Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH:12]=O.C([CH2:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])=[O:30])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:28]/[C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34]([OH:36])=[O:35])=[O:30])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1cc(C=O)ccc1OCc1cccnc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OCc1cccnc1
Yield: 43.5 %

Procedure:
3-Bromomethylpyridine (0.30 mg, 1.2 mmol) was added to a suspension of vanillin (0.12 g, 0.79 mmol), potassium carbonate (0.33 g, 2.4 mmol) in acetone (5.0 mL) and treated according to Procedure 3. 3-Methoxy-4-(pyridin-3-ylmethoxy)benzaldehyde (88 mg, 46%) was obtained as a brown oil. Piperidine (36 μL, 0.36 mmol) was added to a suspension of 3-methoxy-4-(pyridin-3-ylmethoxy)benzaldehyde (0.88 mg, 0.36 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (73 mg, 0.33 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-[[3-(3-Methoxy-4-(pyridin-3-ylmethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (58 mg, 44%) was obtained as a pure brown crystalline solid; mp 245-251° C.; δH (400 MHz, DMSO-d6) 3.84 (s, 3H, OCH3), 5.18 (s, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.12 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.24 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.40-7.45 (m, 2H, H2′, Ar—H), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.87 (d, J=8.0 Hz, 1H, Ar—H), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.55-8.67 (m, 3H, H6, Ar—H), 11.32 (s, 1H, NH); δC (100 MHz, DMSO-d6) 55.7, 67.6, 110.8, 113.4, 116.7, 120.2, 120.3, 122.4, 122.7, 123.6, 127.9, 131.1, 132.4, 133.9, 135.9, 141.0, 141.5, 149.1, 149.2, 149.3, 164.2, 169.5; HRMS (ESI) calculated for C23H20N2O5 [M+H]+ 404.1445 found 404.1445; vmax 758, 1257, 1509, 1586, 1671, 2931 cm−1.
Reaction SMILES: [C:1]1([S:7](Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C@:13]1(O)[C:18](=[CH2:19])[CH2:17][C@H:16]2[C@H:20]3[C:30](=[CH:31][CH2:32][C@:14]12[CH3:15])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)(=[O:12])[CH3:11].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]1([S:7]([CH2:19][C:18]2[CH2:17][C@@H:16]3[C@:14]([CH3:15])([CH2:32][CH:31]=[C:30]4[C@H:20]3[CH2:21][CH2:22][C:23]3[C@:28]4([CH3:29])[CH2:27][CH2:26][C:25](=[O:33])[CH:24]=3)[C:13]=2[C:10](=[O:12])[CH3:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Reactant: O=S(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)C1=C(CS(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C

Procedure:
A solution of phenylsulfinylchloride (2.5N, 1.4 ml) in methylene chloride was added dropwise over a period of 1.5 hrs to a solution of 17-acetyl-17β-hydroxy-16-methyleneandrost-4,9(11)-dien-3-one (VA, Example 12, 1 g) in methylene chloride (10 ml) containing triethylamine (0.82 ml) previously cooled equal to 31 55°. Water was added to the reaction mixture, the organic phase separated, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to a partially crystalline substance. Crystallization from toluene gives the title compound, m.p. 160°-163°; NMR (CDCl3) 0.87, 1.36, 2.11, 4.03, 5.50 and 5.75 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([Cl:23])[CH:14]=2)=[O:11])=[CH:4][C:3]=1[O:24][CH3:25]>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([Cl:23])[CH:14]=2)=[O:11])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc(/C=C/C(=O)Nc2ccc(C(F)(F)F)c(Cl)c2)ccc1Cl
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)Nc2ccc(C(F)(F)F)c(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
The alkene from Step 2 (0.755 g, 1.80 mmol) was suspended in MeOH. To this suspension was added Pd/C (10 wt %). The reaction was placed under an atmosphere of hydrogen gas and allowed to stir at rt for 3 h. The mixture was filtered through Celite and concentrated. The residue was purified by column chromatography to give the desired product (0.546 g, 72%). LCMS: (FA) ES+ 392.0 (M+1), ES− 390.0 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:13][C:14]#[N:15])=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)([O-])=O>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:13][C:14]#[N:15])=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2
Reactant: N#CCc1ccc([N+](=O)[O-])c2[nH]ncc12
Agent: [Ni]
Solvent: C1CCOC1
Product: N#CCc1ccc(N)c2[nH]ncc12
Yield: 87.8 %

