Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OCCCc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(CCCBr)c1
Yield: 78.8 %

Procedure:
Compound 23-1 (10.0 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (17.5 g) and N-bromosuccinimide (11.8 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (11.1 g) as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].OC1C=CC=CN=1.[C:13]([O:17][C:18](=[O:48])[NH:19][C@H:20]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:21][N:22]1[CH2:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[Cl:36])[CH2:24][C:23]1([CH3:38])[CH3:37])([CH3:16])([CH3:15])[CH3:14]>O>[C:13]([O:17][C:18](=[O:48])[NH:19][C@@H:20]([CH2:21][N:22]1[CH2:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[Cl:36])[CH2:24][C:23]1([CH3:38])[CH3:37])[C@@H:39]([OH:40])[CH2:43][C@H:42]([C:41](=[O:47])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:44]([CH3:45])[CH3:46])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CCCCN
Agent: Oc1ccccn1
Solvent: O
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CN1CC(=O)N(c2cc(F)ccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
0.89 ml of n-butylamine (9.5 mmol) and 28 mg of 2-hydroxypyridine (0.48 mmol) were added to 250 mg of {(S)-2-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (62f) (0.48 mmol), and the mixture was stirred at 70° C. for one hour. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 254 mg of the title compound (yield: 89%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.Br[CH2:19][C:20]1[O:28][C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=1>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:19][C:20]2[O:28][C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCc1cc2cnccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2cc3cnccc3o2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
NaH (4.4 mg of a 60% dispersion in mineral oil, 110 μmol) was added to a stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (20.2 mg, 100 μmol) in anhydrous THF (1 mL). After 1 h, the mixture was added to a stirred solution of 2-bromomethylfuro[3,2-c]pyridine hydrochloride (Preparation 5, 25.0 mg, 100 μmol) in anhydrous THF (2 mL) which had been pretreated with NaH (4.4 mg of a 60% dispersion in mineral oil, 110 μmol). The mixture was stirred for 16 h at 20° C., before being treated with Bu4NI (3.7 mg, 10 μmol) and heated at 60° C. for 4 h. On cooling, the reaction mixture was quenched with H2O (5 mL), before being extracted with EtOAc (2×5 mL). The combined organic extracts were dried (MgSO4), filtered, concentrated, and purified by flash chromatography (IH-EtOAc, 2:3) to yield the title compound: RT=2.64 min; m/z (ES+)=333.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]([C:18]#[N:19])=[C:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([CH3:24])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]([C:10]1([C:18]#[N:19])[CH2:24][C:11]1([CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH3:17])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(CCC)=C(C#N)C(=O)OCc1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCC1(CCC)CC1(C#N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of 2-cyano-3-propyl-hex-2-enoic acid benzyl ester (0.91 g, 3.35 mmol) in 50 mL acetonitrile was added nitromethane (0.91 mL, 16.77 mmol), followed by DBU (0.50 mL, 3.35 mmol) resulting in an orange solution. The reaction was stirred at room temperature for 16 hours, then partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 0.71 g (81%) of 1-cyano-2,2-dipropyl-cyclopropanecarboxylic acid benzyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.21 (dd, J=18.3, 12.4 Hz, 2H), 1.79 (d, J=5.1 Hz, 1H), 1.74 (m, 1H), 1.52 (m, 3H), 1.43 (d, J=5.1 Hz, 1H), 1.36 (m, 3H), 1.04 (m, 1H), 0.95 (t, J=7.1 Hz, 3H), 0.73 (t, J=7.1 Hz, 3H). 13C NMR δ 166.40, 135.22, 128.81, 128.69, 128.48, 118.60, 68.23, 41.26, 36.45, 30.27, 29.76, 24.91, 19.74, 19.65, 14.22, 14.10. IR (neat) 2240, 1734 cm−1. Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.38; H, 8.02; N, 4.97.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH:11](OC)[O:12]C)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(O)(=O)C.Cl>O>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH:11]=[O:12])=[CH:16][CH:17]=1)([CH3:1])[CH3:3]
Reactant: COC(COc1ccc(C(C)(C)C)cc1)OC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc(OCC=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5.00 g (0.021 mol.) of 2-[4-(1,1-dimethylethyl)phenoxy]-1,1-dimethoxyethane and 60 ml of acetic acid, there was added 6 ml of hydrochloric acid (36N) and the reaction mixture was stirred at room temperature for one hour. Then the reaction mixture was poured into 300 ml of cold water and filtrated quickly to recover a resultant white precipitate. The precipitate was obtained as a wet cake of 2-[4-(1,1-dimethylethyl) phenoxy]acetoaldehyde without being dried too much and was quickly used in the next step of the production procedure.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:21][C:22]([NH:24][CH2:25][C:26](=[O:28])[CH3:27])=O>O=P(Cl)(Cl)Cl>[CH3:27][C:26]1[O:28][C:22]([CH2:21][N:3]2[C:2](=[O:1])[N:6]3[CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=4)[CH:9]=[CH:10][C:5]3=[N:4]2)=[N:24][CH:25]=1
Reactant: CC(=O)CNC(=O)Cn1nc2ccc(-c3ccc(C(F)(F)F)cc3)cn2c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cnc(Cn2nc3ccc(-c4ccc(C(F)(F)F)cc4)cn3c2=O)o1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
2-(3-oxo-6-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-2 (3H)-yl)-N-(2-oxopropyl)acetamide was dissolved in POCl3 (3 mL) in a 50 mL round bottomed flask. The mixture was heated at 70-90° C. for 2 h and then 100° C. for 15 h. After removal of POCl3 under a reduced pressure, obtained residue was quenched with sat. NaHCO3 aq. solution (30 mL). The whole was extracted with EtOAc (30 mL×3). Combined organic layers were washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give compound 172 as pink crystals, 30.3 mg, 0.0756 mmol, >99%). LCMS (EI: 70 eV) 397 (M++Na), 375 (M++1).
Reaction SMILES: [F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]2=[O:23])[CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH2:35])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:35][CH:7]3[CH2:6][CH2:5][N:4]([CH2:9][CH2:10][N:11]4[C:20]5[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=5)[N:14]=[CH:13][C:12]4=[O:23])[CH2:3][CH:2]3[F:1])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(=O)C(F)C3)c2c1
Reactant: NCc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)C(F)C3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.9 %

