Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][N:36]([CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(CC(F)(F)F)C1
Yield: 47.3 %

Procedure:
The title compound was prepared as described in Example 103C using (S)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea (0.198 g, 0.38 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at 40° C. for 3 hours, which was purified by silica gel chromatography with 70-85% EtOAc/hexane as eluants to afford (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yloxy]quinazolin-4-yloxy}phenyl)urea as solid (0.108 g, 47%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.62 (s, 1H), 7.93 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.39 (t, 1H), 7.32 (m, 1H), 7.20 (s, 1H), 7.01 (d, 1H), 5.89 (s, 1H), 5.06 (m, 1H), 4.03 (s, 3H), 3.41 (m, 1H), 3.18 (q, 2H), 2.9-3.08 (m, 3H), 2.44 (m, 1H), 2.2 (m, 1H), 1.33 (s, 9H); LC-MS (ESI) m/z 601 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]3)=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[CH:28]1(O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:1].[ClH:1].[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:26])[CH2:20][CH2:19]3)=[O:16])[CH2:13][CH2:14]2)[CH2:5][CH2:4]1
Reactant: O=C(O)CN1CCC(NC(=O)N2CCN(C3CCNCC3)CC2)CC1
Reactant: OC1CCCCC1
Agent: Cl
Product: O=C(CN1CCC(NC(=O)N2CCN(C3CCNCC3)CC2)CC1)OC1CCCCC1

Procedure:
Prepared from 4-[[4-(4-piperidinyl)-piperazin-1-yl]carbonylamino]piperidinoacetic acid dihydrochloride and cyclohexanol.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1)(=O)=O>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1)[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: COc1cc(COS(C)(=O)=O)cc(OC)c1
Reactant: O=Cc1cccc2[nH]ccc12
Product: COc1cc(Cn2ccc3c(C=O)cccc32)cc(OC)c1

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 3,5-dimethoxybenzyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 1.29 g of 1-(3,5-dimethoxybenzyl)indole-4-carbaldehyde as a pale brown amorphous substance. The yield thereof was found to be 86%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)([CH3:13])[CH2:11][O:10][S:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[OH2:25]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:25])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)n1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)n2)COS1(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2-oxo-2lambda*4*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (8.83 g, 23.4 mmol) in acetonitrile (60 ml) and H2O (30.0 ml) was added RuCl3 hydrate (0.971 g, 4.68 mmol) and NaIO4 (10.01 g, 46.8 mmol). The reaction mixture was stirred at 0° C. for 2 h. H2O and DCM were added, the phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in DCM and filtered through silica gel, the filtrate was evaporated and the residue was triturated with TBME (10 ml) and n-hexane (100 ml). The resulting precipitate was filtered and washed with n-hexane to yield the title compound as a colourless crystalline solid. HPLC RtH4=1.16 min; ESIMS: 393, 395 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 7.63-7.59 (m, 1H), 7.47-7.42 (m, 2H), 4.73 (d, 1H), 4.47 (d, 1H), 2.00 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH:33]C(=O)OC(C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>>[NH2:33][C@H:3]1[C@H:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])[N:18]=2)[CH2:4]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N
Reactant: CS(=O)(=O)Cl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@@H]1NS(C)(=O)=O
Yield: 13 %

Procedure:
Method 5 was followed using (+/−)-tert-butyl (1R,2R,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate and methanesulfonyl chloride to give N-(4-((1R,3R,4R,5S)-3-amino-5-methyl-4-(methylsulfonamido)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 13% yield; N-(4-((1S,3S,4S,5R)-3-amino-5-methyl-4-(methylsulfonamido)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 14% yield. LC/MS (m/z)=534.2 (MH+), Rt=0.58 min.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C>[I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:3]=1
Reactant: COc1nccc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.150 g) in DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 55.0 mg), and the mixture was stirred at room temperature for 1 hr. Tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (0.351 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [I-:1].[CH3:2][C:3]1([CH3:48])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C@@H:13]([OH:47])[CH2:14][N:15](C(=O)OCC3C=CC=CC=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[C:29]([N+:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=3)=[CH:12][C:6]=2[CH2:5][O:4]1>C(O)C.[Pd]>[I-:1].[CH3:2][C:3]1([CH3:48])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C@@H:13]([OH:47])[CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[C:29]([N+:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=3)=[CH:12][C:6]=2[CH2:5][O:4]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCOCc3cccc([N+](C)(C)C)c3)C(=O)OCc3ccccc3)ccc2O1
Agent: [Pd]
Agent: [I-]
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc([N+](C)(C)C)c3)ccc2O1
Yield: 4.3 %

