Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=4)[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 3-trifluoromethylphenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4 (s, 1H), 8.4 (s, 1H), 8.2 (m, 1H), 8.05 (s, 2H), 8.03 (d, 1H), 8.0 (d, 1H), 7.9 (m, 1H), 7.4-7.75 (m, 6H), 7.0 (d, 1H), 4.3 (t, 2H), 3.6 (m, 4H), 2.9 (t, 2H), 2.55 (m, 4H).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[OH:32][CH:33]1[CH2:37][C:36](=[O:38])[CH:35]=[CH:34]1>C(Cl)Cl>[C:1]([O:38][CH:36]1[CH2:37][C:33](=[O:32])[CH:34]=[CH:35]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=CC(O)C1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1C=CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
A solution of trityl chloride (3.44 g, 12.3 mmol) in methylene chloride (20 mL) is treated sequentially with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.2 mL, 14.7 mmol, DBU) and 4-hydroxy-2-cyclopentenone (1.01 g, 10.0 mmol, in 5 mL of methylene chloride, prepared in example 1). The reaction is stirred for 3 days at room temperature and then poured onto ice (approximately 25 mL). The phases are separated and the organic phase is washed with water (25 mL). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by column chromatography (silica gel, 10-20% ethyl acetate/hexane) to provide the title compound (1.26 g, 36%) as a pale yellow oil; 1H NMR (CDCl3) δ7.5 (m, 6H), 7.3 (m, 9H), 6.85 (dd, 1H), 6.05 (d, 1H), 4.8 (m, 1H), 2.1 (m, 2H); 13C NMR (CDCl3) δ206.6, 162.9, 144.3, 135.2, 128.8, 128.4, 127.7, 88.2, 73.1, 43.4; IR (KBr) νmax 3061, 1719, 1491, 1449, 1352, 1181, 1107, 1053 cm-1.
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)[C@]5(O)[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:30]([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)#N>>[OH:2][C@:49]12[CH2:48][C:47](=[O:50])[CH2:46][CH2:45][C@:44]1([CH3:51])[C@@H:43]1[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]1)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33][C:32]2=[CH2:30]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C=C1C[C@H]2[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCCC[C@]12O
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Yield: 78 %

Procedure:
The title compound II-bo was prepared in 78% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-methyleneandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.93 (s, 1H), 4.83 (m, 1H), 4.60 (m, 1H), 2.83 (d, 1H), 2.90-1.10 (m, 18H), 0.95 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](OC(C)(C)C)[C:29](=C=O)[CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1>C(O)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:25][CH2:26]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: CC(C)(C)ON1CCC(N2CCN(C(=O)[C@@H](Cc3ccc(O)cc3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1=C=O
Solvent: O=CO
Product: O=C(O[C@H](Cc1ccc(O)cc1)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
To a solution of 210 mg (0.30 mmol) of (R)-1-(4-hydroxy-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 124) in 1.5 mL formic acid was stirred for 3 h at RT. The reaction mixture was evaporated down i.vac. and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 90:10:1).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH2:15].C(O)(=O)C>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:14][CH2:15][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1
Reactant: C=Cc1ccccn1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CCN2CCc3c([nH]c4ccccc34)C2)nc1
Yield: 44 %

Procedure:
A mixture of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.72 g., 0.01 mol), 2-vinylpyridine (1.0 g., 0.01 mol) and 2 ml. of glacial acetic acid were refluxed in 25 ml. of methanol for 24 hours. The solvent was removed in vacuo and the separated solid was suspended in water. The solution was made slightly basic via the addition of solid potassium carbonate and it was extracted with methylene chloride (4×150 ml.). The methylene chloride layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 1.2 g. (44% yield) of 2,3,4,9-tetrahydro-2-[2-(2-pyridinyl)ethyl]-1H-pyrido[3,4-b]indole. This intermediate was dissolved in 50 ml. of dimethylformamide and 0.92 g. (0.04 mol) of sodium hydride was added and stirring was continued for 1 hour. To the stirred solution 0.66 g. (0.004 mol) of benzyl bromide was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the solid residue was suspended in water and extracted with methylene chloride (3×100 ml.). The organic layer was separated, dried and evaporated. The remaining oil was dissolved in ethanol and converted to the dihydrochloride salt; mp 278°-280° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[N:4][CH:3]=1.