Procedure:
20.2 g of 2-(7-nitro-1H-indazol-4-yl)-acetonitrile in 750 ml of tetrahydrofuran is hydrogenated in the presence of 20.0 g of Raney nickel. The product is recrystallized from tetrahydrofuran/hexane, yielding 15.1 g of 2-(7-amino-1H-indazol-4-yl)acetonitrile, mp 164°-165° C.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[NH:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH2:31])[CH:27]=2)[N:22]=1>>[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[NH:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH:31][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:27]=2)[N:22]=1
Reactant: CC(C)N=C=O
Reactant: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from isopropyl isocyanate and rac-N2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=460.6 (M+H+).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25]CC)=O)(=O)[CH3:2].O.[NH2:29][NH2:30]>C(O)(=O)C>[CH2:16]([O:15][C:6]1[C:5]2[C:23](=[O:25])[NH:30][N:29]=[C:1]([CH3:2])[C:4]=2[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O

Procedure:
A solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (0.44 g,1.2 mmol; see Example 7, Step 7), and hydrazine monohydrate (0.37 mL, 11.9 mmol) in glacial acetic acid (2 mL) was heated in a microwave oven at 180° C. for 20 minutes. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was dried over MgSO4, filtered, and concentrated to provide the titled dione.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1.CI.[C:33]([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH3:33][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)[CH:20]=4)[CH:16]=[CH:15][N:14]=3)=[CH:10][CH:11]=2)=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: c1cc(-c2ccnc(Nc3ccc(-c4nn[nH]n4)cc3)n2)cc(N2CCOCC2)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nnc(-c2ccc(Nc3nccc(-c4cccc(N5CCOCC5)c4)n3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-(2H-tetrazol-5-yl)phenyl)-4-(3-morpholinophenyl)pyrimidin-2-amine (0.20 g, 0.50 mmol), MeI (0.71 g, 5.0 mmol) and K2CO3 (0.35 g, 2.50 mmol) in acetone (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with EtOAc (3×). The combined organic solution was dried over anhydrous MgSO4 and concentrated in vacuo to give a solid. Purification of this material by column chromatography on silica gel (40% EtOAc/hexane) provided N-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)-4-(3 morpholinophenyl)pyrimidin-2-amine as the major product. 1H NMR (DMSO-d6, 400 MHz) δ 10.00 (s, 1H), 8.60 (d, 1H), 8.05 (d, 2H), 8.00 (d, 2H), 7.78 (s, 1H), 7.65 (d, 1H), 7.50 (d, 1H), 7.42 (t, 1H), 7.18 (dd, 1H), 4.42 (s, 3H), 3.80 (m, 4H), 3.24 (m, 4H). MS (ESI) 415.13 (M+H).
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:34][C@@H:33]([C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)[C@:17]2([N:21]([CH3:22])[C:20](=[O:23])[N:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:18]2=[O:32])[CH2:16]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:31][C:26]1[CH:25]=[C:24]([N:19]2[C:18](=[O:32])[C@@:17]3([C@H:33]([C:35]4[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=4)[CH2:34][NH:15][CH2:16]3)[N:21]([CH3:22])[C:20]2=[O:23])[CH:29]=[C:28]([Cl:30])[CH:27]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1ccccc1)C[C@H]2c1ccc(C#N)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
