Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][O:9]C(C)(C)[O:7]1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(#N)C>CC(C)=O>[Br-:1].[OH:7][CH:6]([CH2:10][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)OCC(CCCCBr)O1
Solvent: CC#N
Solvent: CC(C)=O
Product: OCC(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 0.5 h

Procedure:
A stirred solution of 125 g. of 4-(4-bromobutyl)-2,2-dimethyl-1,3-dioxolane, 154 g. of triphenylphosphine, 800 ml. of acetonitrile, and 270 ml. of acetone is heated at reflux for 69 hours. The solvents are removed under vacuum, and the residue is treated with 250 ml. of chloroform and 15 ml. of water. The resulting mixture is stirred vigorously for 30 minutes. The solvents are removed with the aid of benzene chaser, and the solid product is washed with ether and dried under vacuum to give white crystals, m.p. 152°-170° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20]1([CH:23]=O)[CH2:22][CH2:21]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][CH:20]2[CH2:22][CH2:21]2)[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(N(CC2CC2)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1 g, 3.04 mmol) and cyclopropanecarbaldehyde (1.06 g, 15.24 mmol) in methanol (15 mL), acetic acid (0.456 g, 7.6 mmol) was added The reaction mixture was stirred at room temperature for 8 h. Sodium cyanoborohydride (0.488 g, 7.62 mmol) was then added at 0° C. and reaction mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and the crude product purified by column chromatography to afford methyl 5-bromo-3-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (0.275 g, 23.70%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].CO.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]Cl.O>CO>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
To a solution of N-Boc-tyrosine (281 mg, 1.0 mmol) in methanol (0.5 mL) were added 28% sodium methoxide-methanol solution (0.8 mL, 4.0 mmol) and 2-picolyl chloride hydrochloride (230 mg, 1.4 mmol), and the mixture was stirred at 25° C. for 24 hr. Then, water (3 mL) was added make the system homogeneous, which system was then analyzed by HPLC. As a result, the objective N-Boc-(O-2-picolyl)tyrosine (346 mg, conversion yield 93%) was confirmed.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[C:19](O)(=[O:29])[C:20]1[CH:28]=[CH:27][CH:26]=[C:22]([C:23](N)=[O:24])[CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:23](=[O:24])[C:22]4=[CH:26][CH:27]=[CH:28][C:20](=[CH:21]4)[C:19]3=[O:29])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: NC(=O)c1cccc(C(=O)O)c1
Product: CCOc1cc(CN2CCC(N3C(=O)c4cccc(c4)C3=O)CC2)ccc1Cl
Yield: 48 %

Procedure:
The title compound (20 mg, 48%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with isophthalamic acid (Chem. Ber. 1910, 43, 3474). MS: 416.4 (MH+)
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[NH:24][CH:23]=[CH:22]5)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:30]I>CN(C=O)C.ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([O:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([CH3:30])[CH:23]=[CH:22]5)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc3[nH]ccc3c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc2cc(OC3CN(C(=O)N4CCCN(C5CCC5)CC4)C3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a stirred solution of 5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}oxy)-1H-indole (30 mg, 81 μmol) in DMF (2 ml) was added NaH (4 mg of a 60% dispersion in mineral oil, 97 μmol) at room temperature in one portion. The suspension was stirred for 30 min at room temperature under a nitrogen atmosphere then cooled to 0° C. and MeI (6 μl, 97 μmol) was added. The reaction was allowed to warm to room temperature and stirred for 16 hours then diluted with dichloromethane (30 ml) and washed twice with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to provide the title compound (23 mg, 74%) as light brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C[N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.N>O.CN(C=O)C>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:44])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:32][C:33]=1[C:40]([F:43])([F:42])[F:41])(=[O:37])[NH2:46]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(C(F)(F)F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(N)=O)c(C(F)(F)F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
In a 25 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-(trifluoromethyl)benzoic acid (42 mg, 64.2 μmol, Eq: 1.00) was combined with DMF (2.50 ml) to give a colorless solution. HATU (36.6 mg, 96.3 μmol, Eq: 1.5) and DIPEA (41.5 mg, 56.0 μl, 321 μmol, Eq: 5) were added. The reaction was stirred for 5 minutes and ammonia hydrochloride (34.3 mg, 642 μmol, Eq: 10) was added. The reaction mixture was stirred for overnight. The reaction mixture was poured into 10 mL of H2O and extracted with EtOAc (3×10 mL). The organic layers were combined, washed with H2O (1×10 mL), saturated NaCl (1×10 mL), dried over Na2SO4 and concentrated in vacuum. The crude material was purified by preparative HPLC (65-100% ACETONITRILE/water). The fractions were combined and freeze dried and triturated with CH2Cl2/hexanes to give a white foam (12 mg, 26% yield). (ES+) m/z Calcd: [(M+H)+]: 653. found: 653.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH2:27])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2)c1)C(F)(F)F
Reaction time: 5.2 h
Yield: 41.8 %

