Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.CCCCCC.[CH:20]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])[CH3:21].Br[CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36].Cl>C1COCC1>[CH:20]([O:23][C:24]([C:26]1([CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])[CH3:21]
Reactant: CCC(CC)CBr
Reactant: CC(C)OC(=O)C1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)CC1(C(=O)OC(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 85 %

Procedure:
To a solution of dicyclohexylamine (14.24 g, 78.5 mmol) in THF (35 mL) 1.6 M n-BuLi in hexane (44.2 mL, 70.7 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The resulting orange suspension was stirred 10 min at −20° C. and then added via a teflon tube over 20 min to a stirred solution of cyclohexanecarboxylic acid isopropyl ester (10.0 g, 58.75 mmol) in THF (75 mL) at 0-2° C. To the resulting solution 1-bromo-2-ethylbutane (13.58 g, 82.25 mmol) in THF (37.5 mL) was added at 0° C. over 15 min. The solution was stirred overnight at 0° C. and for an other 3 h at room temperature. At 5° C. ice-water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and ethyl acetate. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (15.5 g) was distilled at 60° C. (0.05 mbar) to give 12.7 g (85%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid isopropyl ester as colorless oil, purity 99.2% (GC area). 1H-NMR (CDCl3, 400 MHz): ppm 0.80 (t, 6H), 1.15-1.39 (m, 11H), 1.23 (d, 6H), 1.40 (d, 2H), 1.51-1.59 (m, 2H), 2.02-2.12 (m, 2H). 4.95-5.05 (m, 1H).
Reaction SMILES: ClC(OC(C)C)=O.C[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=O)[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16].N1CCOCC1.C(N(CC)CC)C>CN(C)C=O.CCOCC>[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[O:31])[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16]
Reactant: NC(=O)c1ncn2c(=O)n(CC(=O)O)nnc12
Reactant: CN1CCOCC1
Agent: CC(C)OC(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: NC(=O)c1ncn2c(=O)n(CC(=O)N3CCOCC3)nnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl chloroformate (1 M in toluene, 1.155 mL, 1.155 mmol) and then N-methyl morpholine (0.127 mL, 1.155 mmol) were added to a stirred solution of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.25 g, 1.050 mmol) in dimethylformamide (1.34 mL) under nitrogen at −10° C. to −15° C. The reaction was stirred for one hour at this temperature then morpholine (0.183 g, 2.100 mmol) and triethylamine (0.146 mL, 1.050 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was stirred at −10° C. to −15° C. for one hour then allowed to warm to room temperature. After 16 hours, ether (5 mL) was added and the resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL) then purified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane) and triturated with ether to furnish the desired product as a white solid. Yield: 105 mg, 0.34 mmol, 33%. LCMS (ES+) m/z 308 (M+H)+ at 0.97 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (1H, s), 7.83 (1H, br s), 7.68 (1H, bs), 5.35 (2H, s), 3.66 (2H, m), 3.51-3.60 (4H, overlapping multiplets), 3.45 (2H, m).
Reaction SMILES: CC1(C)[N:6](C([O-])=O)CCO1.C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@H:23]([C:42]([OH:44])=O)[CH2:24][C:25]1[N:29](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:28]=[N:27][CH:26]=1)=O)(=O)=O)(C)(C)C>>[NH:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:42]([NH2:6])=[O:44])[N:29]=[CH:28]1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cncn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reactant: CC1(C)OCCN1C(=O)[O-]
Product: NC(=O)CCc1c[nH]cn1

Procedure:
In an analogous manner to that described in Example 16, by reacting t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R or S)-hydroxy-[(R or S)-tetrahydro-2-furyl]-methyl]-2,2-dimethyl-3-oxazolidinecarboxylate with N-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamoyl]-3-(2,4-dinitrophenyl)-L-histidine there is obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3[(R or S)-tetrahydro-2-furyl]propyl]imidazole-4-propionamide in the form of a yellow amorphous powder, MS: 827 (M+H)+. The cleavage of the dinitrophenyl group with thiolactic acid is effected in an analogous manner to Example 13 and yields (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl -2,3-dihydroxy-3-[(R or S)-tetrahydro-2-furyl]propyl]imidazole-4-propionamide as a pale yellow amorphous solid, MS: 661 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:23]=[CH:22]C(C#N)=[CH:18][CH:17]=1)[N:11]=2.[C:24]([OH:27])(=[O:26])[CH3:25].OS(O)(=O)=O>O>[CH3:1][C:2]1[O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:17]=[CH:18][C:25]([C:24]([OH:27])=[O:26])=[CH:22][CH:23]=1)[N:11]=2
Reactant: CC(=O)O
Reactant: Cc1oc2ccccc2c2nn(-c3ccc(C#N)cc3)c(=O)c1-2
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1oc2ccccc2c2nn(-c3ccc(C(=O)O)cc3)c(=O)c1-2
Temperature: 100 °C

