), 4.38-4.45 (m, 3H), 5.11 (dd, 1H, J=13.2, J=5.1), 7.38 (d, 1H, J=8.1), 7.44-7.46 (m, 3H), 7.65-7.68 (m, 3H), 8.75 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 41.8, 42.3, 47.0, 51.5, 120.7 (q, J=1.9), 122.1, 122.9, 127.0, 129.6 (q, J=306), 130.4, 136.1, 140.2, 142.3, 143.6, 167.9, 169.5, 171.0, 172.9; LCMS: MH=492; Anal. Calcd for C23H20F3N3O4S+0.15H2O: C, 55.90; H, 4.14; N, 8.50. Found: C, 55.56; H, 4.09; N, 8.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([I:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH2:10]([O:9][C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1cc(I)cc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-5-iodophenol (1.40 g, 4.68 mmol), benzyl bromide (0.89 g, 5.20 mmol) and anhydrous K2CO3 (1.44 g, 10.4 mmol) in anhydrous NMP (8 mL) was stirred under argon at +70° C. for 1 hour. The reaction mixture was partitioned between aqueous NH4Cl and hexanes. Aqueous layer was additionally extracted with hexanes and combined organic layers were washed with 1N NaOH, brine, dried over anhydrous MgSO4 and concentrated under reduced pressure to give 1-(benzyloxy)-3-bromo-5-iodobenzene as a colorless oil. Yield (2.14 g, 99%); 1H NMR (400 MHz, CDCl3) δ 7.45 (t, J=1.4 Hz, 1H), 7.32-7.40 (m, 5H), 7.26 (dd, J=1.4, 2.2 Hz, 1H), 7.09 (t, J=2.0 Hz, 1H), 5.00 (s, 2H).
Reaction SMILES: [CH2:1](I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=O)([O-])[O-].[K+].[K+].[CH2:15]([N:22]([CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O-:31])=[O:30])[S:23]([NH:26][CH3:27])(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C=O)C>[CH2:15]([N:22]([S:23]([NH:26][CH2:27][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])=[O:24])[C@H:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O:31][CH3:9])=[O:30])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ICc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CNS(=O)(=O)N(Cc1ccccc1)C(C(=O)[O-])C(C)C
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C(C)C)N(Cc1ccccc1)S(=O)(=O)NCCc1ccccc1
Reaction time: 96 h
Yield: 60 %

Procedure:
Benzyl iodide (280 mg, 1.28 mmol) and anhydrous potassium carbonate (440 mg, 3.2 mmol) were added to a solution of methyl 2-(R)-([benzyl-(methylaminosulfonyl)amino]-3-methylbutyrate (200 mg, 0.64 mmol), [prepared as described in Step 1 above] in DMF (3 ml) at RT. After 96 h, 1 M HCl was added and the product was extracted into ethyl acetate. The organic layer was washed with dilute sodium thiosulfate and brine and dried over MgSO4. The organics were removed in vacuo and the residue was chromatographed (PTLC, SiO2, 20% ethyl acetate/hexane) to give methyl 2-(R)-[benzyl-(benzylmethylaminosulfonyl)amino]-3methylbutyrate as a colorless oil (60%).
Reaction SMILES: [O-]C#[N:3].[NH4+:4].[C:5](=[O:8])([O-:7])[O-:6].[NH4+].[NH4+]>O>[C:5](=[O:6])([O-:8])[O-:7].[NH4+:3].[NH4+:4].[C:5](=[O:7])=[O:6].[NH3:3]
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: N
Product: O=C=O