Procedure:
To a solution of 5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (37 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (16 mg) prepared in Preparation 14 and WSC.HCl (23 mg) at room temperature, the mixture was stirred for 5.2 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (20 mg).
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:23]([Mg]Br)([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([CH3:26])([CH3:25])[C:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]([F:18])([F:19])[F:20])[O:13][N:12]=2)=[CH:9][CH:10]=1)=[O:21]
Reactant: CC(C)(C)[Mg]Br
Reactant: CON(C)C(=O)c1ccc(-c2noc(C(F)(F)F)c2C)cc1
Product: Cc1c(-c2ccc(C(=O)C(C)(C)C)cc2)noc1C(F)(F)F
Yield: 9 %

Procedure:
Prepared from N-Methoxy-N-methyl-4-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-benzamide and tert-butylmagnesium bromide as described in Example 5. Chromatographed on silica gel with EtOAc/hexanes (5%) as eluant to afford product as a colorless solid (53 mg, 9%). 1H NMR (CDCl3) 1.37 (s, 9 H), 2.29 (d, J=1.3, 3 H), 7.68 (d, J=7.9, 2 H), 7.81 (d, J=8.3, 2 H). 19F NMR −63.2. LC/MS 7.42 min, [M+1]+ 312.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-piperidin-4-ol 1b (1.2, 17 g, 0.05 mol) and p-TsOH (29.3 g, 0.15 mol) in toluene (300 mL) was heated to reflux for 6 h with water being removed through a Dean-Stark apparatus. The mixture was cooled to room temperature and was washed with saturated NaHCO3 (100 mL×3). The organic layer was dried over Na2SO4 and concentrated to afford 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine 1c as a brown liquid.
Reaction SMILES: [O:1]([C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])[C:2]1[CH:7]=CC=CC=1.[C:17]([O:22]CCO)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O1CCOCC1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:17]([O:22][CH2:7][CH2:2][O:1][C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)OCCO
Reactant: CC(CC(=O)Oc1ccccc1)NC(N)=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCOC(=O)CC(C)NC(N)=O
Yield: 77.4 %

Procedure:
One hundred gram (450 mmol) of phenoxycarbonylpropyleneurea and 59 g (450 mmol) of hydroxyehtyl methacrylate were dissolved in 900 ml of dioxane at 85° to 90° C. Then, 400 mg of dibutyltin dilaurate was added thereto and allowed to mix for 13 hours with heat. After completion of the reaction, the mixture was concentrated and recrystalized with ether to obtain 90 g of 2-methacryloyloxyethyloxycarbonylpropyleneurea (77.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C1C=CC(C2(C[O:29][S:30]([CH3:33])(=O)=[O:31])CCCC2)=CC=1>>[CH3:33][S:30]([O:14][CH2:13][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:31])=[O:29]
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: OCC1(c2cccc(Cl)c2)CCCC1
Product: CS(=O)(=O)OCC1(c2cccc(Cl)c2)CCCC1

