Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>C(#N)C.[C-]#N.[Zn+2].[C-]#N>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])=[O:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C(=O)c2ccc(Cl)cc2Cl)C(=O)N(C)C1=O
Yield: 80.2 %

Procedure:
1,3-Dimethylbarbituric acid (15.6 g, 0.1 mole), 2,4-dichlorobenzoyl chloride (20.9 g, 0.1 mole) and zinc cyanide (12.9 g, 0.11 mole) were combined in acetonitrile (175 ml). Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was then heated at reflux for one hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid. The resulting product precipitate was filtered and washed with ether to afford 26.4 grams of the desired product, m.p. 123°-127° C. (80.2% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.[CH3:34][C:35]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=1)([CH2:45][CH3:46])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:34][C:35]([C:47]1[CH:48]=[CH:49][CH:50]=[C:51]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([C:15]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:9]=[C:10]([C:11]([F:12])([F:14])[F:13])[C:3]=23)[CH:52]=1)([CH2:45][CH3:46])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43]
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2nccc(I)c12
Reactant: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(-c2ccnc3c2c(C(F)(F)F)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
4-iodo-3-(trifluoromethyl)-1-trityl-1H-pyrazolo[3,4-b]pyridine (135 mg, 0.2431 mmol) and tert-butyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (94.65 mg, 0.2431 mmol) were dissolved in dry Dioxane (1 mL) and Na2CO3 (364.6 μL of 2 M, 0.7293 mmol) was added. The solution was degassed (vacuum/nitrogen cycles×5), Pd[P(tBu)3]2 (12.42 mg, 0.02431 mmol) was added and stirred at 60° C. overnight. The reaction was allowed to cool to RT and partitioned between EtOAc and saturated Na2CO3. The aqueous layer was extracted with further EtOAc (3×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a dark purple solid. The resulting solid was purified by column chromatography (15% EtOAc in hexanes, ˜75 mL silica) to give a slightly brown gum (164.7 mg, 98% Yield).
Reaction SMILES: C(O[C:4]1[C:5](=[O:21])[C:6](=[O:20])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([CH2:18][CH3:19])[CH:11]=1)C.[NH2:22][C@@H:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24].ClCCl>C(O)C>[O:21]=[C:5]1[C:6](=[O:20])[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([CH2:18][CH3:19])[CH:11]=2)=[C:4]1[NH:22][CH:23]([CH3:24])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOc1c(NCc2ccc(C#N)c(CC)c2)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: ClCCl
Solvent: CCO
Product: CCc1cc(CNc2c(NC(C)C(C)(C)C)c(=O)c2=O)ccc1C#N
Reaction time: 24 h