1-Chloroethyl chloroformate (4.4 ml, 40.3 mmol) was added to a cooled (5° C.) solution of Example 14 (5.1 g, 10.1 mmol) in DCM (250 ml). After 1 h at 5° C., the reaction mixture was stirred at RT for 20 h. The solution was concentrated to dryness and then refluxed in MeOH (350 ml) for 3 h. After concentration in vacuo, the oily residue was triturated in Et2O to give the hydrochloride of the desired compound (4.9 g). After basification, the product was chromatographed over silica gel (DCM/MeOH 90/10) to yield the above-titled compound (3.35 g) as an amorphous solid. 1H NMR (CDCl3): 7.64 (2H, d, J=8.4 Hz), 7.25–7.32 (3H, m), 6.72 (2H, d, J=2 Hz), 3.6–3.75 (2H, m), 3.35–3.55 (3H, m), 3.20 (3H, s), 2.16 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[Cl:1][C:2]1[C:7]([O:8][CH3:12])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1O
Solvent: CC#N
Solvent: CO
Product: COc1c([N+](=O)[O-])ccnc1Cl
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of 2-chloro-4-nitro-pyridin-3-ol (1.05 g, 6.02 mmol) in acetonitrile (45 mL) and methanol (5 mL), trimethylsilyldiazomethane (2M in hexane, 3.9 mL, 7.8 mmol) were added slowly. After 30 minutes, mixture was concentrated and residue was purified by column chromatography on silica gel (hexane/ethyl acetate 5:1) to give 2-chloro-3-methoxy-4-nitro-pyridine as a white solid (0.77 g, 68%). 1HNMR (CDCl3, 400 MHz) δ 8.35-8.34 (d, J=5.1 Hz, 1H), 7.58-7.56 (d, J=5.2 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][C:34]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:35])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(4-benzyloxy-phenyl)-propionic acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.83 (m, 2 H), 2.00 (m, 2 H), 2.66 (t, J=7.64 Hz, 2 H), 2.88 (t, J=7.49 Hz, 2 H), 3.05 (dd, J=10.45, 7.33 Hz, 2 H), 3.53 (m, 2 H), 3.69 (m, 2 H), 4.67 (t, J=6.24 Hz, 2 H), 5.06 (s, 2 H), 6.93 (m, 2 H), 7.07 (m, 1 H), 7.18 (m, 2 H), 7.32 (m, 1 H), 7.40 (m, 4 H), 7.70 (m, 1 H), 8.08 (m, 1 H), 8.28 (s, 1 H), 10.13 (s, 1 H); MS (DCI/NH3) m/z 469 (M+H)+;
Reaction SMILES: [CH3:1][C:2]([CH3:26])=[CH:3][CH2:4][C:5]1[C:6]([OH:25])=[CH:7][C:8]([O:23]C)=[C:9]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[O:11][C:10]=12>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3].C1COCC1>[CH3:1][C:2]([CH3:26])=[CH:3][CH2:4][C:5]1[C:10]2[O:11][C@H:12]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[CH2:13][C:14](=[O:15])[C:9]=2[C:8]([OH:23])=[CH:7][C:6]=1[OH:25]
Reactant: COc1cc(O)c(CC=C(C)C)c2c1C(=O)CC(c1ccc(O)cc1)O2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C1CCOC1
Product: CC(C)=CCc1c(O)cc(O)c2c1O[C@H](c1ccc(O)cc1)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a mixture of isoxanthohumol (50 mg, 0.14 mmol), KI (34 mg, 0.21 mmol) and Sc(OTf)3 (105 mg, 0.21 mmol), 10 ml of THF are added and the solution is heated for 2.5 h under reflux. The mixture is stirred overnight at room temperature and concentrated in vacuum. The scandium salt is separated off via a short silica gel column (eluted with CHCl3/methanol=100:1). The resultant solution is concentrated to dryness in vacuum, the residue is taken up in CHCl3 and eluted through a silica gel column using CHCl3/-methanol=100:1. 8-Prenylnaringenin (formula (III) where R1=prenyl, R2=H) (44 mg, 92%) is obtained as a light-yellowish solid.
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:9]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[N:23](C(=O)C)[N:22]=2)=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][CH:13]=1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>CCO>[C:1]([O:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:9]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C=C/c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)n(C(C)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OC/C=C/c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.1 %