Procedure:
To 2 mL of a dichloromethane solution containing 48 mg of 1-(2-(3-fluoro-4-oxopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 30 mg of 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methaneamine, 26 μL of acetic acid was added, and stirred at room temperature for 1.5 hours. To the reaction mixture, 48 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography [eluent; chloroform:methanol=50:1], to give 31 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-fluoropiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:33][CH:32]([OH:34])[CH2:31][CH:30]1[CH:35]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:36][CH:37]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:28]>>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[O:36][CH:35]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:30]2[CH2:31][CH:32]([OH:34])[CH2:33][N:29]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:39][CH:40]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Yield: 90 %

Procedure:
Using the above described procedure, stearic acid 101e (2.84 g, 10 mmol) was coupled with the amine 100 and after work-up and column purification the pure amide was isolated as a foam (7.17 g, 90%). 1H NMR (DMSO-d6, 400 MHz) δ=7.76-7.65 (m, 1H), 7.34-7.10 (m, 9H), 6.90-6.79 (m, 4H), 4.96 (d, J=3.90 Hz, 0.7H), 4.88 (d, J=3.90 Hz, 0.3H), 4.40-4.05 (m, 2H), 3.71 (s, 6H), 3.59-3.42 (m, 1H), 3.34-3.13 (m, 2H), 3.10-2.87 (m, 3H), 2.20-1.80 (m, 6H), 1.50-1.08 (m, 36H), 0.83 (t, J=6.1 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.83, 170.92, 170.82, 162.29, 158.10, 157.97, 145.08, 144.74, 135.86, 135.42, 135.47, 129.59, 129.54, 127.84, 127.76, 127.57, 126.56, 113.18, 113.09, 85.78, 85.10, 68.57, 67.44, 65.19, 63.32, 54.97, 40.12, 38.21, 36.29, 35.77, 35.42, 34.16, 31.30, 30.75, 29.04, 28.78, 28.72, 28.65, 26.18, 25.33, 24.14, 22.10, 13.95.
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[CH2:15]([C@@H:19]([CH2:23][CH:24]=[CH2:25])[C:20](O)=[O:21])[CH:16]([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:15]([C@@H:19]([CH2:23][CH:24]=[CH2:25])[C:20]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: C=CC[C@H](CC(C)C)C(=O)O
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CC[C@H](CC(C)C)C(=O)NCC(=O)OC
Reaction time: 16 h
Yield: 59.7 %

