Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]2[C:6]([CH3:21])([C:7]3[C:8](=[O:20])[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]=1[C:22]([OH:24])=[O:23].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[OH:20][C:8]1[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11]([OH:16])=[C:12]2[C:7]=1[C:6]1([CH3:21])[CH:15]([CH2:14][CH2:13]2)[C:2]([CH3:1])=[C:3]([C:22]([OH:24])=[O:23])[CH2:4][CH2:5]1
Reactant: CC1=C(C(=O)O)CCC2(C)C3=C(CCC12)C(=O)C(C(C)C)=CC3=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)CCC2(C)c3c(O)cc(C(C)C)c(O)c3CCC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
In 10 ml of THF was dissolved 300 mg of 3,4,4a,5,8,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-5,8-dioxo-2-phenanthrenecarboxylic acid obtained by the same extraction procedure as in Example 16, followed by addition of 16 ml of an aqueous solution containing 1.6 g of sodium dithionite, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent=chloroform:methanol=100:1) to provide 290 mg of 3,4,4a,9,10,10a-hexahydro-5,8-dihydroxy-1,4a-dimethyl-7-(1-methylethyl)-2-phenanthrenecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:15]3[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[N:14]3)=[C:8]([CH3:9])[N:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccc(F)c3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cccc(F)c4)n3n2)cc1
Yield: 20.4 %

Procedure:
Applying the Cyclization Procedure 1, using 3-fluoro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 67) (130 mg, 0.35 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.25 mL, 2.68 mmol), to afford 7-(3-fluorophenyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (25 mg) as a yellow solid. MS m/z 350 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[C:22]([F:27])[CH:21]=1
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Nc1ccc(Cl)cc1F
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Nc3ccc(Cl)cc3F)c2cc1OC

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.4 g, 1.5 mmol), (prepared as described for the starting material in Example 2), and 4-chloro-2-fluoroaniline (282 μl, 2.5 mmol) in DMF (5 ml) was treated as described in Example 2, to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (450 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:16][CH2:17][CH2:18]Br)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[C:13]([O:16][CH2:17][CH2:18][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)(=[O:15])[CH3:14]
Reactant: CC(=O)OCCBr
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCCOc1cccc2ccc(C)nc12
Temperature: 70 °C
Yield: 62.2 %

Procedure:
A mixture of 2-methylquinolin-8-ol (0.30 g, 1.9 mmol), 2-bromoethyl acetate (0.8.2 mL, 7.6 mmol) and potassium carbonate (1.6 g, 12 mmol) in acetone (7.5 mL, 1.9 mmol) was heated at 70° C. for 12 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to provide the title compound (0.29 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6](/[CH:7]=[N:8]/[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]2[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][C:18]3[C:9](=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=3)[N:8]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(/N=C/c2ccc(OC)cc2)c1
Reactant: O=CCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2cc(-c3ccccc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
A mixture of (E)-methyl 3-(4-methoxybenzylideneamino)benzoate (1.1 g, 4.08 mmol, 1.00 equiv), 2-phenylacetaldehyde (480 mg, 4.00 mmol, 1.00 equiv), hydrochloric acid in tetrahydrofuran (0.5 mL, 10M) and DMSO (2 mL) was placed in a 10-mL sealed tube and stirred overnight at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum and purified via Flash-Prep-HPLC (H2O/CH3CN=10% increasing to H2O/CH3CN=60% within 5 min; Detector, UV 254 nm) affording 70 mg (5%) of methyl 2-(4-methoxyphenyl)-3-phenylquinoline-7-carboxylate as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: COc1ccc(B(O)O)cc1
Product: CCn1nc2c(c1-c1ccc(OC)cc1)CCNCC2
Yield: 93.2 %

Procedure:
The title compound (134 mg) was prepared according to Example 193 using 219 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 241 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C16H21N3O, 271.17; found, m/z 272.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.33 (m, 2H), 7.15-7.12 (m, 2H), 4.12 (q, J=7.3 Hz, 2H), 3.88 (s, 3H), 3.49-3.47 (m, 2H), 3.36-3.34 (m, 2H), 3.28-3.25 (m, 2H), 2.88-2.85 (m, 2H), 1.35 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)O1>>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: COC(=O)C1(c2ccc(-c3ccc(O)cc3)cc2)CC1

Procedure:
According to a method similar to Example (8-1), from methyl 1-(4-bromophenyl)cyclopropanecarboxylate (2.96 g, 11.6 mmol) obtained in Example (15-1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.55 g, 11.6 mmol), methyl 1-(4′-hydroxy-1,1′-biphenyl-4-yl)cyclopropanecarboxylate was obtained as a white powder (2.49 g, yield: 80%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](O)(=[O:34])[C:25]1[CH:33]=[CH:32][C:31]2[O:30][CH2:29][O:28][C:27]=2[CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24]([C:25]5[CH:33]=[CH:32][C:31]6[O:30][CH2:29][O:28][C:27]=6[CH:26]=5)=[O:34])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc5c(c4)OCO5)nc3cc21