Procedure:
The mixture of (E)-3-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-yl)allyl acetate (80 mg, 0.192 mmol, 1.0 equiv.) and NaHCO3 (144 mg, 1.724 mmol, 9.0 eqiv.) in EtOH (20 mL) was stirred at room temperature for 24 h. The reaction mixture was filtered, the filtrate was concentrated. The residue was diluted with EtOAc and washed with water, brine, dried (Na2SO4), and filtered. The filtrate was concentrated and purified by silica gel chromatography (EtOAc/MeOH 20:1) to afford (E)-3-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-yl)allyl acetate (Compound 81) (8 mg, 11.1%). LC-MS (m/z): 376.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 0.72-0.73 (m, 2H), 0.96-0.98 (m, 2H), 1.91-1.98 (m, 1H), 2.07 (s, 3H), 4.70 (d, J=5.6 Hz, 2H), 6.35 (d, J=15.2 Hz, 1H), 6.46 (s, 1H), 7.10 (d, J=15.2 Hz, 1H), 7.47-7.49 (m, 3H), 8.29-8.30 (m, 2H), 8.54 (s, 1H), 9.29 (s, 1H), 12.16 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.1 %

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decan-8-ol (1.85 mg, 11.70 mmol), phenol (1.0 g, 10.64 mmol), PPh3 (3.07 g, 11.70 mmol) in 15 mL of THF at 0° C. was added diisopropyl azodicarboxylate (6 mL, 11.70 mmol, 40% in toluene). The reaction mixture was stirred at room temperature for 48 h. Excess THF was removed in rotary evaporator and the residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:19) to obtain 8-phenoxy-1,4-dioxa-spiro[4.5]decane (1.3 g, 52%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([NH:27][C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])[CH2:25][CH3:26]>>[O:29]=[C:28]([NH:27][CH2:24][CH2:25][CH3:26])[CH2:30][CH2:31][CH2:32][C:33]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:34]
Reactant: CCCNC(=O)CCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCNC(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-propylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-oxo-5-(propylamino)pentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+H]=938; RT=1.19 min; UPLC Method I
Reaction SMILES: [ClH:1].[C:2]1([NH:8][C:9]([O:11][C:12]2[C:25]3[CH2:24][CH2:23][C@H:22]4[C@@H:17]([CH2:18][CH2:19][CH2:20][N:21]4CC4C=CC=CC=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[ClH:1].[C:2]1([NH:8][C:9]([O:11][C:12]2[C:25]3[CH2:24][CH2:23][C@H:22]4[C@@H:17]([CH2:18][CH2:19][CH2:20][NH:21]4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)Oc1cccc2c1CC[C@H]1[C@H]2CCCN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(Nc1ccccc1)Oc1cccc2c1CC[C@@H]1NCCC[C@@H]21

Procedure:
(±)-trans-7-Phenylcarbamoyloxy-4-benzyl-1,2,3,4,4a,5,6,10b-Octahydrobenzo(f)quinoline hydrochloride (40 mg, 0.12 mmol) was dissolved in MeOH (5 ml) and hydrogenolyzed in the presence of 10% Pd/C (40 mg) at 25 psig at room temperature. After filtration of the catalyst and evaporation of the solvent the desired product (20 mg) was obtained. MS shows M+ at m/e 322.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][CH:8]([OH:10])[CH3:9])[CH:2]=[CH2:3].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][CH:8]([CH2:7][CH2:6][CH:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH3:11])[CH3:9]
Reactant: BrCCCCBr
Reactant: C=CCOC(C)CCC(C)O
Product: C=CCOC(C)CCC(C)OCCCCBr