Procedure:
A mixture of 4-(4-methyl-3-oxo-3H-chromeno[4,3-c]pyrazol-2-yl)-benzonitrile (0.030 g, 0.10 mmol), acetic acid (0.4 ml), H2SO4 (0.4 ml) and water (0.4 ml) was heated at 100° C. in an oil bath for 19 h. After cooling water was added and the precipitation collected, washed with water and dried to yield 4-(4-methyl-3-oxo-3H-chromeno-[4,3-c]pyrazol-2-yl)-benzoic acid (0.029 g): 1H NMR (400 MHz, DMSO-d6) δ 8.21 (2H, d), 8.13 (1H, d), 8.01 (2H, d), 7.67-7.75 (2H, m), 7.54-7.58 (1H, m), 2.78 (3H, s); ESI MS m/z 321 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.O>[Si:20]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNc1ccc(CO)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of [4-(methylamino)phenyl]methanol (500 mg, 3.7 mmol) and imidazole (248 mg, 3.7 mmol) in DCM (20 mL) was added TBSCl (548 mg, 3.7 mmol) at r.t., and the reaction was stirred for 2 h. The reaction was diluted with water (50 mL) and extracted with DCM (50 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=40:1) to give 600 mg (66%) of the title compound as a yellow oil. [M+H] Calc'd for C14H15NOSi, 252. Found 252.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[CH3:18][C:19]1([CH3:28])[CH:24]2[CH2:25][CH:20]1[C:21](=[O:27])[CH2:22][C:23]2=[O:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH3:9])=[C:2]([CH:22]3[C:21](=[O:27])[CH:20]4[CH2:25][CH:24]([C:19]4([CH3:18])[CH3:28])[C:23]3=[O:26])[CH:3]=2)=[C:11]([F:17])[CH:12]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2F)cc1Br
Reactant: CC1(C)C2CC1C(=O)CC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1C1C(=O)C2CC(C1=O)C2(C)C
Temperature: 160 °C

Procedure:
3-Bromo-4′-chloro-4-ethyl-2′-fluorobiphenyl (0.213 g, 0.68 mmol) is added to a mixture of 6,6-dimethylbicyclo[3.1.1]heptane-2,4-dione (0.124 g, 0.81 mmol), powdered potassium phosphate (0.316 g, 1.49 mmol), palladium (II) acetate (0.008 g, 0.034 mmol) and (2-dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.024 g, 0.051 mmol) in degassed 1,2-(2.5 ml) and the mixture is stirred and heated to 160° C. for 1 hour under microwave irradiation. The mixture is cooled to room temperature, diluted with ethyl acetate and washed with 2 M aqueous hydrochloric acid. The organic phase is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is taken up in N,N-dimethylformamide (2 ml) and purified by preparative reverse-phase HPLC. Fractions containing the desired product are taken up in ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, filtered and the fitrate is evaporated under reduced pressure to give 3-(4′-chloro-4-ethyl-2′-fluorobiphen-3-yl)-6,6-dimethylbicyclo[3.1.1]-heptane-2,4-dione.
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[C:21]([Cl:26])[C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14].C1C[O:36]CC1>>[ClH:26].[F:2][C:3]([F:32])([F:31])[C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[C:21]([OH:36])[C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(NCCNCCOc1ccccc1C(F)(F)F)c1cccc2c(Cl)nccc12
Reactant: C1CCOC1
Agent: Cl
Product: O=S(=O)(NCCNCCOc1ccccc1C(F)(F)F)c1cccc2c(O)nccc12
Yield: 33 %

