Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H-].[Na+].[CH3:25]I>O1CCCC1>[CH3:25][N:6]1[C:2]([CH3:1])=[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CI
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (85 g, 0.28 mol) in dry tetrahydrofuran (240 mL) was added to a suspension of sodium hydride (60% w/w; 17 g, 0.425 mol) in dry tetrahydrofuran (200 mL) at 0° C. over 45 min. The mixture was warmed to room temperature and stirred for 1 h before cooling back to 0 C. Methyl iodide (71 mL, 1.13 mol) was added dropwise over 30 min and the reaction mixture and then stirred at room temperature for 18 h. The mixture was quenched with ice-water (100 mL) and concentrated in vacuo to remove volatile organics. The aqueous phase was decanted off and the residual solid was extracted with dichloromethane (350 mL). The aqueous phase was extracted with dichloromethane (2×100 mL) and the combined extracts were washed successively with water (2×200 mL), brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated to afford diethyl 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylate (80 g, 90%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[C:7]([F:16])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O>>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[C:7]([F:16])[C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)cc(F)c(C(F)(F)F)c1F
Product: O=C(Cl)c1c(F)cc(F)c(C(F)(F)F)c1F
Temperature: 50 °C

Procedure:
5.8 g (0,024 mol) of 2,4,6-trifluoro-3-trifluoromethylbenzoic acid are added in portions at room temperature to 40 ml of thionyl chloride. After metering has ended, the mixture is heated at 50° C. until the evolution of gas has ceased. The excess thionyl chloride is then removed by distillation, and the crude product is reacted further directly.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[CH3:26])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (85 μL, 0.62 mmol) in methylene chloride (15 mL) was added dropwise 2-methylbenzoyl chloride (66 mg, 0.43 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3.5) as the eluent. Yield: 100 mg (80%) of the title compound as white crystals: mp 179-180° C.; [α]21D −22° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 363 (21, M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:8][C@@H:7]1[CH3:41])=[O:5])[CH3:2].[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH2:46]>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:18](=[O:20])[NH:46][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:38])([F:40])[F:39])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:8][C@@H:7]1[CH3:41])=[O:5])[CH3:2]
Reactant: CN(C)CCN
Reactant: CCOC(=O)N1c2cc(OC)c(C(=O)O)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(OC)c(C(=O)NCCN(C)C)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 1.5 h

Procedure:
A mixture of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,6-dicarboxylic acid 1-ethyl ester (Example 60) (75 mg, 1.26 mmol) and 1.5 ml SOCK was heated at reflux for 1.5 h. The cooled solution was evaporated to dryness and the residue dried under high vacuum for 30 min. The residue was diluted with 0.75 ml dichloromethane, and triethylamine (0.021 ml) and N,N-dimethyl ethylenediamine (11 mg, 1.26 mmol) were added sequentially. After 1.5 h, the reaction mixture was concentrated and the residue was chromatographed (5% MeOH-dichloromethane) to afford the desired product (72 mg (86%). MS m/z 663 (M+ +1); 1H NMR (CDCl3) δ 3.75 (s, 3H), 7.22 (s, 1H).
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cc1
Temperature: 80 °C