[CH2:9]1COCC1.C[Mg+].[Br-]>C(OCC)C>[Br:1][C:2]1[S:6][C:5]([CH:7]([OH:8])[CH3:9])=[N:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1ncc(Br)s1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1ncc(Br)s1
Temperature: 0 °C

Procedure:
To an ice cold solution of 5-bromothiazole-2-carbaldehyde (3 g, 15.6 mmol) in diethyl ether (20 mL) was added a THF solution of MeMgBr (3M, 50 ml, 150 mmol). Solid was produced rapidly. LCMS showed a new product with desired mass. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO CombiFlash® chromatography eluting 10-40% ethyl acetate in heptanes. The title compound was obtained as a viscous yellow oil (3.25 g, 62% yield).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[CH2:26])[C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:12]([F:28])[CH:11]=2)[C:7]([CH3:29])=[N:6][C:5]=1[CH3:30])(=[O:3])[NH2:2].C1(C)C=CC=CC=1>CO.[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh].CC1C(P([C@H]([C]2[C](P(C(C)(C)C)C(C)(C)C)[CH][CH][CH]2)C)C2C(C)=CC=CC=2)=CC=CC=1.[CH]1[CH][CH][CH][CH]1.[Fe]>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C@H:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:12]([F:28])[CH:11]=2)[C:7]([CH3:29])=[N:6][C:5]=1[CH3:30])(=[O:3])[NH2:2]
Reactant: C=C(C(=O)O)c1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Agent: [Fe]
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1=CCCC=CCC1
Product: Cc1nc(C)c(-c2ccc(-c3ccc([C@H](C)C(=O)O)cc3Cl)c(F)c2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
2-[4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoic acid (Intermediate 31-10; 142 g, 283.44 mmol), bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (1.381 g, 3.40 mmol), (R)-1-[(Sp)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine (2.102 g, 3.68 mmol) in degassed methanol (2.5 L) and degassed toluene (836 mL) were stirred under an atmosphere of hydrogen at 5 bar and 45° C. for 4 hours. Chiral HPLC analysis (chiralpak AD 5 μm, 250 mm×4.6 mm column, eluted with 60% isohexane/40% ethanol/0.2% acetic acid, retention time for required enantiomer 14.5 minutes) indicated the ratio of desired to undesired enantiomer was 87:13. The solvent was removed in vacuo. The crude product was dissolved in 5% methanol/dichloromethane and then chromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column), eluting with a solvent mixture of 5% methanol/dichloromethane. Pure fractions were evaporated to dryness to afford the mixture of the enantiomers, chiral prep HPLC chromatography (5 Kg of chiralpak AD 20 μm, 200 mm diameter column, eluted with 70% isohexane/30% ethanol/0.2% acetic acid, retention time for required enantiomer 17 minutes) then gave (2S)-2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]propanoic acid (58 g, 40%, 99% ee) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CS[C:12]1[N:17]=[C:16]([OH:18])[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][N:13]=1>C(O)C>[OH:18][C:16]1[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][N:13]=[C:12]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[N:17]=1
Reactant: CCOC(=O)c1cnc(SC)nc1O
Reactant: c1ccc2c(c1)CCN2
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1O
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a solution of indoline (3.58 g, 30 mmol) in ethanol (50 mL) was added ethyl 2-methylthio-4-hydroxypyrimidine-5-carboxylate (5.35 g, 25 mmol) and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool to room temperature and the precipitated crystals were collected by filtration. The crystals were washed several times with cold ethanol and dried to give the title compound (5.5 g, 77%) as crystals.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:28]([O:30][CH3:31])=[O:29])=[N:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(#N)C>[NH2:8][C:9]1[C:10]([C:28]([O:30][CH3:31])=[O:29])=[N:11][C:12]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:13][N:14]=1
