Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38](Br)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])[CH3:28].CN(C=O)C>C(OCC)C.[Cu]I.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>[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:33]=1)=[O:31])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
6-Chloro-3-tributylstannyl-1H-indazole (1.04 g, 2.35 mmol), copper(I) iodide (17 mg, 0.09 mmol,) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (400 mg, 0.90 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with bubbling nitrogen for 10 min, then tetrakis(triphenylphosphine)palladium (0) (52 mg, 0.045 mmol) was added and the reaction was stirred under nitrogen at 90° C. for 15 h. The reaction mixture was cooled, diluted with diethyl ether (60 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane with 0.5% ammonium hydroxide) to afford 300 mg (65%) of 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a foaming solid. MS: (M+H)+=516.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1)=[O:2].[Mn]([O-])(=O)(=O)=[O:20].[K+].OS([O-])=O.[Na+]>CC(C)=O.CC(C)=O.O.Cl>[CH2:12]([O:11][C:9]([C:6]1[N:7]([CH3:8])[C:3]([C:1]([OH:20])=[O:2])=[CH:4][CH:5]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cn1c(C=O)ccc1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1c(C(=O)O)ccc1C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Next, to a stirred solution of benzyl 5-formyl-1-methyl-1H-pyrrole-2-carboxylate (400 mg, 1.64 mmol) in acetone (25 mL) is added a solution of potassium permanganate (520 mg, 3.29 mmol) in 40 mL acetone/water (1:1) dropwise and the mixture is stirred for 3 hours. The mixture is poured into a solution of 60 mL 10% NaHSO3 in 1N HCl and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound. HPLC retention time 1.10 minutes (condition C); MS 260.3 (M+H).
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[C:1]([C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:23][CH:22]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(CC)s1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)c1cc(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)c(CC)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
To a mixture of 4-{[(5-butanoyl-2-ethylthiophen-3-yl)(cyclohexyl)methyl]amino}benzoic acid (125 mg) synthesized above, ethyl β-alaninate hydrochloride (69.6 mg), 1-hydroxybenzotriazole monohydrate (69.4 mg) and triethylamine (63 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86.8 mg), and the mixture was stirred at room temperature for 5 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (93.1 mg, 64%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:29]([C:31]1[S:35][CH:34]=[C:33]([C:36]([OH:38])=[O:37])[CH:32]=1)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([CH2:29][C:31]3[S:35][CH:34]=[C:33]([C:36]([OH:38])=[O:37])[CH:32]=3)[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Reactant: O=Cc1cc(C(=O)O)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)O)cs1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
To a solution of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile (0.1 g, 0.24 mmol) (Example 15a) in 1,2-DCE (4 mL) were sequentially added 5-Formyl-3-thiophenecarboxylic acid (0.045 g, 0.29 mmol) and sodium sulfate (150 mgs) under a nitrogen atmosphere at room temperature. The contents were stirred at room temperature for twenty hours and sodium triacetoxyborohydride (0.075 g, 0.336 mmol) was added. The reaction was allowed to continue at room temperature for six hours and quenched by the addition of water (15 m]L). DCM (15 mL) was added, and sulfurdioxide gas was bubbled through the reaction mixture for ten minutes and the contents transferred into a separating funnel. The organic layer was separated, washed with brine (2×20 μL), dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography using DCM and MeOH to yield 0.1 g of the titled compound. Retention time: 3.09 min. YMC S5 Combiscreen 4.6×50 mm (4 minute gradient). Solvent A=10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B=90% MeOH, 10% water and 0.2% phosphoric acid.
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[OH:34][CH:35]1[C@H:40]2[CH2:41][NH:42][CH2:43][C@@H:36]1[CH2:37][N:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:42]5[CH2:41][C@H:40]6[CH:35]([OH:34])[C@H:36]([CH2:37][N:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]6)[CH2:43]5)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@@H](C1)C2O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Agent: [Cl-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5CN(C(=O)OC(C)(C)C)C[C@@H](C4)C5O)cn3)nc2n1C1CCCCCC1
Yield: 83 %