Procedure:
To 30 mL of 1,4-dioxane, was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (500 mg, 1.54 mmol), 4-methoxycarbonylphenylboronic acid (333 mg, 1.85 mmol), PdCl2(PPh3)2 (54 mg, 0.077 mmol), 1M Na2CO3 aqueous solution (6.2 mL, 6.2 mmol). The mixture was heated at 80° C. under N2 for 1 hour, cooled to room temperature and poured into 200 mL of water. The brown precipitates were filtered, washed with water and dried to give the crude product. Purification through silica gel column with 1-5% MeOH/CHCl3 led to methyl 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate as orange/red solid. Yield: 500 mg, 86%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][CH3:18])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)[CH:3]=1.Br[CH:21]([CH3:25])[C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][CH3:18])=[CH:14][N:13]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[C:12](=[O:19])[CH:11]=2)[CH:3]=1
Reactant: CC(Br)C(=O)O
Reactant: CCOc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Product: CCOc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
134 mg (0.37 mmol) of 4-chloro-2-(5-ethoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 89 mg (purity 86%, 60% of theory)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of [4-(Methyloxy)phenyl][4-(methylsulfonyl)phenyl]methanone (92) (0.20 g, 0.69 mmol) and aluminum chloride (0.38 g, 2.76 mmol) were refluxed in benzene (10 mL) for 2 h and then cooled to 0° C. in an ice bath. Water (10 mL) was added slowly, and the mixture was extracted with EtOAc (2×75 mL). The combined organic extract washed with water, brine, and dried over Na2SO4. Concentration of the extract gave the title compound (93) as light brown solid (0.19 g, 100%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 3.28 (s, 3H), 6.89 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 8.05 (d, J=8.2 Hz, 2H), 10.56 (s, 1H). LCMS (ES): m/z 277 (M+H)+, m/z 275 (M−H)−.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.Cl.C(OC(=O)[NH:39][CH2:40][C@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)(C)(C)C>>[NH2:39][CH2:40][C@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[CH2:29][C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=3[CH3:13])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:31])[CH:15]=2)[C:20](=[O:24])[N:19]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:18]=1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCCN1
Agent: Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC[C@@H]3CN)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (R)-1-pyrrolidine-2-ylmethyl-carbamic acid tert-butyl ester hydrochloride. The product was purified using SCX ion-exchange chromatography (eluting with methanol followed by 3N ammonia in methanol), followed by HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[S:18].[C:19]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>N1CCCCC1>[C:19]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:6]2[C:5](=[S:18])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[O:8][CH:7]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: Cc1ccc2c(c1)C(=S)CC(c1ccccc1)O2
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc(C=C2C(=S)c3cc(C)ccc3OC2c2ccccc2)cc1

Procedure:
A solid mixture of 10 g 6-methyl-thioflavanone, 13 g 4-acetylaminobenzaldehyde and 8 drops piperidine is heated at 150°-160° C. for 3 hours. After allowing to cool, the crude brown glass is crystallized from ethanol. Pure 3-(4-acetylaminobenzylidene)-6-methyl-thioflavanone is obtained as a yellow solid; m.p. 197°-198° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]([N:19]([CH:23]4[CH2:32][CH2:31][C:30]5[C:25](=[CH:26][C:27]([O:33]C)=[CH:28][CH:29]=5)[CH2:24]4)[CH2:20][CH2:21][CH3:22])=O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.B.C1COCC1.CO>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:19]([CH2:20][CH2:21][CH3:22])[CH:23]4[CH2:24][C:25]5[CH:26]=[C:27]([OH:33])[CH:28]=[CH:29][C:30]=5[CH2:31][CH2:32]4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCCN(C(=O)CN1CCN(c2ccc3[nH]ccc3c2)CC1)C1CCc2ccc(OC)cc2C1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCN1CCN(c2ccc3[nH]ccc3c2)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
To a stirring cold solution of compound 51 (220 mg, 0.492 mmol) in dry THF was added BH3.THF (211 mg, 2.46 mmol) and the reaction mixture was refluxed overnight. After cooling the reaction mixture to room temperature, 1 ml of methanol was added and the solvent was evaporated. The residue was dissolved in 15 ml of conc. HBr and refluxed for 1 h. The solvent was evaporated and the crude product was dissolved in dichloromethane (50 ml). The organic layer was washed with saturated NaHCO3 (30 ml) and dried over Na2SO4. The solvent was evaporated and the crude product was purified by flash column chromatography over silica gel using ethyl acetate/MeOH/Et3N (95:5:0.2) to afford 52 (20 mg). 1H NMR (400 MHz, CD3OD) δ 0.95 (t, 3H, J=7.6 Hz), 1.53-1.67 (m, 3H), 2.08 (d, 1H, J=9.6 Hz), 2.60-2.88 (m, 14H), 3.10-3.13 (m, 5H), 6.35 (d, 1H, J=2.8 Hz), 6.52-6.55 (m, 2H), 6.87 (d, 1H, J=8.8 Hz), 6.91-6.94 (dd, 1H, J=8.8 Hz and 2.4 Hz), 7.16-7.17 (m, 2H), 7.29 (d, 1H, J=8.8 Hz). Free base converted into oxalate salt, m.p. 179-183° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].[CH2:19]1N2CN3CN(C2)CN1C3.O.Cl>C(O)(=O)C.O>[C:10]([C:9]1[C:4]([CH2:3][NH:2][CH3:19])=[C:5]([OH:18])[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 1.25 g (4.60 mmol) of the product of Example 19 (as the hydrochloride salt) in 10 mL of acetic acid-water (11:3) was added 0.75 g (5.35 mmol) of hexamethylenetetramine. The mixture was refluxed for 3 h then treated with 6 mL of water and 3 mL of conc. hydrochloric acid. Heating was continued for 10 min at which point the reaction mixture was cooled and concentrated in vacuo to remove the acetic acid. The residue was partitioned between EtOAc and water, and the aqueous layer was separated and extracted. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[NH2:11])=[O:5])C.C(O)(=O)C.[CH:22](N)=[NH:23]>CCO>[CH2:15]([O:14][C:12]([C:9]1[C:10]2[N:11]=[CH:22][N:23]=[C:4]([OH:5])[C:6]=2[NH:7][C:8]=1[CH3:17])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1N
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)[nH]c2c(O)ncnc12

