Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OP([O-])(O)=O.[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[N:12][CH:13]=1.Cl([O-])=[O:17].[Na+].[Na+].[Cl-]>O.CS(C)=O.CCOC(C)=O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:17])=[O:15])=[N:12][CH:13]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])(O)O
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(F)cn1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Potassium phosphate monobasic (1.4 g, 10 mmol) in water (10 mL) was added to a solution of 5-fluoropyridine-2-carbaldehyde (0.50 g, 4.0 mmol, Frontier) in DMSO (10 mL). Sodium chlorite (0.9 g, 0.008 mol) in water (10 mL) was added, and the reaction continued for 1 hour. The mixture was saturated with NaCl, then diluted with EtOAc. The organic layer was further washed with brine, dried over sodium sulfate and concentrated to afford product (370 mg, 65%). 1H NMR (400 MHz, CDCl3): δ□8.50 (d, 1H), 8.29 (ddd, 1H), 7.66 (ddd, 1H); LCMS (M+H)+: 142.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Cl[CH2:11][C:12](=O)[CH3:13].C([O-])(O)=O.[Na+]>C(O)C.O>[Cl:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]2[N:3]([CH:11]=[C:12]([CH3:13])[N:1]=2)[CH:4]=1
Reactant: CC(=O)CCl
Reactant: Nc1ncc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cn2cc(Cl)cc(Cl)c2n1

Procedure:
A mixture of 30 g 2-amino-3,5-dichloropyridine and 39 ml chloroacetone dissolved in 260 ml ethanol is heated under reflux for 64 hours. The volatile components are stripped off in vacuum and the residue suspended in 200 ml water. This is brought to pH 7-8 by means of saturated aqueous NaHCO3 -solution. A filtrate is obtained under suction and dried to constant weight in vacuo and recrystallized from cyclohexane. 17.8 g of the title compound of m.p. 156°-158° C. is obtained.
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][N:31]4[CH3:1])=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1Cl
Reactant: C1CN2CCN1CC2
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CCC(=O)O)cn(C)c4c3)no2)cc1Cl
Temperature: 90 °C
Yield: 29 %

Procedure:
DABCO (64 mg) was added to a solution of 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E81) (60 mg) in dimethyl carbonate (3 mL) and DMF (2 mL). The resulting mixture was heated at reflux for 5 days. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in iPrOH (3 mL) and water (3 mL). Sodium hydroxide (20 mg) was added to the mixture. The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E82) (18 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.60 (2H, t), 2.96 (2H, t), 3.84 (3H, s), 5.46 (1H, m), 7.32 (1H, s), 7.75 (2H, m), 8.12 (1H, s), 8.57 (1H, d), 8.94 (1H, d), 12.08 (1H, br s). MS (ES): C22H21ClN4O4 requires 440. found 441.1.
Reaction SMILES: Br[C:2]1[C:3]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:20][CH:19]=1
Reactant: COCCN(C)c1ncc(C(=O)O)cc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Product: COCCN(C)c1ncc(C(=O)O)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to example 32c, 5-bromo-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinic acid was reacted with 4-chlorophenylboronic acid to give 5-(4-chloro-phenyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinic acid as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@H:14]2[C:18]([OH:20])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@H:14]2[C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=C(CC1CCc2ccccc21)C1SCN[C@H]1C(=O)O
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C(CC1CCc2ccccc21)C1SCN[C@H]1C(=O)N1CCCC1
Yield: 44 %

Procedure:
Colorless crystals of 1-[3-(2-indanylacetyl)-D-thioprolyl]pyrrolidine were prepared in the same manner as in Example 1, except that 3-(2-indanylacetyl)-D-thioproline prepared in Reference Example 26 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 44%).
Reaction SMILES: I[C:2]1[C:7]([C:8]([NH:10][NH:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[O:9])=[C:6]([O:17][CH3:18])[N:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][O:17][C:6]1[C:7]2[C:8](=[O:9])[NH:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: COc1nccc(I)c1C(=O)NNC1CCOC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1nccc2c1c(=O)[nH]n2C1CCOC1
Yield: 32.2 %

Procedure:
A solution of 4-iodo-2-methoxy-N′-(tetrahydrofuran-3-yl)nicotinohydrazide (1.26 g), L-proline (0.080 g), potassium carbonate (0.957 g) and copper(I) iodide (0.066 g) in DMSO (25 mL) was stirred under nitrogen atmosphere at room temperature for 3 hr. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.263 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([OH:31])=[CH:23][N:22]=1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[CH:23]=[N:22]2)[CH:7]=1
Reactant: Oc1cnnc2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ncc(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C