Procedure:
A 0.6 mL 5N HCl solution is added to a stirred solution of 1-chloro-isoquinoline-5-sulfonic acid {2-[2-(2-trifluoromethyl-phenoxy)-ethylamino]-ethyl}-amide (70 mg, 0.15 mmol) in THF (1 mL) at ambient temperature under nitrogen. The resultant mixture is heated at 65° C. for 16 hours. At ambient temperature, the mixture is concentrated. The crude product is dissolved in a small amount of MeOH/CH2Cl2 before it is treated with Et2O to form a white suspension. After filtration and vacuum drying, 24 mg (0.49 mmol, 33% yield) of the title compound is obtained as a white powder. ESIMS: m/z 456 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[NH:25][N:24]=[N:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[N:25]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[N:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: O=c1[nH]nnn1-c1ccc(Cl)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nnn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 60.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.38 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.09 g of 1-(4-chlorophenyl)-5(1H,4H)-tetrazolone, 1.27 g of 1-(4-chlorophenyl)-4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-5(1H,4H)-tetrazolone was obtained as a cololess oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Br[CH2:23][CH2:24][CH3:25].Cl>>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[N:12]([CH2:23][CH2:24][CH3:25])[C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Reactant: CCCBr
Agent: Cl
Product: CCCN1C(=O)c2cc3c(cc2C1=O)CC(N(CCC)CCC)C3

Procedure:
Using procedure 48, 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (93, 0.15 g, 0.52 mmol) was treated with 1-bromopropane (0.07 mL, 0.78 mmol). Purification via silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 96 as a white solid (m.p. 217-218° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10](=O)[CH2:11]Br)[CH:7]=[CH:6][C:5]=1[Cl:14].[C:16]([NH2:19])(=[S:18])[CH3:17]>C(O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]2[N:19]=[C:16]([CH3:17])[S:18][CH:11]=2)[CH:7]=[CH:6][C:5]=1[Cl:14]
Reactant: CC(N)=S
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1Cl
Solvent: CCO
Product: COC(=O)c1cc(-c2csc(C)n2)ccc1Cl
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
A mixture of 5-(2-bromo-acetyl)-2-chloro-benzoic acid methyl ester (25 mg, 0.09 mmol) and thioacetamide (6.5 mg, 0.08 mmol) in ethanol (2 mL) and stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (10 mg).
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[C:31]1([C@@H:37]([CH2:39][OH:40])[NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH:41]1[C:45]2=[N:46][CH:47]=[CH:48][C:49]([NH:50][C:51]3[C:52]4[CH:62]=[CH:61][CH:60]=[CH:59][C:53]=4[S:54][C:55]=3[C:56](O)=[O:57])=[C:44]2[CH:43]=[CH:42]1>>[OH:40][CH2:39][C@@H:37]([NH:38][C:56]([C:55]1[S:54][C:53]2[CH:59]=[CH:60][CH:61]=[CH:62][C:52]=2[C:51]=1[NH:50][C:49]1[CH:48]=[CH:47][N:46]=[C:45]2[NH:41][CH:42]=[CH:43][C:44]=12)=[O:57])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1sc2ccccc2c1Nc1ccnc2[nH]ccc12
Reactant: N[C@H](CO)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(N[C@H](CO)c1ccccc1)c1sc2ccccc2c1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (S)-2-phenylglycinol instead of 1-BOC-3-aminopyrrolidine and 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-benzo[b]thiophene-2-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 429 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (1H, br. s.) 9.24 (1H, br. s.) 8.57 (1H, d, J=7.96 Hz) 8.09 (1H, d, J=8.10 Hz) 7.84 (1H, d, J=5.66 Hz) 7.59 (1H, d, J=7.96 Hz) 7.52 (1H, td, J=7.60, 1.15 Hz) 7.40 (1H, dd, J=15.13, 0.88 Hz) 7.28 (1H, dd, J=2.95, 1.44 Hz) 7.10-7.18 (1H, m) 7.06 (2H, t, J=7.32 Hz) 6.99-7.03 (2H, m) 6.50 (1H, br. s.) 6.04 (1H, d, J=5.66 Hz) 4.92-5.00 (1H, m) 4.90 (1H, t, J=5.30 Hz) 3.48 (2H, td, J=11.20, 5.71 Hz)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 93.4 %