Procedure:
(1-(3-Chlorophenyl)cyclopentyl)methyl methanesulfonate (497) was synthesized from (1-(3-chlorophenyl)cyclopentyl)methanol (496) following the procedure described for Methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:26]=[C:11]3[N:12]=[C:13]([CH3:25])[C:14]([C@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl.CCOCC>[C:31]([O:24][C@@H:19]([C:14]1[C:13]([CH3:25])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:26]=2)[C:15]=1[CH:16]([CH3:18])[CH3:17])[C:20]([O:22][CH3:23])=[O:21])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Reaction time: 3 h
Yield: 131.9 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.069 g, 0.185 mmol) and tert-butyl acetate (1.247 ml, 9.23 mmol) in CH2Cl2 (5 mL) was added 70% perchloric acid (0.048 ml, 0.554 mmol) at rt. After 3 h, the reaction mixture was diluted with Et2O (35 mL), washed with sat Na2CO3 (2×5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated to give colorless paste which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0496 g, 0.244 mmol, 62.5% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.98 (t, J=1.7 Hz, 1H), 7.87 (dt, J=7.6, 1.4 Hz, 1H), 7.41-7.32 (m, 2H), 6.77 (s, 1H), 5.42 (s, 1H), 4.07 (dt, J=13.6, 6.9 Hz, 1H), 3.71 (s, 3H), 2.73 (s, 3H), 1.68 (d, J=7.0 Hz, 3H), 1.56 (d, J=7.0 Hz, 3H), 1.26 (s, 9H). LCMS (M+H) calcd for C23H29ClN3O3: 430.19. found: 430.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.O>[C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCCCCCCOc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)O)cc1
Reaction time: 16 h
Yield: 94.4 %

Procedure:
4-(9-Methoxycarbonylnonyloxy)benzoic acid tert-butyl ester (858 mg, 2.27 mmol) was dissolved in THF (5 ml), and 1N NaOH (2.27 mmol) was added. The mixture was stirred for 16 h. AcOEt (40 mL) and 1N HCl (2.38 ml) in water (25 ml) were added. The phases were separated, and the organic phase was dried over MgSO4, and concentrated under vacuum to yield a white solid (781 mg, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].[C:11](Cl)(=O)[CH3:12]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:11]([CH3:12])[NH:7][CH2:6][CH2:5]2
Reactant: CC(=O)Cl
Reactant: NCCc1cccc(F)c1
Product: CC1NCCc2cc(F)ccc21

Procedure:
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using 3-fluorophenethylamine and acetyl chloride, 6-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 55%) The product was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1)[CH3:5])[CH3:2]>CC(C)=O>[CH:12]#[C:11][C:10]1[CH:13]=[CH:14][C:7]([OH:6])=[CH:8][CH:9]=1.[CH:1]([O:3][CH2:4][CH3:5])=[CH2:2]
Reactant: C=Cc1ccc(OC(C)OCC)cc1
Solvent: CC(C)=O
Product: C#Cc1ccc(O)cc1
Product: C=COCC