Procedure:
Benzo[1,3]dioxole-5-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and piperonylic acid (147 mg, 0.89 mmol). The title compound was obtained as grey powder (150 mg, 40%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[O:27][N:35]=[C:31]([CH:32]([CH3:34])[CH3:33])[N:30]=3)[CH2:10]2)=[O:8])[CH2:3]1
Reactant: CC(C)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Product: CC(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 76 mg (0.75 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 125 mg (54% of theory).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.I[CH3:34].O>C1COCC1>[CH3:34][N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19]
Reactant: CI
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Sodium hydride (10 mg of a 60% dispersion in mineral oil, 0.25 mmol) was added to a stirred suspension of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (70 mg, 0.17 mmol) in THF (2.0 mL) under a nitrogen atmosphere. This resulted in degassing and the formation of a yellow solution. Iodomethane (0.031 mL, 0.5 mmol) was added and the mixture was stirred for 3 h. Water (10 mL) was added and the mixture was extracted with DCM (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (2 g Si II SPE eluted with 0-50% EtOAc in DCM in 10% increments). Concentration of the appropriate fractions in vacuo gave the title compound which was freeze-dried from acetonitrile/water to afford a fluffy white solid (50 mg).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:44])[C:35]1[CH:43]=[CH:42][C:41]2[O:40][CH2:39][O:38][C:37]=2[CH:36]=1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:34]([C:35]2[CH:43]=[CH:42][C:41]3[O:40][CH2:39][O:38][C:37]=3[CH:36]=2)=[O:44])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1ccc2c(c1)OCO2)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and piperonylic acid (19.9 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[Cl:40])[CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1.O[Li].O>O1CCCC1.O>[Cl:40][C:31]1[C:32]([C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][N:14]([CH2:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzoic acid methyl ester (0.20 g, 0.34 mmol) in tetrahydrofuran (7.5 mL) and H2O (2.5 mL) at ambient temperature was treated with LiOH.H2O (0.029 g, 0.68 mmol). The mixture was stirred overnight at ambient temperature. The mixture was then treated with additional LiOH.H2O (0.058 g, 1.37 mmol) and heated at 50° C. overnight. The reaction was cooled to 0° C. and was quenched with H2O (5 mL). The mixture was the acidified to a pH=2 with 1 N HCl (aq.). The mixture was then extracted three times with EtOAc, dried, filtered and concentrated in-vacuo to afford the carboxylic acid product. The acid was purified via reverse-phase HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to yield the title compound, 0.140 g (72%); MS (ESI) m/e 569 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.[OH:30]O.[OH-].[Na+]>C1COCC1>[CH2:18]([CH:15]1[CH2:16][CH2:17][CH:12]([CH:9]2[CH2:10][CH2:11][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:30])[CH2:7][CH2:8]2)[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: OO
Reactant: C=CCCCC1CCC(C2CCC(CCC)CC2)CC1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CCCCCO)CC2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
4′-pent-4-enyl-4-propyl-bicyclohexyl [JP10046150] (9.9 g, 36 mmol) in THF (200 ml) are cooled to 0° C. and a 0.5 M solution of 9-BBN in THF (100 ml, 50 mmol) is added dropwise. The reaction is stirred overnight at room temp., cooled to −20° C. and 30% hydrogen peroxide (12 ml, 0.11 mol) are added followed by 32% aq. sodium hydroxide (7 ml, 76 mmol). The cooling bath is removed and the reaction is stirred overnight. Water is added and the mixture is extracted three times with ethyl acetate. The combined org. layers are washed with water and brine and are dried (Na2SO4). The solvent is evaporated and the crude product is recrystalised from ethanol to give 5-(4′-propyl-bicyclohexyl-4-yl)-pentan-1-ol as colourless crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:51]2[C:52]3[C:32]([CH2:33][C@@H:34]4[C:46]([C:47]=3[CH:48]=[CH:49][CH:50]=2)=[CH:45][C@@H:37]([C:38](=[O:44])[N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:36][N:35]4[CH3:53])=[CH:31]1.C(N(CC)CC)C>C1COCC1>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[C:51]4[C:52]5[C:32]([CH2:33][C@@H:34]6[C:46]([C:47]=5[CH:48]=[CH:49][CH:50]=4)=[CH:45][C@@H:37]([C:38](=[O:44])[N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])[CH2:36][N:35]6[CH3:53])=[CH:31]3)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Cl)c1ccc(-c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Reactant: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCN)C[C@H]2N(C)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCNC(=O)c3ccc(-c4ccc(C(=O)ON5C(=O)CCC5=O)cc4)cc3)C[C@H]2N(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A solution of 850 mg (2.375 mmol) of 12 in 65 mL of dry THF under argon was cooled to 0° C. in an icebath, then treated with a solution of 900 mg (2.365 mmol) of 10 in 50 mL of dry THF and 0.6 mL (4.3 mmol) of triethylamine added dropwise over a 20 minute period. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature, with stirring, for 1 hour. The mixture was concentrated at reduced pressure and the residue was dissolved in 100 mL of methylene chloride. The solution was washed with 100 mL of H2O, 100 mL of saturated sodium bicarbonate solution, 100 mL of saturated brine solution, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a brown residue. This was chromatographed on a short column of 100 g of silica gel using first methylene chloride as eluent, then 9:1 methylene chloride-ether as eluent to elute front running impurities, then 14:1 methylene chloride-isopropyl alcohol as eluent to elute the product to yield 650 mg (39%) of 13 as a cream colored solid [α]D=+34.3° (c=0.45%; CHCl3).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:10][C:11]=2[I:12])[CH:6]=[CH:7][N:8]=1>C(O)(C)C.C1COCC1>[NH2:1][C:3]1[C:4]2[N:5]([C:9]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:10][C:11]=2[I:12])[CH:6]=[CH:7][N:8]=1
Reactant: N
Reactant: CC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC1(O)CC(c2nc(I)c3c(N)nccn23)C1
Temperature: -78 °C