Procedure:
This compound was prepared according to the procedure described in Example 24, Step 1. From 3-ethyl-4-cyanobenzaldehyde oxime (0.88 g, 5.05 mmol), zinc powder (1.32 g, 20 mmol), glacial acetic acid (10 mL), and 3,4-diethyoxy-3-cyclobutene-1,2-dione (0.75 mL, 5.07 mmol) in absolute ethanol (100 mL) there was obtained after chromatography on silica gel (hexane:ethyl acetate (1:1), 5% methanol in dichloromethane) 0.64 g (45%) of a solid. Following the procedure described in Example 34, a portion of this solid, 3-ethoxy-4-(3-ethyl-4-cyano-benzylamino)-cyclobut-3-ene-1,2-dione (0.38 g, 1.34 mmol), (R)-2-amino-3,3-dimethylbutane (10 mL of a 0.2M solution in absolute ethanol, 2.0 mmol), and dichloromethane was allowed to stand for 24 hours at room temperature. The resulting solid was filtered, rinsed with acetonitrile (5×1 mL) and dried. This gave 0.22 g (48%) of the (R) isomer of the title compound as a white solid: mp 251°-253° C.; [α]25D =+28.48° (4.2 mg/mL, DMSO); 1H NMR (DMSO-d6) δ7.79 (d, 1H), 7.68 (br m, 1H), 7.44 (s, 1H), 7.34 (d, 1H), 7.28 (br d, 1H), 4.78 (m, 2H), 3.91 (br m, 1H), 2.79 (q, 2H), 1,21 (t, 3H), 1.10 (d, 3H), 0.85 (s, 9H) ppm. IR (KBr): 3210, 2980, 2210, 1790, 1650 cm-1 ; MS (m/z) 339 (M+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:33]=[CH:34][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a flask charged with 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 2)(1000 mg, 2.60 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (561 mg, 3.11 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.260 mmol) and potassium carbonate (1076 mg, 7.79 mmol) was added DME (20 mL) and water (4.0 mL). The resulting mixture was stirred at 100° C. under nitrogen for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic phase was dried (MgSO4), concentrated in vacuo and the residue was purified by chromatography (10 g column, MeOH/DCM gradient) to give methyl 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (1002 mg, 2.275 mmol, 88% yield) as an orange foam.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]([C:29]1[S:33][C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[N:31][C:30]=1[CH3:44])(=[O:28])[CH3:27].C(N(CC)CC)C.O>CS(C)=O>[C:26]([C:29]1[S:33][C:32]([NH:34][C:35]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:36])=[N:31][C:30]=1[CH3:44])(=[O:28])[CH3:27]
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1sc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)nc1C
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine hydrochloride (0.100 g; Example 1a, Step 5), phenyl 5-acetyl-4-methylthiazol-2-ylcarbamate (0.089 g, 1.2 equiv), and triethylamine (0.045 mL, 1.2 equiv) in dimethyl sulfoxide (1 mL, 0.3 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and then the solution was extracted with ethyl acetate (2×). The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a 12 g silica gel column using 10-30% ethyl acetate/dichloromethane over 20 minutes as the eluent to give the title compound as a light yellow foam. 0.065 g, 47% yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.44-2.54 (5H, m), 2.61 (2H, t, J=5.7 Hz), 2.66 (3H, s), 3.63 (2H, t, J=5.8 Hz), 3.73 (2H, t, J=5.9 Hz), 6.42 (1H, s), 6.92-7.04 (3H, m), 7.07 (1H, d, J=7.8 Hz), 7.38 (1H, t, J=8.0 Hz), 7.89 (1H, dd, J=8.6, 2.7 Hz), 8.43 (1H, s).
Reaction SMILES: C[O-].[Na+].[O:4]=[C:5]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[O:8][C:7]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:6]1.[CH:27](OCC)=[O:28].O>C1COCC1>[OH:28][CH:27]=[C:6]1[C:7]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[O:8][C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]1=[O:4]
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ncccc1O2
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cccnc1C(=O)C2=CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a suspension of sodium methoxide (594 mg, 11.0 mmol) in THF (5 mL) was added a suspension of tert-butyl 4′-oxo-3′,4′-dihydrospiro[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (1.0 g, 3.1 mmol) in THF (10 mL), followed by ethyl formate (2.5 mL, 31 mmol) and the reaction mixture was stirred at 25° C. for 3 hours. Additional sodium methoxide (170 mg, 3.1 mmol) and ethyl formate (0.25 mL, 3.1 mmol) were added and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate (4×). The aqueous layer was saturated with solid NaCl and was extracted with ethyl acetate (5×). The organic layers were combined and dried over sodium sulfate. The precipitate formed was filtered and washed with ether (2×). The solid product was dissolved in hot dichloromethane/MeOH (1:1) and filtered, and the filter cake was rinsed with additional hot dichloromethane/MeOH (1:1) (4×) to dissolve all product and remove solid sodium sulfate. The combined filtrates were evaporated to afford tert-butyl 3′-(hydroxymethylene)-4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (560 mg, 52%) as a yellow solid. ESI-MS m/z calc. 346.2. found 347.5 (M+1)+; Retention time: 0.98 minutes (3 min run).
Reaction SMILES: [OH:1][CH:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH:5]1[N:6]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]3[N:29]=[N:30][NH:31][N:19]=3)=[CH:20][CH:21]=2)[C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: N#Cc1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C1CCC(CCC(O)Cc2ccccc2)N1CCCc1ccc(-c2nn[nH]n2)cc1
Yield: 82.3 %