Procedure:
Following general amide formation method 1, 6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid with 5 equiv LiCl was combined with (1R,5S)-tert-butyl 9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate which gave (1R,5S)-tert-butyl 7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (170 mg) in 83% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (s, 1H), 8.67 (d, J=8.59 Hz, 1H), 8.42 (s, 1H), 8.31 (br s, 1H), 7.92 (d, J=8.08 Hz, 1H), 6.46 (s, 1H), 4.74-3.40 (m, 7H), 3.22-2.94 (m, 7H), 2.65 (m, 2H), 2.16-1.54 (m, 13H), 1.49 (s, 9H); LCMS m/z 647.1 (M+H)+.
Reaction SMILES: CS[C:3](=[N:18][CH2:19][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[NH:11][CH:12]2[CH2:15][S:14][CH2:13]2)=[C:6]([CH3:17])[CH:5]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([Cl:37])[CH:26]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2([C:33]([F:36])([F:34])[F:35])[CH2:19][N:18]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([C:10]([NH:11][CH:12]4[CH2:15][S:14][CH2:13]4)=[O:16])=[C:6]([CH3:17])[CH:5]=3)[CH2:32]2)[CH:28]=[C:27]([Cl:37])[CH:26]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(C(=O)NC2CSC2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of 3-methyl-4-(thietan-3-ylcarbamoyl)-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (Example I19) (16 mg) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (see WO 2007/125984) (12 mg) in THF (2 ml) was added at −5° C. tetrabutylammonium fluoride trihydrate (TBAF) (0.41 g) dissolved in THF (1.5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:2) to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-N-thietan-3-yl-benzamide (20 mg). 1H-NMR (400 MHz, CDCl3): 7.75-7.25 (m, 6H), 6.30 (s, 1H), 5.45 (m, 1H), 4.90 (d, 1H), 4.45 (d, 1H), 3.82 (d, 1H), 3.55-3.38 (m, 5H), 2.48 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:33]=[C:32]([F:34])[C:5]([CH2:6][S:7][C:8]2[N:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[CH:17]=3)([CH3:15])[CH3:14])=[CH:11][N:12]=2)=[C:4]([F:35])[CH:3]=1.[CH2:36]([OH:39])[C:37]#[CH:38].N1CCCC1>CN(C=O)C.[Cu]I.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]>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]([C:10]2[N:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:8]([S:7][CH2:6][C:5]3[C:32]([F:34])=[CH:33][C:2]([C:38]#[C:37][CH2:36][OH:39])=[CH:3][C:4]=3[F:35])=[N:12][CH:11]=2)([CH3:15])[CH3:14])=[CH:17][C:18]=1[O:23][CH3:24]
Reactant: C#CCO
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(Br)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C#CCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 80 °C
Yield: 94.9 %

Procedure:
A mixture of 2-(4-bromo-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (0.79 g, 1.35 mmol), propargyl alcohol (122 μL, 2.03 mmol), pyrrolidine (169 μL, 2.03 mmol), CuI (26 mg, 0.13 mmol) and PdCl2(dppf)2 (50 mg, 0.07 mmol) in DMF (6.80 mL) was purged with argon and then heated to 80° C. for 3 h. The reaction mixture was filtered through Celite™ to remove solids. The filter agent was rinsed with EtOAc (3×75 mL). The filtrate was washed with water and brine, dried over anhyd Na2SO4, concentrated and purified by flash chromatography (80% EtOAc/Hex) to give the title compound (714 mg, 94%) as a yellow solid. MS (EI) m/z 557 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19]CC3C=CC=CC=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCc3ccccc3)cc2C(O)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C(O)C1

Procedure:
6.0 g (17 mmol) 6-Benzyloxy-4-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XL) in 80 mL THF are hydrogenated (3 bar, r.t.) using 200 mg Pd/C (10%). The reaction mixture is filtered and the solvent is removed in vacuo.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:39]([F:42])([F:41])[F:40])=[CH:14][C:15]=2[CH2:17][O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH:10]=[CH:9]1>O1CCCC1>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:39]([F:41])([F:42])[F:40])=[CH:14][C:15]=2[CH2:17][O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[CH:10]=[CH:9]1
Reactant: Cn1ccc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3ccn(C)c23)(c2ccccc2)CC1
Yield: 90.8 %