Procedure:
A solution of 3-{12-[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-13-oxo-15-phenyl-2,5,14-trioxa-12-azapentadec-1-yl}-N,N,N-trimethylbenzenaminium iodide (195 mg) in ethanol (15 ml) was hydrogenated over 10% palladium on carbon (194 mg) for 5 h. The mixture was filtered through celite and the solvent evaporated in vacuo. The residue was purified by mass directed autopreparative HPLC to give the title compound (7 mg). LCMS RT=2.13 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([F:21])=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 80 °C

Procedure:
A 50 mL Schlenk tube was charged with (3-fluorophenyl)boronic acid (140 mg, 1.0 mmol), 5-bromo-2-fluorobenzoic acid (263 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.05 mmol) and cesium carbonate (1.3 g, 4.0 mmol). Ethanol (5 mL) and toluene (5 mL) were added and the tube was sealed and heated at 80° C. for 3 h. The cooled mixture was transferred to a flask, washing with ethanol, and concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The aqueous phase was acidified with 1.0 N aqueous HCl (10 mL) and extracted with EtOAc (3×10 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo. 1H-NMR showed the desired product, 3′,4-difluoro-[1,1′-biphenyl]-3-carboxylic acid, was slightly contaminated with 2-fluorobenzoic acid. The impure product (215 mg, ˜92%) was used without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([Cl:3])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NCc1ccc(C(=O)O)c(OCc2ccccc2)c1)OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(=O)Cl)c(OCc2ccccc2)c1)OCc1ccccc1

Procedure:
Thionyl chloride (1.55 ml) and dimethylformamide (2 drops) were added to a solution of 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoic acid (7.1 mg) in dichloromethane (50 ml), and the mixture was refluxed under heating for 1.5 hours. After the reaction, the solvent was evaporated under reduced pressure to give 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (50 ml), and the solution was dropwise added to a solution of 4-aminopyridine (1.42 g) and diisopropylethylamine (5.27 ml) in acetonitrile (50 ml) under ice-cooling. The mixture was stirred at room temperature for 4 hours. After the reaction, water was added, and the mixture was extracted with chloroform. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give N-(4-pyridyl)-2-benzyloxy-4-benzyloxycarbonylaminomethylbenzamide as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:51]([O:55][C:56](=[O:77])[NH:57][C@H:58]([CH2:64][NH:65][C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67])[CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[C:51]([O:55][C:56](=[O:77])[NH:57][C@H:58]([CH2:64][NH:65][C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67])[CH2:59][CH2:60][CH2:61][CH2:62][NH:63][C:17](=[O:19])[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)CCc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-benzyloxyphenyl)propionic acid (0.19 g, 0.74 mmol) and HATU (0.29 g, 0.75 mmol) in DMF (10 mL) is added N-methylmorpholine (0.32 mL, 2.91 mmol) followed by ((S)-5-amino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (Intermediate B) (0.30 g, 0.75 mmol). The resulting mixture is stirred at RT for 16 h. The solvent is removed in vacuo and the residue is purified by column chromatography (basic alumina, 2% MeOH in DCM) to afford the title compound as yellow solid. [M-Boc+H]+ 540.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)C>O>[F:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[N:12][OH:13]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)cc1F
Yield: 76.8 %

Procedure:
In a fashion similar to that for preparation 13, 4-bromo-2-fluorobenzaldehyde (5.00 g, 24.6 mmol), hydroxylamine hydrochloride (2.05 g, 29.6 mmol), NaOH (4.92 g, 61.5 mmol; in a 50% by weight solution), ethanol (15 ml), water (15 ml), and ice (30 g) gave the title compound (4.12 g, 77%) which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10])=[O:4].C1C(=O)N([Br:18])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][Br:18])=[O:4]
Reactant: COC(=O)c1sccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sccc1CBr
Yield: 89.1 %

Procedure:
3-Methyl-thiophene-2-carboxylic acid methyl ester (1 g, 6.4 mmol) is dissolved in CCl4 (15 mL), and NBS (1.19 g, 6.7 mmol) and benzoyl peroxide (15 mg) are added. The reaction mixture is refluxed for 6 hours, then water is added and the mixture is extracted with EtOAc (3×). The organic layers are dried over MgSO4, filtered and concentrated. The crude product is purified by silica gel column chromatography eluting with 98:2 petroleum ether-EtOAc to give the title compound (1.34 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]([F:33])([F:32])[CH:17]([OH:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:31][CH:17]([C:16]([F:15])([F:32])[F:33])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Reactant: OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)C(C(=O)OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F)c1ccc(Cl)cc1
Yield: 98.3 %