Procedure:
To a suspension of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (216 mg) and cinnolin-4-ol (V. G. Chapoulaud et al., Tetrahedron, 2000, 56, pp. 5499-5507) (216 mg) in anhydrous ethanol (1.2 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 276 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (eluted with 40% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (26 mg), m.p. 122° C.-123° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[NH2:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:13][C:14]1[C:19]([O:20][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ncccc1OCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A mixture of 2-trifluoromethylbenzyl chloride (50 g, 0.257 mol) and 2-amino-3hydroxypyridine (25.2 g, 0.233 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product (45.3 g, 66%), m.p. 105°-110° C.
Reaction SMILES: [Cl-:1].[Cl-].[Zr+2:3].[CH:4]1([C:9]([CH:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)([CH2:11][CH2:12][CH2:13][O:14][Si](C)(C)C)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5]1>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[Zr+2:3].[CH:19]1([C:9]([CH:4]2[CH:5]=[CH:6][CH:7]=[CH:8]2)([CH2:11][CH2:12][CH2:13][OH:14])[CH3:10])[CH:20]=[CH:21][CH:22]=[CH:23]1
Reactant: CC(CCCO[Si](C)(C)C)(C1C=CC=C1)C1C=CC=C1
Agent: [Zr+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(CCCO)(C1C=CC=C1)C1C=CC=C1
Reaction time: 90 h
Yield: 18.8 %

Procedure:
XPO 2407 silica, provided by Grace, (7.2 g) was placed in a 250 ml dark-coloured Schlenk flask and washed with toluene (2×200 ml). Toluene (150 ml) and a solution of 2,2-bis(cyclopentadienyl)-5-trimethylsiloxypentane zirconium dichloride (2.0 g, 0.0045 mol) in toluene (50 ml) were added and the slurry was stirred for 90 h. After this time the mixture was filtered and the solvent removed under vacuum. Affording a yellow solid (0.16 g, 9.5% yield). 1H NMR (CDCl3): Λ6.70 (C5H4, d, 4H), 5.83 (C5H4, d, 4H), 3.85 (CH2, t, 2H), 2.32 (CH2H m, 2H), 1.88 (CH2, m, 2H), 1.80 (CH3, s, 3H, 1.45 (OH, s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](/[CH:24]=[CH:25]/[CH:26]([OH:36])[CH2:27][C:28](=[O:35])[CH2:29][C:30]([O:32][CH2:33]C)=[O:31])=[C:10]([CH:21]([CH3:23])[CH3:22])[N:11]3[N:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=23)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](/[CH:24]=[CH:25]/[CH:26]([OH:36])[CH2:27][CH:28]([OH:35])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:10]([CH:21]([CH3:23])[CH3:22])[N:11]3[N:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=23)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)c2c3ccccc3cnn2c1C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(O)CC(O)/C=C/c1c(-c2ccc(F)cc2)c2c3ccccc3cnn2c1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of ethyl (E)-7-{1-(4-fluorophenyl)-3-isopropylpyrrolo[2,1-a]phthalazin-2-yl}-5- hydroxy-3-oxohept-6-enoate (3.98 g) in methanol (120 ml) under an argon atmosphere at 0°-5° C. was treated with sodium borohydride (243 mg). After 3 hours the solution was allowed to warm to room temperature, and was then evaporated to small volume (20 ml). The solution was treated with water (300 ml), and extracted with a mixture of diethyl ether and ethyl acetate (2×250 ml; 1:1 v/v). The combined extracts were dried over magnesium sulphate and evaporated, to give methyl (E)-7-{1-(4-fluorophenyl)-3-isopropylpyrrolo[2,1-a]-phthalazin-2-yl}-3,5-dihydroxyhept-6-enoate, in the form of an orange foam (3.16 g).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=[O:7].FC1C(F)=C(F)C=CC=1N[C@H](C)C(OC)=O>P([O-])([O-])([O-])=O>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@@H:5]([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Agent: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Product: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 30 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
Microbial cells (IFO-1575; Zygoascus hellenicus) were cultured in an MY medium (pH 6.0; 50 ml) at 30° C. for 48 hours. Methyl 2-(2,3,4-trifluoroanilino)propionate (1.0 g) was suspended in a 0.1 M phosphate buffer solution (pH 6.5; 90 ml). Then the above-described liquid culture (10 ml) was added thereto and gently stirred. The mixture was stirred for additional 16 hours while maintaining at 30° C. Then it was treated as in Example 43 to thereby give methyl (2R)-2-(2,3,4-trifluoroanilino)propionate (0.39 g, optical purity 91% ee) and the title compound (0.45 g, optical purity 84% ee).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH:17]=2)=[CH:9][C:8]=1[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(N(CC)CC)C.ClCCl>C1COCC1>[CH3:1][S:2]([O:21][CH2:20][CH2:19][CH2:18][N:16]1[CH:17]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([NH2:6])=[C:8]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[CH:9]=2)[CH:14]=[N:15]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(-c2cnn(CCCO)c2)cc1-c1nc2ccccc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonyl chloride (0.577 ml) was added to 3-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]propan-1-ol (1.25 g, Example 29-1), triethylamine (1.559 ml) dissolved dichloromethane (20 ml) and THF (20 ml) at 0° C. The resulting suspension was stirred at 25° C. for 2 hours. The suspension was filtered and washed with water (3 time) and dried over night on reduce pressure to afford 3-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]propyl methanesulphonate (0.988 g). NMR Spectrum: (DMSOd6) 2.21-2.32 (m, 2H), 3.23 (s, 3H), 4.21-4.33 (m, 4H), 7.42-7.51 (m, 2H), 7.68 (bs, 2H), 7.81 (d, 1H), 7.86 (d, 1H), 7.98 (s, 1H), 8.30 (s, 1H), 8.44 (s, 1H), 8.54 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([O:16][CH:17]([CH:20]3[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]3)[C:18]#[CH:19])[C:10]([F:15])=[C:11]2[F:14])=[CH:6][CH:5]=1)[CH3:2]>C(N(CC)C1C=CC=CC=1)C.CC(OC)(C)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH:19]=[CH:18][CH:17]([CH:20]4[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)[O:16][C:9]=3[C:10]([F:15])=[C:11]([F:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: C#CC(Oc1cc2ccc(OCC)cc2c(F)c1F)C1CCC(CCC)CC1
Solvent: CCN(CC)c1ccccc1
Solvent: COC(C)(C)C
Product: CCCC1CCC(C2C=Cc3c(c(F)c(F)c4cc(OCC)ccc34)O2)CC1