Procedure:
Using 5-allyloxy-2-hexanol and 1,4-dibromo-butane, the above compound is produced.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:22][CH:23]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:22][CH:23]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: CCOC(=O)c1cncc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Product: CCOC(=O)c1cncc(N2CC[C@H](N)[C@H](OC)C2)c1
Yield: 46.7 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-4-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)pyridine-2-carboxylate obtained in Example (162a) (436 mg) and a 10% palladium-carbon catalyst (500 mg), to obtain 137.5 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: BrC1C=CC(S([O:11][C@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=4)[CH2:18]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH3:30]O>>[CH3:30][O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:18]2)[CH2:14][CH2:13]1
Reactant: O=S(=O)(O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Br)cc1
Reactant: CO
Product: CO[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21

Procedure:
(3aR,4R,6aS)-2-[6-(Trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl 4-bromobenzenesulfonate (100 mg, 0.204 mmol) from Example 39 was heated at 85° C. for 3 days in methanol (0.3 mL) to give a colorless solution. The methanol was removed in vacuo, and the crude material was purified by silica gel chromatography using 100% dichloromethane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.57-7.53 (m, 1H), 7.01 (d, J=7.3, 1H), 6.54 (d, J=8.6, 1H), 3.58 (dd, J=11.0, 8.8, 1H), 3.52 (dd, J=7.1, 4.8, 1H), 3.47 (dd, J=10.7, 7.8, 1H), 3.28 (dd, J=11.1, 4.8, 1H), 3.24-3.18 (m, 4H), 2.81-2.64 (m, 2H), 1.93 (dq, J=12.9, 7.9, 1H), 1.80 (dtd, J=13.2, 7.8, 5.4, 1H), 1.68 (ddd, J=17.7, 11.3, 6.7, 1H), 1.38-1.25 (m, 1H); MS (ESI+) m/z 287 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C1COCC1.[OH-].[Na+]>O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=3)=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2cn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of methyl 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylate (27.0 mg) obtained in Example 3 in a mixed solvent of methanol (2 mL)/THF (2 mL)/water (2 mL) was added 8N aqueous sodium hydroxide solution (0.025 mL) at 0° C. The reaction mixture was stirred at 90° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (26.0 mg).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([CH2:22][CH3:23])[C:19]([OH:24])=[CH:18][C:17]=3[O:25][CH3:26])[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[CH:33]=O.CC1C=NC2N(N=C(C=O)N=2)C=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([CH2:22][CH3:23])[C:19]([OH:24])=[CH:18][C:17]=3[O:25][CH3:26])[O:11][C:10](=[O:12])[C:9]([CH2:27][C:28]3[N:29]=[CH:30][NH:31][C:32]=3[CH3:33])=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc[nH]c1C=O
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)cc1O
Agent: Cc1cnc2nc(C=O)nn2c1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc[nH]c3C)C(=O)O2)c(OC)cc1O

Procedure:
The title compound was prepared analogously to Example A(126), where 6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione was substituted in place of 6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl-dihydro-pyran-2,4-dione and 4-methyl-5-imidazol carboxaldehyde was substituted in place of 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (t, J=7.5 Hz, 3H), 1.10-1.56 (m, 10H), 1.73-1.68 (m, 1H), 1.92 (s, 3H), 2.21-2.5 (m, 6H), 3.20-3.22 (m, 2H), 3.44 (s, 3H), 6.17 (s, 1H), 6.50 (s, 1H), 7.53 (s, 1H). Anal. Calcd. For C26H34N2O5.1H2O: C, 66.08; H, 7.68; N, 5.93. Found: C, 65.93; H, 7.66; N, 5.89. MS(ESI): 455.2 (M+H)+.