Procedure:
Lithium aluminum hydride (1M in tetrahydrofuran, 1.07 ml, 1.07 mmol) was added to a solution of tert-butyl 4-(((1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (60 mg, 0.119 mmol) in tetrahydrofuran (5 ml). The reaction was heated at reflux for 3 h. The reaction was quenched by sequential dropwise addition of water (0.2 mL), 1N sodium hydroxide (0.6 mL), and more water (0.2 mL). The mixture was filtered and the filtrate evaporated. The residue was purified by chromatography on silica gel with a gradient from 5% to 10% 2M ammonia in methanol/dichloromethane. The product 1-methyl-7-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indole (45 mg, 0.108 mmol, 91% yield) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.82 (s, 1H), 7.22-7.36 (m, 6H), 6.93 (s, 1H), 6.49 (s, 1H), 4.65 (s, 2H), 3.63 (s, 3H), 3.42 (s, 2H), 2.53 (m, 2H), 2.20 (s, 3H), 2.13-2.25 (m, 4H), 1.94 (m, 2H); Mass spec. (MH)+: 417.13.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH3:23])([CH3:22])[C:16](=[O:21])[N:17]2[CH3:20])=[CH:13][CH:12]=1>>[CH3:20][N:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([NH:10][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH:19]=2)[C:15]([CH3:22])([CH3:23])[C:16]1=[O:21]
Reactant: O=C(O)c1cccnc1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)cc21

Procedure:
Prepared in analogy to example 1b from nicotinic acid and 6-amino-1,3,3-trimethylindolin-2-one (W. von der Saal et al., J. Med. Chem. 1989, 32(7), 1481-1491). The title compound was obtained as light yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])C.[CH3:15][CH:16]([NH:18][CH2:19][CH2:20][OH:21])[CH3:17].C1(C)C=CC=CC=1>CCOCC>[CH3:15][CH:16]([N:18]([CH2:19][CH2:20][OH:21])[C:4]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:17]
Reactant: CCOC(=O)c1noc2ccccc12
Reactant: CC(C)NCCO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)N(CCO)C(=O)c1noc2ccccc12
Temperature: 140 °C
Yield: 81.6 %