Procedure:
A reaction flask equipped with a mechanical stirrer, a reflux condenser and a nitrogen bubbler is charged with EtOH (5000 mL), 3-amino-5-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester from example A2 (565.57 g; 2.50 mol) and formamidine acetate (1041.10 g; 10.00 mol). The well-stirred reaction mixture is heated to gentle reflux for five days under an atmosphere of nitrogen.
Reaction SMILES: [NH3:1].[CH2:2]([O:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:3]1[O:5][CH2:4]1>>[OH:5][CH:3]([CH2:2][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:4][NH2:1]
Reactant: N
Reactant: Cc1ccccc1OCC1CO1
Product: Cc1ccccc1OCC(O)CN

Procedure:
As previously described, the addition of ammonia to o-cresyl glycidyl ether is carried out in an autoclave. The amine so obtained has a purity of 96% and consists of colourless crystals with a melting point of 64° C.
Reaction SMILES: [Br-:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])=[C:7]2[C:11]=1[O:10][CH:9]=[CH:8]2>ClC(Cl)(Cl)Cl>[Br:1][C:9]1[O:10][C:11]2[C:7](=[C:6]([CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])[CH:5]=[CH:4][C:3]=2[Cl:2])[CH:8]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)c2occc12
Reactant: [Br-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C(C(=O)O)c1ccc(Cl)c2oc(Br)cc12
Yield: 78.9 %