Procedure:
Step M (1): NMM (11.0 mL, 100 mmol) was added to a mixture of methyl 2-aminoacetate hydrochloride (4.44 g, 35.3 mmol), (S)-2-isobutylpent-4-enoic acid [prepared as described in WO 2004/013098] (4.6 g, 29.5 mmol), HATU (13.4 g, 35.3 mmol in DCM (200 mL) at room temperature. The mixture was stirred for 16 h. Poured the reaction mixture into 150 mL H2O. Extracted with DCM (3×250 mL). Washed combined organic extracts with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give (S)-methyl 2-(2-isobutylpent-4-enamido)acetate 4.0 g (60% yield) as a colorless oil: ESI (M+H)+=228.22. 1H NMR (300 MHz, CDCl3) δ ppm 0.79-0.93 (m, 6H) 1.15-1.30 (m, 1H) 1.48-1.71 (m, 2H) 2.08-2.38 (m, 3H) 3.72 (s, 3H) 4.01 (d, J=5.12 Hz, 2H) 4.92-5.09 (m, 2H) 5.63-5.78 (m, 1H) 5.92 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1[CH3:24]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1[CH3:24]
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc(O)c2cc(F)ccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of (4-benzyloxy-6-fluoro-1-methyl-naphthalen-2-yl)-acetic acid methyl ester (50 mg) in methanol was added 10% palladium on carbon (10 mg). After being stirred at room temperature under a hydrogen atmosphere overnight, the resulting mixture was filtered. The filtrate was concentrated in vacuo to afford (6-fluoro-4-hydroxy-1-methyl-naphthalen-2-yl)-acetic acid methyl ester (30 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
10.8 g (26.2 mmol) of the compound of Example 26A are provided in 236 ml of 1,4-dioxane, 236 ml (472 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 2 h. The mixture is concentrated and a 2N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 9.90 g (99% of theory) of the title compound are obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([O:27][CH3:28])[CH:10]=2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[CH3:28][O:27][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]([CH2:3][OH:2])[CH:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:17]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)C1c2ccc(OC)cc2C2CCCCC2C1c1ccc(OC)cc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2C(CO)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 3 h
Yield: 89.9 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-carboxylic acid methyl ester (4.25 g, 11.17 mmol), lithium aluminum hydride (1.20 g, 32.39 mmol), and tetrahydrofuran (150 mL), and reflux under nitrogen atmosphere. After 3 hours, quench reaction by adding reaction to a stirred solution of Rochelle's salt (Na K Tartrate) and ethyl acetate. After several hours, separate the organic phase and wash with brine. Dry the organic phase with anhydrous sodium sulfate and flash chromatograph using 5% to 30% ethyl acetate/hexanes to yield the titled compound (3.54 g, 90%) as a white solid. TLC Rf=0.13 in 4:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.43 (d, 1H, J=8.8 Hz), 7.26 (d, 2H, J=8.4 Hz), 7.00 (m, 1H), 6.93 (d, 2H, J=8.8 Hz), 6.84 (dd, 1H, J=8.4, 2.6 Hz), 4.05 (dd, 1H, J=11.2, 3.3 Hz), 3.86 (m, 6H), 3.62 (dd, 1H, J=11.0, 2.6 Hz), 3.34 (m, 3H), 2.49 (d, 1H, J=13.7 Hz), 1.95 (m, 1H), 1.65 (m, 2H), 1.45 (m, 2H), 1.30 (m, 1H), 1.16 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][C@H:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][C:26](=[C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>>[C:30]1([C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:12]([C@@H:10]3[CH2:9][S:8][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11]3)=[O:14])[CH2:28][CH2:27]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCCCCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)[C@@H]1CSC(c2cccnc2)N1
Product: O=C(NCCCCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)[C@@H]1CSC(c2cccnc2)N1
Yield: 46 %