Procedure:
A solution of 2M ammonia in isopropanol (80 mL) and THF (5 mL) was added to 3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (2.77 g, 7.62 mmol) in a Parr pressure reactor. The mixture was cooled to at −78° C. then ammonia gas was bubbled into the solution for 4-6 min. The reactor was sealed then heated at 110° C. for 15 h. The solvent was then removed in vacuo and the residue purified by chromatography over silica gel eluting with 7% MeOH in DCM to afford desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 3 H), 2.32-2.51 (m, 4 H), 3.33-3.52 (m, 1 H), 6.61 (br.s., 2 H), 7.03 (d, J=5.05 Hz, 1 H) and 7.62 (d, J=5.05 Hz, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C#N)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(NC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.3 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(3-cyanophenyl)amino]-1-piperidinecarboxylate (D5) (750 mg, 2.43 mmol) in DCM (30 ml) was cooled in an ice bath and TFA (6 ml) was added. The reaction mixture was then stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue loaded onto an Isolute SCX cartridge. Elution with MeOH (100 ml) followed by 2M NH3 in MeOH (100 ml) gave the title compound as a white solid (613 mg). δH (CDCl3, 250 MHz) 7.21 (2H, t), 6.93 (1H, m), 6.77 (2H, m), 3.78 (1H, m), 3.35 (1H, m), 3.14 (2H, m), 2.73 (2H, m), 2.06 (2H, m), 1.34 (2H, m). MS (ES): MH+ 202.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F-:10].[K+]>CN1CCCC1=O.O>[F:10][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: [F-]
Reactant: N#Cc1ccc(Br)cn1
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(F)cn1
Temperature: 175 °C
Reaction time: 18 h

Procedure:
The mixture of 5-bromo-pyridine-2-carbonitrile (0.50 g, 2.73 mmol), and KF (0.48 g, 8.20 mmol) in 10 ml of 1-methyl-2-pyrrolidinone was stirred at 175° C. for 18 h, cooled to RT, diluted with H2O, extracted with EtOAc, the combined organic portions were washed with H2O, brine, dried with Na2SO4, filtered, condensed, the crude compound was purified by flash column chromatography (5 to 20% of EtOAc in hexanes). The titled compound was obtained as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][CH:24]=[CH2:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (500 mg, 1.67 mmol) in methyl ethyl ketone (6 mL) was treated with allyl bromide (232 mg, 1.92 mmol, 0.17 mL) and potassium carbonate (311 mg, 2.25 mmol) and then heated to reflux. After 18 h, the mixture was cooled to ambient temperature and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and then the organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100 mL SiO2, hexanes to 10% EtOAc/hexanes) to provide the desired product (478 mg, 84%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J=8.0 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.97 (dt, J=7.6, 1.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 2H), 6.84 (t, J=8.4 Hz, 2H), 6.05 (ddd, J=17.2, 10.6, 5.2 Hz, 1H), 5.41 (dd, J=17.2, 1.6 Hz, 1H), 5.28 (dd, J=10.8, 1.4 Hz, 1H), 4.22 (d, J=5.2 Hz, 2H), 4.19 (q, J=6.8 Hz, 2H), 3.27 (A of AB, J=14 Hz, 1H), 3.11 (B of AB, J=14 Hz, 1H), 1.40 (s, 3H), 1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:24]C)[CH2:22]C)C.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH3:19][N:21]([CH3:24])[C:22]1[O:12][C:11]2[C:10]3[CH:9]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NCCC1CCc2ccc3nc(N(C)C)oc3c21
Reaction time: 0.25 h
Yield: 7 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was suspended in dichloromethane (3.7 mL), triethylamine (51.5 μg, 0.369 mmol) was added at room temperature, and the mixture was stirred for 15 min. Thereto was added dichloromethylenedimethyliminium chloride (59.9 mg, 0.369 mmol), and the mixture was heated under reflux for 1 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (7.4 mg, yield 7%).