Procedure:
7.75 g (about 18.6 mmol) of 7-ethoxy-1,2-difluoro-3-[1-(4-propylcyclohexyl)prop-2-ynyloxy]naphthalene are heated at 205° C. for 4.5 h in 80 ml of N,N-diethylaniline. The batch is diluted with MTBE and washed a number of times with hydrochloric acid. The organic phase is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1). The further purification is carried out by recrystallisation from n-heptane, giving 8-ethoxy-5,6-difluoro-3-(4-propylcyclohexyl)-3H-benzo[f]chromene as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[C:8](=O)([O-])[O-:9].[K+].[K+]>CC(C)=O>[OH:9][CH2:8][NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(N)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)NCO
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A flask is charged with 2,2-dimethyl-propionamide (1.00 g, 9.98 mmol), p-formaldehyde (0.736 g, 9.98 mmol), and potassium carbonate (0.054 g, 3.95 mmol). The reaction mixture is stirred at 75° C. for 16 h, whereupon it is cooled to room temperature and diluted with acetone. Filtration and concentration of the filtrate give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 4:1) to afford N-hydroxymethyl-2,2-dimethyl-propionamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (s, 9H), 4.73 (d, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[C:14]([NH2:16])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][NH2:16]
Reactant: CN1CCN(c2ccccc2)CC1C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCN(c2ccccc2)CC1CN

Procedure:
In a manner similar to preparation 2, react 1-methyl-4-phenyl-2-piperazinecarboxamide with lithium aluminum hydride toobtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:18]1[CH:22]=[CH:21][C:20](B(O)O)=[N:19]1>CN(C=O)C.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]>[CH3:11][C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([C:20]3[NH:19][N:18]=[CH:22][CH:21]=3)[CH:3]=2)[NH:8][N:9]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: Cc1n[nH]c2cnc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1n[nH]c2cnc(-c3ccn[nH]3)cc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 15.1 %

Procedure:
To a solution of 5-Bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine from Example 102 (106 mg, 0.5 mmol) in DMF (5 mL) was added Pd(dppf)Cl2 (20 mg), saturated solution of Na2CO3 (1 mL) and 1H-pyrazol-3-ylboronic acid (67 mg, 0.6 mmol). The mixture was stirred under argon for 16 h at 80° C. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography (mobile phase: EA:PE=1:1) to afford 103 (15 mg, 15%). 1H NMR (500 MHz, MeOD) δ 8.96 (s, 1H), 8.23 (s, 1H), 7.71 (s, 1H), 6.90 (d, J=1.5, 1H), 2.65 (s, 3H). ESI MS m/z=200.1 (M+1)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH2:31][CH:32]([O:38][CH2:39][CH3:40])[C:33]([O:35]CC)=[O:34])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].C1COCC1.S([O-])(O)(=O)=O.[K+]>O.C(O)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH2:31][CH:32]([O:38][CH2:39][CH3:40])[C:33]([OH:35])=[O:34])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)OCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 20 %