Procedure:
A solution of bromide (0.90 g, 5.7×10-3 mol) and 7-chloro-α-isopropylbenzofuran-4-acetic acid (1.44 g, 5.7×10-3 mol) in tetrachloromethane (50 cm3) was heated to reflux for 2 hr. The solvent was removed and the residue was subjected to column chromatography on silica using ethyl acetate as the eluant. The appropriate fractions were combined and the solvent was removed to give 2-bromo-7-chloro-α-isopropylbenzofuran-4-acetic acid (1.50 g, 4.5×10-3 mol, 79.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:11]#[N:12])[N:6]=1.N1C=CC=CC=1.[C:25]1([CH2:31][CH2:32][O:33][C:34](Cl)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:11](/[C:10](=[N:9]\[O:8][CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:34](=[O:35])[O:33][CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:3][CH:4]=1)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:12]
Reactant: N#C/C(=N\OCc1csc(N)n1)c1ccccc1
Reactant: O=C(Cl)OCCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#C/C(=N\OCc1csc(NC(=O)OCCc2ccccc2)n1)c1ccccc1
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a solution of (2Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)acetonitrile (1 g, 3.87 mmol, 1 eq.) in dry dichloromethane (15 ml) at room temperature was added pyridine (0.38 ml, 4.65 mmol, 1.2 eq). After stirring for 15 min at room temperature 2-phenylethylcarbonochloridate (858 mg, 4.65 mmol, 1.2 eq) was added and stirring was allowed during 5 h. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in DCM (5 mL) and 5 ml of 1N NaOH was added. The layers were separated and the organic phase was dried over MgSO4 then concentrated to give 2-phenylethyl {4-[({[(Z)-cyano(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}carbamate (1.2 g, 55% yield) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([C:27]([N:26]([CH3:30])[CH3:25])=[O:28])[OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CN(C)C(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc2c(c1)c(CN(O)C(=O)N(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 30 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 14 eq of dimethylcarbamoyl chloride and 3.5 eq of sodium acetate (added in portions). The crude product is purified by column chromatography (silica gel, 1:4/ethyl acetate:methylene chloride). Recrystallization from methylene chloride:hexane, followed by column chromatography (silica gel, ether) and recrystallization from methanol:water gives pure 1-(4-chlorobenzoyl)-N-[(dimethylamino)carbonyl]-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine (30%); mp 173°-174° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]1)([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH:35][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Yield: 94.7 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (16.9 g, 49.9 mmol), racemic trans (3-amino-cyclopentyl)-carbamic acid tert-butyl ester (10.0 g, 49.9 mmol: Prepared according to J. Org. Chem. 2004, 69(13), 4538; Tetrahedron 1997, 53(9), 3347; WO94/17090 and Org. Lett. 2000, 2, 4169) and diisopropylethylamine (12.0 mL, 69.9 mmol) in propan-2-ol (175 mL) was heated at reflux for 4 hours. After cooling, the mixture was concentrated in vacuo and the residue triturated (water) to give 23.7 g (94%) of racemic trans [3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT=4.25 min, m+H=502.3; 1H NMR (400 MHz, DMSO) δ: 8.89 (s, 1H), 8.87 (d, 1H), 8.12 (d, 2H), 7.83 (d, 1H), 7.76 (m, 1H), 7.65 (t, 2H), 7.17 (d, 1H), 7.06 (br d, 1H), 4.62 (m, 1H), 3.99 (m, 1H), 2.24 (m, 1H), 1.97 (m, 3H), 1.56 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[C:8]2[S:16][C:15](=[O:17])[N:14]([C@H:18]3[C@H:22](OS(C(F)(F)F)(=O)=O)[CH2:21][C@@H:20]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[O:19]3)[C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1)(=O)=O.[C-:42]#[N:43].[Na+].CCOC(C)=O>CN(C=O)C>[NH2:13][C:11]1[NH:12][C:7](=[O:6])[C:8]2[S:16][C:15](=[O:17])[N:14]([C@H:18]3[C@H:22]([C:42]#[N:43])[CH2:21][C@@H:20]([CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:34])[CH3:35])[O:19]3)[C:9]=2[N:10]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(=O)(=O)C(F)(F)F)[C@H](n2c(=O)sc3c(OS(=O)(=O)C(F)(F)F)nc(N)nc32)O1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](C#N)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118 %

Procedure:
To a stirred solution of [5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]-2-oxo-thiazolo[4,5-d]pyrimidin-7-yl] trifluoromethanesulfonate (compound 38g, crude, 120 mg, 0.2 mmol) in DMF (2 mL) was added sodium cyanide (100 mg, 2.3 mmol). After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 100 mg crude product of (2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-carbonitrile (compound 38h), which was used in next step without further purification. MS obsd. (ESI+) [(M+H)+]: 424.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1)[CH2:19][O:20][C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.