Procedure:
A mixture of ethyl-1,2-benzisoxazole-3-carboxylate (10.0 g), 2-(1-methylethylamino)ethanol (16.1 g) and toluene (80 ml) was heated to 140° C. in a bomb for 4 hrs. The solution was diluted with ether (50 ml), washed with 5% sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 60% ethyl acetate in hexanes to give 10.6 g (81.4%) of product. Recrystallization from dichloromethane/hexanes afforded the analytical sample, mp 92°-94° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccc(F)cc1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4F)c3)cnc2c1F
Yield: 2 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2,4-difluorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2,2′,4′-trifluorobiphenyl-5-yl)-imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (3 mg, 2%): δH (400 MHz, d6-DMSO) 1.56 (6H, s), 7.18-7.23 (2H, m), 7.34 (1H, t, J 8), 7.51 (1H, t, J 9), 7.61-7.69 (2H, m), 7.73-7.77 (2H, m), 8.36 (1H, dd, J 7 and 3); m/z (ES+) 401 [MH+].
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:21]([CH:22]3[CH2:24][CH2:23]3)[CH:20]=[N:19][N:18]=2)[CH:12]=1)C1C=CC=CC=1>Br>[CH:22]1([N:21]2[CH:20]=[N:19][N:18]=[C:17]2[C:13]2[CH:12]=[C:11]([NH2:10])[CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23]1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)OCc1ccccc1
Agent: Br
Product: Nc1cccc(-c2nncn2C2CC2)c1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
[3-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-phenyl]-carbamic acid benzyl ester (60 mg, 0.17 mmol) was dissolved in HBr solution (1 mL, 33% in acetic acid) and the reaction mixture was stirred overnight. The solvent was removed and the residue was neutralized with saturated sodium bicarbonate solution before being poured into brine. The aqueous phase was extracted 5 times with ethyl acetate. The organic phase was dried with sodium sulfate and the solvent was removed to obtain 3-(4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-phenylamine as an off-white powder (30 mg, 88%). 201.1 (M+1). 1H NMR of HBr salt (DMSO) d 9.24 (s, 1H), 7.50-7.63 (m, 3H), 6.6-8.0 (br, 4H+H2O), 3.65 ppm (m, 1H), 1.05 (m, 4H).
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC.C(=O)(O)[O-].[Na+]>CO>[CH3:17][O:16][CH:11]([O:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(C=O)c1
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C(OC)OC)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
m-Anisaldehyde (204.3 g, 1.5 mol) was placed in a 1 liter flask under an argon atmosphere. Trimethyl orthoformate (191 g, 1.8 mol) was added quickly, followed by 150 ml anhydrous methanol. Amberlyst XN-1010 resin (2.1 g, Aldrich Chemical Co.), which had been previously boiled with methanol was added. The mixture was stirred at room temperature for 22 hours with the exclusion of moisture. Sodium bicarbonate (1.5 g) was added with stirring. After 20 minutes the mixture was filtered under vacuum into a 2 liter flask which was placed on the rotory evaporator with the water bath temperature at 40° C. Over 30 minutes the bath was heated to 80° to produce a clear, colorless oil. With magnetic stirring, the oil was pumped at 65° under vacuum (2 mm Hg) for 30 minutes. The resulting product weighted 272.5 g (99.8%). I.R. (near, cm-1): 2935, 2824, 1598, 1584, 1350, 1258, 1100, 1050, 984, 772. 1HNMR (400 MHz, CDCl3) δ 3.33 (6H, s, OCH3); 3.81 (3H, s, ArOCH3); 5.35 (1H, s, ArCH(OCH3)2 ; 6.87 (1H, br d, 8.1 Hz); 7.00-7.03 (2H, m); 7.27 (1H, t, 8.1 Hz). These data indicated that the product was pure enough for use in the next step and were consistent with the following structure: ##STR27##
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:12])[C:8]=1[C:9]([OH:11])=[O:10].O>C(O)(=O)C>[Br:1][C:6]1[S:5][C:4]([CH3:3])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[CH3:12]
Reactant: Cc1csc(C)c1C(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(Br)c(C)c1C(=O)O
Temperature: 10 °C
Yield: 88.3 %

Procedure:
A solution of bromine (0.73 mL, 2.25 g, 14 mmol) in glacial acetic acid (8 mL) was added to a solution of 2,4-dimethylthiophene-3-carboxylic acid (2.1 g, 13 mmol) in glacial acetic acid (24 mL) at 6° C. Upon completion, the reaction was stirred at 10° C. for an hour, diluted with glacial acetic acid (30 mL), stirred for 14 hours at room temperature, poured into water (400 mL) and extracted with ether (3×40 mL). The combined ethereal extracts were extracted with dilute sodium hydroxide (0.2 N, 3×30 mL). The combined basic extracts were cooled in an ice bath and then acidified to pH 3 using concentrated hydrochloric acid. Precipitated solids were extracted with ether (3×40 mL). Pooled organic extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane to give product as an amorphous white solid (2.7 g, 85%): mp 183–184° C.; 1H NMR (CDCl3) δ 2.67 (s, 3H), 2.38 (s, 3H); EI/MS 235 m/e (M+); IR (liq film) 1674 cm−1; Calcd. for C7H7BrO2S: C, 35.8; H, 3.00; S, 13.6; Found: C, 35.8; H, 2.99; N, 13.5.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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]>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([C:24]3[CH:25]=[C:20]([CH3:19])[CH:21]=[CH:22][CH:23]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (540 mg, 2.0 mmol, Preparation 2), 3-methyl-phenylboronic acid (78) (299.2 mg, 2.2 mmol), K3PO4 (818 mg, 4.0 mmol), in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl2 (73.2 mg, 0.1 mmol) then the reaction mixture was stirred at 90° C. under nitrogen atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with EtOAc (50 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give 3-(3-m-tolyl-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (30) (597 mg, 1.84 mmol, yield 91.85%).