Procedure:
Analogous to the procedure described for Compound 4A, Step E, 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzonitrile (157.8 mg, 0.419 mmol) was reacted with azidotrimethylsilane (0.11 mL, 0.84 mmol) and dibutyltin oxide (20 mg, 0.08 mmol) in toluene (8.6 mL) heated under reflux for 60 h. Purification by medium pressure chromatography (CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2) provided 5-(3-hydroxy-4-phenyl-butyl)-1-{3-[4-(2H-tetrazol-5-yl)-phenyl]-propyl}-pyrrolidin-2-one (144.7 mg). 1H NMR (CDCl3) δ 8.02 (m, 2H), 7.27 (m, 7H), 3.84 (m, 1H), 3.67 (m, 2H), 3.10 (m, 1H), 2.84 (m, 1H), 2.67 (m, 2H), 2.53 (m, 1H), 2.42 (m, 1H), 2.14 (m, 1H), 1.97-1.40 (m, 9H); MS 420.3 (M+1), 418.3 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:15][C:14]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:29][CH:28]=4)=[O:25])=[CH:13][C:12]=3[CH:40]=2)=[CH:4][CH:3]=1.[CH3:41][I:42]>CN(C)C=O>[I-:42].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:15][C:14]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][N+:34]5([CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[CH:31][CH:32]=4)=[O:25])=[CH:13][C:12]=3[CH:40]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CC(c2ccccc2)O3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CC(c2ccccc2)O3)cc1
Product: [I-]

Procedure:
A solution of 7—(4-methylphenyl)-2-phenyl-N-(4—(piperidinomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0. 08 g) and methyl iodide (0.05 ml) in dimethylformamide (15 ml) was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-ethyl acetate to give 1—(N-(7—(4-methylphenyl)-2-phenyl-2,3-dihydro-1-benzoxepin-4-carbonyl)-4-aminobenzyl)-1-methylpiperidinium iodide (Compound 103) (0.057 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH2:10]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH:26]=[O:27])[CH3:11]
Reactant: CCc1cc(Br)ccc1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(C=O)ccc1OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 42.4 %

Procedure:
A solution of 4-bromo-2-ethyl-1-methoxybenzene (J. Chem. Soc., Perkin Trans. 1, 1987, 1423; 2.13 g, 9.9 mmol) in THF (30 ml) was cooled to −78° C. A 1.6M solution of n-BuLi in hexane (7.42 ml, 11.9 mmol) was added slowly and the mixture was stirred for 1.5 h. at −78° C. The mixture was warmed slowly to −10° C. and subsequently again cooled to −78° C. DMF (2.29 ml, 29.7 mmol) was added slowly and the mixture was stirred for 1 h. at −78° C. and for 1 h. at 0° C. The reaction mixture was poured into ice-cold 3M HCl and extracted with diethyl ether. The organic phase was dried and filtered, and the filtrate was concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 8:1=>2:1). There were obtained 690 mg (42%) of 3-ethyl-4-methoxy-benzaldehyde as a yellowish liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>ClCCl>[C:34]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH3:35]
Reactant: Oc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(2R)-1-(3'-Hydroxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.34 g, Example 99) was dissolved in dichloromethane (10 ml) and cooled to 0° C. using ice and water. Triethylamine (0.14 ml) and acetic anhydride (0.09 ml) were added and the reaction mixture allowed to room temperature with stirring for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (97:3) to give the title compound as an oil (0.20 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[O:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]([OH:28])[CH2:17][N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:13]>CCN(CC)CC.C(Cl)Cl>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][N:18]1[CH2:17][CH:16]([OH:28])[CH2:15][NH:14][C:12](=[O:13])[CH2:11][O:10][C:9]1[CH:29]=[CH:30][CH:31]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reaction time: 2 h