Procedure:
A mixture of methyl 4-bromo-3-methylbenzoate (25.0 g, 110 mmol), o-tolylboronic acid (16.5 g, 120 mmol) and potassium carbonate (50 g, 360 mmol) in dioxane:water (300 mL: 200 mL) was purged with nitrogen for 1 hour. [1,1′bis(Diphenylphosphino)ferrocene]dichloropalladium[II] (4.5 g, 5.5 mmol) was added and the reaction mixture was heated to 100° C. with vigorous stirring for 3.5 hours. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate (500 mL). The organic phase was separated, washed with 1 M sodium hydroxide (500 mL) and brine (500 mL), dried over anhydrous potassium carbonate and concentrated in vacuo to give the crude product as a dark oil (28.6 g). Purification by flash chromatography using a solvent gradient of 2% ethyl acetate in hexane afforded the title compound (24.7 g, 93%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24]O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:2].CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][N:48]4[CH2:49][CH2:50][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46][CH2:47]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CO)ccn34)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccn34)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.091 mmol) in DCM (3 mL) was added methanesulfonyl chloride (21 mg, 0.18 mmol). The reaction mixture was stirred for 30 minutes, diluted with DCM (10 mL), washed with saturated NaHCO3 aqueous solution (3 mL) and brine (3 mL). The organic phase was concentrated under reduced pressure to a residue, to which was added DMF (2 mL), K2CO3 (38 mg, 0.27 mmol) and tert-butyl piperazine-1-carboxylate (51 mg, 0.27 mmol). The reaction mixture was heated to 50° C. for 2 hours. The mixture was concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH) gave the product (22 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](O)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][CH:2]2[CH2:6][S:5][CH2:4][CH:3]2[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C(=O)O)c1ccc(CC2CSCC2O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC2CSCC2Cc2ccc(C(C)C(=O)O)cc2)cc1
Yield: 44.3 %

Procedure:
2-[4-(4-Hydroxythiolan-3-ylmethyl)phenyl]propionic acid (1.0 g) obtained in Example 9 was dissolved in toluene (30 ml), and p-toluenesulfonic acid (710 mg) was added to the solution and refluxed by heating for 5 hours. After completion of the reaction, the reaction mixture was quenched with water, and the organic layer was separated, and washed with water and saturated brine. Then, the solvent was evaporated under reduced pressure to give a crude product of 2-{4-[4-(4-toluenesulfonyloxy)thiolan-3-ylmethyl]phenyl}propionic acid (700 mg). A part of the product (474 mg) was dissolved in tetrahydrofuran (4.0 ml), and potassium tert-butoxide (506 mg) was added to the solution, and refluxed by heating for 5 hours. After completion of the reaction, the reaction mixture was acidified with 2.0 M aqueous hydrochloric acid under ice cooling, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (90 mg, 14.4% for 2 steps).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH:11][CH:12]([C:15]1[C:16](=[O:26])[NH:17][C:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:19][N:20]=1)[CH2:13][CH3:14])=O.P(Cl)(Cl)(Cl)=O>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]1[N:20]2[C:15]([C:16](=[O:26])[NH:17][C:18]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:19]2)=[C:12]([CH2:13][CH3:14])[N:11]=1
Reactant: CCC(NC(=O)CC1CC2CCC1C2)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(CC2CC3CCC2C3)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.56 mmol) crude 2-bicyclo[2.2.1]hept-2-yl-N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)-propyl]acetamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1>CCO>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:34][CH2:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: NCc1ccncc1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NCc3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 90 °C
Yield: 36.5 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (60 mg, 0.16 mmol) and (4-pyridinylmethyl)amine (0.065 ml, 0.64 mmol) in EtOH (2 mL). The vessel was sealed and the reaction mixture was heated at 90° C. overnight. An additional 1 mL of (4-pyridinylmethyl) amine was added and the mixture was heated in a microwave at 160° C. for 90 min. The EtOH solvent was removed under reduced pressure, 2 mL of NMP was added, and the mixture was then irradiated (microwave) at 180° C. for 90 min. The mixture was evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water. The crude residue was extracted with EtOAc, DCM and DCM/isopropanol (70:30). The combined organics were washed with water (2×) and brine, dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated yellow oil was treated with EtOAc and sonicated. The filtered solid was washed with hexanes and dried to afford the title compound (26 mg, 36%) as a white solid. LCMS E-S (M+H)=446.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H) 8.50 (t, J=5.18 Hz, 1H) 8.43-8.48 (m, 2H) 7.89 (t, J=5.94 Hz, 1H) 7.84 (s, 1H) 7.34 (d, J=6.06 Hz, 2H) 6.73 (s, 1H) 5.89 (s, 1H) 4.83 (quin, J=6.69 Hz, 1H) 4.58 (d, J=5.81 Hz, 2H) 4.32 (d, J=5.05 Hz, 2H) 2.21 (s, 3H) 2.13 (s, 3H) 1.32 (d, J=6.82 Hz, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:47])[CH2:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=2)[CH:36]=[CH:37][CH:38]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][C:31]([OH:47])=[O:30])[CH:34]=4)=[CH:40][CH:41]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)Cc1cccc(-c2ccc(C=O)cc2)c1
Product: O=C(O)Cc1cccc(-c2ccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and (4′-formyl-biphenyl-3-yl)-acetic acid methyl ester. MS (ESI) m/z 601.