Procedure:
The ammonium cyanate further decomposes with water to ammonium carbonate. NH4OCN+2H2O(NH4)2CO3  3. At elevated temperature ammonium carbonate finally results in the formation of carbon dioxide, ammonia and water: (NH4)2CO3→2HN3+CO2+H2O  4.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]([C:13]([F:37])([F:36])[C@@:14]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C@@H:16]([CH:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[OH:19])[OH:17])[OH:15])=[O:12].[NH3:38]>C(O)C>[NH2:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]([C:13]([F:37])([F:36])[C@@:14]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C@@H:16]([CH:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[OH:19])[OH:17])[OH:15])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(Cl)ncnc21
Reactant: N
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.5 g (0.936 mmol) of 1-(6-chloro-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose dissolved in 75 ml of absolute ethanol was saturated with anhydrous ammonia at about 0° C. The reaction flask was sealed, and the mixture was allowed to warm to room temperature. The mixture was stirred for about 72 hours at room temperature and the volatiles were evaporated under reduced pressure to provide 420 mg of 1-(6-amino-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose.
Reaction SMILES: B(F)(F)F.CCOCC.N[C:11]1[C:12]([CH3:18])=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1.N(OC(C)(C)C)=O.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>COCCOC.CCCCCC>[Cl:17][C:14]1[N:13]=[C:12]([CH3:18])[C:11]([O:29][C:26](=[O:28])[CH3:27])=[CH:16][CH:15]=1
Reactant: Cc1nc(Cl)ccc1N
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: COCCOC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)Oc1ccc(Cl)nc1C
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A mixture of boron trifluoride etherate (667 μL, 5.3 mmol) and 1,2-dimethoxyethane (2 mL) was cooled to −15° C. in an ice/acetonitrile bath and stirred at this temperature for 15 min under nitrogen. A solution of 3-amino-6-chloro-2-picoline (Oakwood Products, Inc., West Columbia, S.C., USA; 500 mg, 3.5 mmol) in 1,2-dimethoxyethane (16 mL) was added dropwise at −15° C. and the mixture was stirred at this temperature for 15 min. tert-Butyl nitrite (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 1.15 mL, 4.2 mmol) was added dropwise and the mixture was stirred at −15° C. for 15 min and then at 0° C. (ice/water bath) for 1 h. Hexane (20 mL) was added and the precipitate was filtered off and washed with hexane. This solid was added to acetic anhydride (5.00 g, 49 mmol) and the mixture was heated at 100° C. for 2 h. The acetic anhydride was evaporated under high vacuum and then 1 M aqueous sodium carbonate was added to pH 9. The mixture was stirred, and then extracted three times with dichloromethane. The solvent was evaporated and the residue purified using a silica gel column, eluting with 0-10% ethyl acetate) to give acetic acid 6-chloro-2-methyl-pyridin-3-yl ester (316 mg, 49%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2([CH2:35][C:36]([NH2:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C:29]2([CH2:35][C:36]([NH2:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[N:14]([CH3:16])[CH3:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(NC3(CC(N)=O)CCCCC3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide in an analogous manner to Example 61e. Product isolated as a pale yellow foam (0.064 g, 51%). MP: 90-107° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.92 (s, 1H), 7.87 (s, 1H), 7.17 (s, 1H), 6.65 (s, 1H), 5.43 (br s, 1H), 5.25 (s, 1H), 5.07 (br s, 1H), 3.85 (s, 3H), 3.29 (s, 2H), 3.14 (s, 3H), 2.98 (s, 3H), 2.92-2.86 (m, 6H), 2.72-2.67 (m, 4H), 2.38 (m, 2H), 1.70-1.58 (m, 5H), 1.50-1.40 (m, 3H). MS: 544.27 (MH)+.
Reaction SMILES: Cl[C:2]1C=C(C=CC=1)C(OO)=O.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH3:2])[CH:18]=1
Reactant: COc1cncc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOc1cncc(Br)c1
Reaction time: 8 h

Procedure:
As shown in step 2-iii of Scheme 2, 3-chloroperoxybenzoic acid (9.426 g, 42.06 mmol) was added to 3-bromo-5-methoxypyridine (4.25 g, 21 mmol) in 200 mL of DCM at RT. The reaction was stirred overnight and the mixture was washed with 200 mL of 2 N NaOH and 2×200 mL brine. The organic phase was dried over MgSO4, filtered and the volatiles removed under reduced pressure to provide 3-bromo-5-ethoxypyridine, 1-oxide (Compound 1002, 4.4 g): 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.9 (s, 1H), 7.0 (s, 1H), 4.12 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: P(OC)(OC)OC.CN1CCCC1=O.F[C:16]([F:36])(F)/[C:17](=[N:24]\[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][N:34]=1)[C:28]([O:30][CH3:31])=[O:29])/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[F:36][C:16]1[N:34]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]2=[N:24][C:17]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccnc(/N=C(/c2ccccc2)C(F)(F)F)c1
Agent: COP(OC)OC
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccn2c(F)c(-c3ccccc3)nc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Trimethyl phosphite (1.9 ml) was added to an N-methylpyrrolidone (10 ml) solution of the (Z)-methyl 2-((2,2,2-trifluoro-1-phenylethylidene)amino)isonicotinate (2.5 g) obtained in (Example 2.19) <Step 1>, and the obtained mixture was then stirred in microwave at 150° C. for 60 minutes. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were gathered, and the gathered organic layer was then dried over sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=90:10-50:50), so as to obtain the title compound (1.9 g) in the form of a brown solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1(Cl)[NH:10][C:9]([Cl:11])=[CH:8][S:7]1)(=[O:5])=[O:4].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:1][N:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[S:3]([C:6]1[S:7][CH:8]=[C:9]([Cl:11])[N:10]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)C1(Cl)NC(Cl)=CS1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: CN(Nc1ccccc1)S(=O)(=O)c1nc(Cl)cs1
Yield: 15 %

Procedure:
In analogy to Example 5, the N-methyl-2-N-phenylamino-4-chlorothiazole-sulphonamide was prepared by reacting N-methyl-2,4-dichlorothiazole-sulphonamide from Example 2 with aniline. Following chromatography on silica gel using methylene chloride as the eluent, the product having a melting point of 157-8° C. was obtained in 15% yield.