Procedure:
This compound was prepared in the manner of Example II, using 5.3 g of 2-(4-chlorophenyl)-3-methylbutanoyl chloride, whose preparation is described in Agr. Biol. Chem., 38, 881 (1974), together with J. Kagaku To Seibutsu, 14, 427 (1976), 4.6 g of α-trifluoromethyl-3-phenoxybenzyl alcohol, and 1.5 g of pyridine in 50 ml of toluene. Volatiles were removed from the crude reaction product at 100° C./0.02 mm through a short path Kugelrohr distillation system to give as a residue 7.8 g of α-trifluoromethyl-3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanoate. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[C:34]([CH2:36][O:37]C3CCCCO3)[CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[C:34]([CH2:36][OH:37])[CH:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cc(COC4CCCCO4)cn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cc(CO)cn3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M58) (590 mg, 0.91 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (299 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15]C(C)(C)C)=O)[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:21](F)(F)C(O)=O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:21])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccnc2F)C1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cccnc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 3-(2-fluoropyridin-3-yl)pyrrolidine-1-carboxylate (0.25 g, 0.939 mmol) dissolved in DCM (3.1 mL) was added trifluoroacetic acid (1.05 mL, 14.1 mmol). The reaction mixture was stirred at RT for 1 h. The solvent was evaporated in vacuo and to the residue dissolved in DCM (1 mL) was added acetic anhydride (0.44 mL, 4.7 mmol) and sodium bicarbonate (0.4 g, 4.7 mmol). The reaction mixture was stirred at RT under N2 for 3 h. The reaction mixture was partitioned between 1N NaOH and DCM. The aqueous layer was back extracted with DCM (3×) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 10% MeOH in EtOAc, to provide 1-(3-(2-fluoropyridin-3-yl)pyrrolidin-1-yl)ethanone as tan oil. [M+H]=209.2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+2].[CH3:6][O:7][N:8]([CH3:17])[C:9]([C:11]1[N:12]=[C:13](Br)[S:14][CH:15]=1)=[O:10].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CN(C=O)C.CCOC(C)=O>[CH3:6][O:7][N:8]([CH3:17])[C:9]([C:11]1[N:12]=[C:13]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[S:14][CH:15]=1)=[O:10]
Reactant: CON(C)C(=O)c1csc(Br)n1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1csc(-n2ccnc2)n1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
Cesium(II)carbonate (1.36 g, 4.18 mmol) was added to a solution of 2-bromo-thiazole-4-carboxylic acid methoxy-methyl-amide (500 mg, 1.99 mmol) and imidazole (135 mg, 1.99 mmol) in DMF (5 mL) under a nitrogen atmosphere at r.t. prior to heating at 120° C. for 40 minutes in the microwave reactor. The reaction was then cooled to r.t., diluted with EtOAc (100 mL), washed with 1M NaOH (75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to a white solid. Purification was achieved using column chromatography (CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford 435 mg (92%) of 2-imidazol-1-yl-thiazole-4-carboxylic acid methoxy-methyl-amide as a white solid. [M+H]+ 239.02.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[C:7]([Cl:16])[C:8]2[N:9]([C:11]([CH:14]=O)=[CH:12][N:13]=2)[CH:10]=1)=[O:4].C(O)(=O)C.[CH3:30][NH2:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[C:7]([Cl:16])[C:8]2[N:9]([C:11]([CH2:14][NH:31][CH3:30])=[CH:12][N:13]=2)[CH:10]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1cn2c(C=O)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CNCc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)OC)cn12
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A suspension of 7-(4-bromo-2-chlorophenylamino)-8-chloro-3-formylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (58) (25 mg, 0.056 mmol), acetic acid (7 μL, 0.11 mmol), and methylamine (2.0 M solution in THF, 56 μL, 0.11 mmol) was stirred for 0.5 hours. Sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added and the solution allowed to stir overnight. The reaction mixture was concentrated to dryness and purified by flash column chromatography (dichloromethane followed by 10:1 dichloromethane/methanol) to provide the desired product as a yellow solid (12 mg, 46%). MS (APCI+) m/z 455, 457, 459 (M+; Cl, Br pattern) detected.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14]C)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:26])=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1CCc2cc(C(=O)c3ccc(C)cc3)c(O)cc21
Temperature: 25 °C

Procedure:
A solution of 20.6 g of 6-methoxy-indane-1-carboxylic acid methyl ester in a little methylene chloride is first slowly added dropwise, at 0° C. to 10° C., to a suspension of 66.8 g of finely powdered aluminium chloride in 100 ml of methylene chloride, which is being stirred under anhydrous conditions; 46.3 g of p-methylbenzoyl chloride are then added dropwise under such conditions that the reaction mixture boils gently under reflux. After completion of the addition, the mixture is heated to the boil for a further 31/2 hours. It is then allowed to cool to room temperature, poured onto 500 g of ice and extracted with twice 500 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo (finally in a high vacuum). The evaporation residue, when crystallised from cold ether-petroleum ether, gives 5-(p-toluoyl)-6-hydroxyindane-1-carboxylic acid methyl ester which after a further crystallisation from ethanol-petroleum ether, melts at 74°-76° C.