Procedure:
MsCl (23 mg, 0.2 mmol) was added to a cooled 0° C. stirred solution of 2-(3-aminophenoxy)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)acetamide (71 mg, 0.2 mmol) in Et3N (0.1 mL) and DCM (10 mL). After stirred for 2 h, the solvent was removed by concentration. The residue was purified by prep-HPLC to afford the title compound. 1H NMR (400 MHz, MeOD): δ 7.26-7.22 (m, 1H), 7.11-7.01 (m, 4H), 6.91-6.85 (m, 2H), 6.71-6.68 (m, 1H), 4.53 (s, 2H), 4.03-4.00 (m, 1H), 3.69 (s, 2H), 3.43-3.88 (m, 1H), 3.13-3.12 (m, 1H), 2.96 (s, 3H), 2.89 (d, J=6 Hz, 1H), 2.82 (d, J=5.6 Hz, 1H), 2.57 (t, J=6 Hz, 1H) ppm; ESI-MS (m/z): 434.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([CH:28]([OH:31])[CH2:29][CH3:30])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:32])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:44])[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](=[O:31])[CH2:29][CH3:30])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:32])[CH2:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To 20 mL of a chloroform solution containing 165 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-hydroxypropyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 115 mg of Dess-Martin Periodinane was added, and stirred at room temperature for 2 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was 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 silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 115 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxo-5-propionylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O.[OH-].[Na+]>ClCCl>[CH2:12]1[C:11]2([CH2:14][CH2:15][CH:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:17][CH2:18]2)[CH2:10][CH2:9][NH:8][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccc(Cl)c(Cl)c3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(NC2CCC3(CCNCC3)CC2)cc1Cl
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To an ice-cooled solution of 9-(3,4-dichloro-phenylamino)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (258 mg, 0.624 mmol) in dichloromethane (10 mL) a solution of trifluoroacetic acid (4 mL) in dichloromethane (5 mL) was added. The mixture was stirred a room temperature over night. Water was added followed by sodium hydroxide 3 M to pH 9-10. The aqueous layer was extracted with dichloromethane (4×40 mL). The combined organic layers were washed with brine, dried with sodium sulphate and evaporated to give (3-aza-spiro[5.5]undec-9-yl)-(3,4-dichloro-phenyl)-amine (164 mg 84%) as a brownish solid. Mp. 128-132° C.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[N:7]3[CH2:13][CH2:12][CH2:11][C@H:8]3[CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:17][O-:18].[Na+]>CN(C)C=O.O>[CH3:17][O:18][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[N:7]3[CH2:13][CH2:12][CH2:11][C@H:8]3[CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: O=C1c2ccc(F)cc2OC[C@@H]2CCCN12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC[C@@H]1CCCN1C2=O
Temperature: 110 °C

Procedure:
A solution of (S)-8-fluoro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]-benzoxazepine-5-one (0.5 g; 2.14 mmol), prepared as described in Example 5A, and sodium methoxide (0.244 g; 4.52 mmol) in dimethylformamide (2 mL) was heated at 110° C. for 3 h. The reaction was diluted with water and extracted with ethyl acetate and the organic layer washed with water then dried (Na2SO4) and evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane) to give the title product, m.p. 104-106° C.; EIMS: m/z=234 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:17].[C:21](#[N:23])[CH3:22]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:23][C:21](=[O:17])[CH3:22])([CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Reactant: CC#N
Product: CC(=O)NC1(C)CCN(Cc2ccccc2)CC1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-benzyl-4-methyl-4-piperidinol obtained in Example 10-1 (3.34 g) in acetonitrile (19 mL) was added dropwise conc. sulfuric acid (16 mL) with cooling on an ice bath. The mixture was warmed to 20° C. and stirred for 15 hrs. After cooling, the reaction mixture was quenched by adding 3N potassium hydroxide solution, and the resulting solution (pH9) was extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The residual solid was triturated with ether to give the title compound as a white powder (3.55 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:21])([CH3:20])[CH2:5][C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:2][CH2:3][C:4]([CH3:21])([CH3:20])[CH2:5][C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COC(=O)C(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (7 g, 22.21 mol) in THF was added with LiAlH4 (1.27 g, 33.31 mol). The reaction mixture was stirred overnight at rt. Water was added and extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the crude product (S)-tert-butyl 4-(3-hydroxy-2,2-dimethylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (6.6 g, 100%) as an oil that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 3.69 (m, 4H), 3.32 (m, 1H), 1.82 (m, 1H), 1.54 (s, 3H), 1.48 (s, 9H), 1.42 (s, 3H), 1.22 (m, 1H), 0.91 (m, 3H), 0.72 (s, 2H).