Procedure:
Ethyl 3-[3-benzyl-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethoxy)phenyl]-2-ethoxypropanoate (0.3 g, 0.5 mmol) and lithium hydroxide (0.015 g, 0.6 mmol) was added to a mixture of THF (10 ml), ethanol (2 ml) and water (2 ml). After stirring in room temperature for 5 h the mixture was acidified to pH 3 with saturated potassium hydrogen sulphate. Water was added and the mixture was extracted with ethylacetate. The organic layer was separated and evaporated. The residue was purified on silica gel using isooctane/ethylacetate/methanol 10:10:1. This yielded 70 mg (0.1 mmol) of the title product.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCCCCC>CN(C)C=O>[C:13]1([O:21][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C1CCCCCCC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC1=CCCCCCC1
Yield: 79.4 %

Procedure:
To a solution of 42 g (0.38 mol) of chlorotrimethylsilane and 78 g of triethylamine in 100 ml of dimethylformamide, a solution of 32 g (0.254 mol) of cyclooctanone in 40 ml of dimethylformamide was added. The resultant mixture was stirred at 100° to 115° C. for 48 hours. At the end of the reaction, the reaction mixture was combined with 240 ml of n-hexane and washed twice with 300 ml of a saturated aqueous sodium bicarbonate solution. The mixture was washed under cooling with 180 ml of 1.5N hydrochloric acid, then washed sequentially with an aqueous sodium bicarbonate solution, water, and saline and then dried with magnesium sulfate. The mixture was concentrated and distilled under vacuum, to afford 40 g (80% yield) of 1-cyclooctenyloxytrimethylsilane having a boiling point of 82° to 84° C./5 mmHg.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([CH3:23])=[C:19]([CH3:22])[CH:20]=3)[NH:15][C:14]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([CH3:23])=[C:19]([CH3:22])[CH:20]=3)[NH:15][C:14]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:11][CH:12]=1
Reactant: COC(=O)c1[nH]c2cc(C)c(C)cc2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1[nH]c2cc(C)c(C)cc2c1-c1ccc(O)cc1
Reaction time: 2 h
Yield: 44.3 %

Procedure:
A solution of boron tribromide (BBr3) (0.18 ml) in dichloromethane (0.36 ml) was dropwise added to a solution of methyl 3-(4-methoxyphenyl)-5,6-dimethylindole-2-carboxylate (0.3 g) in dichloromethane (10 ml) at 0° C. The reaction mixture was stirred for 2 hours at the same temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from acetone to give methyl 3-(4-hydroxyphenyl)-5,6-dimethylindole-2-carboxylate (0.127 g, 44%) as colorless needles.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=O)=[C:26]([CH3:31])[S:25][C:24]=4[CH:32]=3)[CH:11]=2)=[O:9])[CH2:4]1.[NH2:33][CH2:34][CH:35]1[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:35]1([CH2:34][NH:33][C:28]([C:27]2[C:23]3[CH:22]=[CH:21][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:32][C:24]=3[S:25][C:26]=2[CH3:31])=[O:30])[CH2:37][CH2:36]1
Reactant: NCC1CC1
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCC6CC6)c(C)sc5c4)c3s2)C1
Yield: 29 %

Procedure:
This material was prepared by the reaction of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg, 0.278 mmole) with (aminomethyl)cyclopropane (120 μL, 1.39 mmole), diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg, 0.694 mmole) in a manner similar to that previously described for example 117 to afford a pale yellow solid (42 mg, 24%). 1H NMR (DMSO-d6, 300 MHz) δ 8.61 (1H, d, J=5.56 Hz), 8.49 (1H, t, J=5.56 Hz), 8.06 (1H, s), 7.97 (1H, s), 7.84 (1H, d, J=8.59 Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.79 (1H, d, J=5.56 Hz), 4.11–3.80 (3H, m), 3.70–3.46 (2H, m), 3.27, 3.24 (3H, s), 3.20 (2H, t, J=6.19 Hz), 2.62 (3H, s)2.18–1.91 (2H, m), 1.08 (1H, m), 0.47 (2H, m), 0.26 (2H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:18])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([OH:17])=[CH:11][C:8]=2[C:9]=1[CH3:10].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C.C(Cl)(Cl)Cl>[OH:17][C:12]1[C:13]([O:15][CH3:16])=[CH:14][C:7]2[O:6][C:5](=[O:18])[C:4]([CH2:3][CH2:2][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[C:9]([CH3:10])[C:8]=2[CH:11]=1
Reactant: COc1cc2oc(=O)c(CCCl)c(C)c2cc1O
Reactant: COc1ccccc1N1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1O
Yield: 14 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-6-hydroxy-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 27) and 1-(2-methoxyphenyl)piperazine; yield 14%; m.p. 235°-237° C. (from ethanol/chloroform).