Reactant: COC(=O)c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(C2CCNCC2)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-tert-butoxycarbonyl-4-piperidyl)pyrazine-2-carboxylate (285 mg) in DCM (7 mL) was added TFA (3 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h, then diluted with acetonitrile and concentrated in vacuo. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The product was not able to be extracted from aqueous layer with ethyl acetate, and was taken forward directly to the subsequent acylation step using Schotten-Baumen conditions LC/MS m/z 237.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[S:4].[F:17][C:18]([F:34])([F:33])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)=[N:23][CH:24]=1>CN(C)C=O>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:34])([F:17])[F:33])=[CH:24][N:23]=3)=[CH:27][CH:28]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CN(C)C=O
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)N(C)C1=S

Procedure:
2.5 g (10 mmol) of 1,3-dimethyl-5-ethoxycarbonyl-2-thiobarbituric acid, 2,55 g (10 mmol) of 4-(5-trifluoromethylpyrid-2-yloxy)aniline and 5 ml of dimethylformamide are stirred for 6 hours at 118° C. The reaction mixture is then cooled, triturated with water and the crystalline precipitate is isolated by filtration. The crude product is recrystallised from ethanol. Melting point 156°-158° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH3:2].[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=2[CH2:30][N:31]([CH2:32][CH3:33])[C:43]([NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])[C:9]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OCc1ccccc1
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using the following starting materials: (6-benzyloxy-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO.C(Cl)Cl>[C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[CH:21])=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1c(-c2ccc(C#C[Si](C)(C)C)s2)nc2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(-c2nc3ccccn3c2NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
11.5 g (31.3 mmol) of tert-butyl-[2-(5-trimethylsilanylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl]-amine were dissolved in a mixture of MeOH (230 ml) and DCM (50 ml) and combined with 431 mg (3.13 mmol) of potassium carbonate The reaction solution was stirred at RT for 30 min and then combined with water (200 ml). The mixture was then extracted with DCM and the organic phase was washed with water and dried over MgSO4. After filtration and evaporation under a vacuum, 9.0 g (30.5 mmol, 97%) of tert-butyl-[2-(5-ethynyl-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl]-amine were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Solvent: NC1CCCCC1
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Yield: 70 %

Procedure:
Prepared analogous to Example 42 from 4-(2',4'-dichloro-4-biphenylyl)-4-oxo-butyric acid. Yield: 70% of theory. Melting point of the cyclohexylamine salt: 168°-169° C. (from water).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]([F:16])([F:15])[C:6](=O)[CH:7]([CH3:13])[C:8](OCC)=[O:9].Cl>C(O)C>[CH3:1][N:2]1[C:8]([OH:9])=[C:7]([CH3:13])[C:6]([C:5]([F:16])([F:15])[F:4])=[N:3]1
Reactant: CNN
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1c(C(F)(F)F)nn(C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 20.9 g (454.2 mmol) of methylhydrazine in 500 ml of ethanol was added dropwise under stirring 90.0 g (454.2 mmol) of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate under ice-cooling so that the temperature did not exceed 10° C. After the completion of the dropwise addition, the whole was stirred at room temperature for 30 minutes. Then, 10 ml of concentrated hydrochloric acid was added into the reaction solution, followed by 2 days of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 61.0 g (yield: 74.6%) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole as white crystals (melting point: 148 to 151° C.).