Procedure:
The title compound was prepared in a yield of 46% in a similar manner to that described in Example 17' by reacting 2-(3-pyridyl) thiazolidine-4(R)-carboxylic acid and 1-(7-aminoheptyl)-4-(diphenylmethylen) piperidine (prepared as described in Preparation 43').
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:8]([CH3:9])=[N:7][N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)#[N:2].[CH3:16][C:17]1[S:18][C:19]([C:23](N2C=CC=N2)=[O:24])=[C:20]([CH3:22])[N:21]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[CH3:16][C:17]1[S:18][C:19]([C:23]([OH:24])=[C:3]([C:4]2[C:8]([CH3:9])=[N:7][N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)[C:1]#[N:2])=[C:20]([CH3:22])[N:21]=1
Reactant: Cc1nn(-c2ccccc2)nc1CC#N
Reactant: Cc1nc(C)c(C(=O)n2cccn2)s1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(O)=C(C#N)c2nn(-c3ccccc3)nc2C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
0.90 g of 4-cyanomethyl-5-methyl-2-phenyl-1,2,3-triazole and 1.04 g of 1-(2,4-dimethylthiazol-5-carbonyl)pyrazole were dissolved in tetrahydrofuran, and 1.02 g of potassium tert-butoxide was added thereto at 0° C. After stirring for 1 hour at room temperature, diluted hydrochloric acid was added to the reaction solution to make it acid. The solution was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was washed with isopropyl ether to obtain 0.79 g of the aimed compound. m.p.: 117-118° C.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:10]([CH2:12][O:13][CH3:14])=[CH:9][N:8]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:3]1[OH:26].S(=O)(=O)(O)O.[CH3:32]O>O.[OH-].[Na+]>[OH:26][C@H:3]1[C@@H:2]([O:1][CH3:32])[C:11]2[C:10]([CH2:12][O:13][CH3:14])=[CH:9][N:8]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CO
Reactant: COCc1cn2c(C)c(C)nc2c2c1[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1cn2c(C)c(C)nc2c2c1[C@H](OC)[C@H](O)[C@@H](c1ccccc1)N2
Reaction time: 16 h

Procedure:
180 mg of (7R,8R,9R)-7,8-dihydroxy-6-methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine, dissolved in 10 ml of methanol, are admixed with 110 mg of concentrated sulfuric acid and allowed to stand at room temperature for 16 hours. The mixture is then diluted with 100 ml of water and adjusted to pH 8 using aqueous IN sodium hydroxide solution and aqueous saturated sodium hydrogen carbonate solution and extracted 3 times with in each case 50 ml of methylene chloride. The combined organic phases are evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase: methylene chloride/methanol=100/3). This gives 100 mg of the title compound [Rf=0.62 (methylene chloride/methanol=13/1)] of melting point 126-9° C. (decomp.).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14].CC(OC(N(C)C)N(C)C)(C)C>CC#N>[CH3:12][N:13]([CH:15]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCc2ccccc21
Agent: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CC#N
Product: CN(C)C=C1CCc2ccccc2C1=O

Procedure:
A solution of 3,4-dihydro-2H-naphthalen-1-one in MeCN and 20 eq. of DMF-DMA were stirred at 90° C. overnight. Thin layer chromatography indicated there is almost no desired product, hence 1.2 equivalents of Bredereck's reagent was added, and the reaction mixture stirred at 80° C. overnight. The solvent was removed under reduced pressure and the crude material was used for the next step with no further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[N:32][C:31]([CH3:34])=[N:30]1)[NH2:25].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CN1CCCC1=O.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:6]3[N:7]=[C:2]([NH:25][C:24]4[CH:26]=[CH:27][C:28]([N:29]5[CH:33]=[N:32][C:31]([CH3:34])=[N:30]5)=[C:22]([O:21][CH3:20])[CH:23]=4)[N:3]=[C:4]([NH:18][CH3:19])[C:5]=3[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Reactant: COc1cc(N)ccc1-n1cnc(C)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNc1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hh) (141.2 mg, 0.508 mmol) and 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation D) (208 mg, 1.017 mmol) in N-Methyl-2-pyrrolidinone (4067 μL) was added H2SO4 (43.4 μL, 0.813 mmol). The solution was heated to 100° C. When the reaction was complete, water and NaHCO3 were added. After extraction into CH2Cl2, the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Applied the residue to SG and eluted with a EtOAc/Hex gradient, which yielded 7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 44).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CS[C:11](=N)[N:12](C1C=CC=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH:12]([C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1N
Reactant: CSC(=N)N(c1ccccc1)c1ccccc1
Product: c1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
Then, 101.2 g (0.973 mol) of o-phenylenediamine and 235.5 g (0.973 mol) of S-methyl-N,N-diphenylisothiourea were changed into a four-necked flask of 1l capacity, and reacted at 140° C. for 10 hours. The reaction product was cooled and filtered, and the filter cake was washed with xylene to obtain the aimed 2-anilinobenzimidazole having a melting point of 193.2°-194.5° C. in an yield of 149.2 9 (73.2%).