Reaction SMILES: I[CH2:2][I:3].[NH2:4][C:5]1[N:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])[C:8]([CH2:15][O:16][CH2:17][CH3:18])=[N:7][C:6]=1C#N.N(OCCC(C)C)=O>C(Cl)(Cl)Cl>[CH2:17]([O:16][CH2:15][C:8]1[N:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])[C:2]([I:3])=[C:6]([C:5]#[N:4])[N:7]=1)[CH3:18]
Reactant: ICI
Reactant: CCOCc1nc(C#N)c(N)n1CC(C)(C)O
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc(C#N)c(I)n1CC(C)(C)O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
Diiodomethane (14.5 ml, 180 mmol) was added under argon with stirring to a suspension of 5-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile (4.36 g, 18.3 mmol) in chloroform (170 mL). The reaction mixture was heated to 80° C., a solution of isoamyl nitrite (9.86 ml, 73.2 mmol) in chloroform (30 mL) was added with a syringe pump over a period of 40 min and the mixture was stirred for another 30 min at 80° C. After cooling to room temperature the mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 20% to 50% ethyl acetate in heptane) to give the title compound (3.66 g, 57%) as brown oil; LC-MS (UV peak area, ESI) 90%, 350.0374 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:34]([F:37])([F:36])[F:35])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:39]>C(O)C>[ClH:39].[NH2:7][C:8](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:20]([C:34]([F:35])([F:36])[F:37])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(OCCCc3ccccc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(/C=C/c1ccc(OCCCc2ccccc2)c(C(F)(F)F)c1)(CO)CO
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 100-1 (560 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (380 mg) as a white powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[Br:22][CH2:23][CH2:24]Br.[Cl-].[NH4+]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([CH2:24][CH2:23][Br:22])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: BrCCBr
Reactant: COC(=O)C1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(CCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of diisopropylamine (56 mL, 396 mmol) in TI-IF (85 mL) was added dropwise a solution of n-butyl lithium (240 mL, 393 mmol, 1.6M) in hexanes at −10° C. while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. To this, a solution of cyclopentanecarboxylic acid methyl ester (37.4 g, 263 mmol) in THF (50 mL) was added dropwise at −70° C. maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 1 h at −50 to −60° C. Then, a solution of 1,2-dibromoethane (47 mL, 545 mmol) in THF (50 mL) was added dropwise and the light brown suspension was stirred for 1 h at −70 to −60° C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (200 mL) and the organic compound was extracted into ether (2×100 mL). The combined extracts were washed with a saturated solution of sodium chloride (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was distilled at 95-105° C./2.5 mm Hg to obtain 49.6 g (80% yield) of 1-[2-bromoethyl]cyclopentanecarboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1>O1CCCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1
Reactant: COc1cc(C#N)nc(-c2ccccn2)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1cc(CN)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Over a suspension of Ra—Ni (400 mg, excess) in tetrahydrofuran, under hydrogen, a solution of 4-Methoxy-[2,2′]bipyridinyl-6-carbonitrile (500 mg, 2.37 mmol) was added in tetrahydrofuran (10 mL) and the reaction mixture was stirred for 16 h at 25° C. The reaction was then filtered through celite, washed with tetrahydrofuran (100 mL) and the organic phase evaporated to dryness affording C-(4-Methoxy-[2,2′]bipyridinyl-6-yl)-methylamine as a pale yellow oil (466 mg, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C@@H:10]([CH3:20])[N:11]([C:16](=[O:19])[CH:17]=[CH2:18])[O:12][CH2:13]C=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:21])[C@H:10]([N:11]1[C:16](=[O:19])[CH:17]=[CH:18][CH2:13][O:12]1)[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCON(C(=O)C=C)[C@H](C)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: C[C@H](C(=O)OCc1ccccc1)N1OCC=CC1=O

Procedure:
A solution of(R)-N-acryloyl-N-allyloxyalanine benzyl ester (6a) (7.32 g, 25.3 mmol) and bis(tricyclohexylphosphine)benzylidene ruthenium dichloride (Grubb's catalyst) (1.04 g, 1.26 mmol, 5 mol %) in dry CH2Cl2 (250 mL) was refluxed with Silica Gel 60H (for TLC) followed by washing with CH2Cl2 (50 mL). After removal of the solvent, the dark oily residue was purified by dry flash chromatography (Silica Gel 60H for TLC, 5% EtOAc-hexanes→15% EtOAc-hexanes) to afford 6.05 g (92%) the olefin 7a identical to that described above.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH:18]([CH2:23][CH3:24])[C:19]([O:21][CH3:22])=[O:20]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH:18]([CH2:23][CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CCC(Br)C(=O)OC
Product: CCC(C(=O)OC)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 1 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and methyl 2-bromobutanoate: MS (ESI): m/z 325 (MH+).