Procedure:
To a solution of poly(p-hydroxystyrene) (4.0 g) obtained in Synthesis Example 3, (2) and ethyl vinyl ether (1.5 g) in acetone, a catalytic amount of pyridinium p-toluenesulfonate was added, and reacted with stirring at room temperature for 12 hours. The reaction mixture was poured into H2O (1 liter) and was precipitated. The precipitate was filtered, washed with H2O and dried under reduced pressure to give 3.9 g of the desired product as a white powder having Mw 10000 (GPC with polystyrene calibration). The polymer was found to have p-(1-ethoxyethoxy)styrene unit and p-hydroxystyrene unit in a molar ratio of ca. 35:65 based on 1HNMR.
Reaction SMILES: [C:1]([CH:8]([NH2:14])[CH2:9][O:10][CH2:11][CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].C(O)(C)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:13][CH2:12][CH2:11][O:10][CH2:9][CH:8]([NH2:14])[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH3:32]
Reactant: CC(C)(C)OC(=O)C(N)COCCO
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)COCCOCC(N)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 2-(2-Boc-aminoethoxy)-ethanol (4.5 g, 24.39 mmol) in toluene (100 mL) was added 1.0 M potassium t-butoxide in t-butanol (36.6 □L, 36.6 mmol) between −10 to −20° C. for 1.5 hrs and followed by addition of ethyl bromoacetate (8.15 g, 48.78 mmol). The resulting mixture was stirred for 3 hrs at a temperature between −10 to −20° C., followed by the addition of 0.25 N HCl (50 mL). The organic layer was separated and dried over anhydrous MgSO4. The solvent was removed and the residue purified using silica gel column chromatography (30 to 50% ethylacetate in hexane) to give [2-(2-Boc-aminoethoxy)-ethoxy]-acetic acid ethyl ester (4.0 g, 15.36 mmol, 63%). 1H NMR (300 MHz, CDCl3) δ 5.20 (s, 1H), 4.22 (q, 2H, J=7.29 Hz), 4.14 (s, 2H), 3.66-3.75 (m, 4H), 3.55 (m, 2H), 3.31 (m, 2H), 1.44 (s, 9H), 1.29 (t, 3H, J=7.29 Hz); 13C NMR (67.8 MHz, CDCl3δ170.02, 155.72, 78.68, 70.52, 69.94, 68.29, 60.44, 40.04, 28.06, 13.85.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Yield: 90 %

Procedure:
Ethyl 4-(diphenylmethoxy)piperidine carboxylate (9.7 g) was dissolved in ethanol (85 ml) and water (35 ml), and sodium hydroxide (6.1 g) was added to the mixture, followed by heating the mixture to reflux for 40 hours. Ethanol was removed and water was added to the residue, followed by extraction of the resultant with dichloromethane. Organic layers were combined and dried over anhydrous sodium sulfate. Dichloromethane was removed and the residue was purified with Chromatorex® column chromatography for amines (ethyl acetate:ethanol=5:1) to obtain 7.1 of 4-diphenylmethoxypiperidine. Yield: 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[CH:13]([Mg]Br)=[CH2:14]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[NH:10][CH:14]=[CH:13]2
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(Cl)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 28.7 %

Procedure:
To a solution of 4-chloro-3-nitroanisole (6.0 g, 32.0 mmol) in tetrahydrofuran (140 mL) at −40° C. was added vinylmagnesium bromide (1M in tetrahydrofuran, 112 mL, 112.0 mmol). The mixture was stirred at −40° C. for 1.5 hours and then quenched by the addition of saturated aqueous ammonium chloride solution (150 mL). The reaction mixture was allowed to warm to room temperature and then the product extracted into ethyl acetate (×2). The combined organic layers were dried over magnesium sulphate, filtered and concentrated at reduced pressure. The product was purified by silica gel chromatography eluting with 2-15% ethyl acetate in hexane to yield the title compound (D11), (1.67 g).
Reaction SMILES: [CH2:1]=[O:2].[ClH:3].O[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1>>[Cl:3][CH2:5][C:6]1[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:1]=1[OH:2]
Reactant: C=O
Reactant: Cl
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(O)c(CCl)c1
Temperature: 50 °C

Procedure:
To a mixture of 260 ml. of 37% formaldehyde and 1800 ml. of concentrated hydrochloric acid is added 400 g. of 4'-hydroxyacetophenone at a temperature of about 45°C. The mixture is maintained at 50°C. for two hours, filtered, and washed with water to give 3'-chloromethyl-4'-hydroxyacetophenone, m.p. 154° C. dec.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:40])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:39])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH2:29]4)=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1[O:49]N=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCN(C(C)C)CC4)=CN=3)=CC=2)C=1)(C)(C)C>>[CH3:38][S:35]([O-:36])(=[O:37])=[O:49].[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:40])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:21]3[N:22]=[CH:23][C:24]([O:27][CH:28]4[CH2:32][CH2:31][NH+:30]([CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH2:29]4)=[CH:25][CH:26]=3)=[O:39])=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCN(CCS(C)(=O)=O)C4)cn3)cc2)no1
Reactant: CC(C)N1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)CC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CC[NH+](CCS(C)(=O)=O)C4)cn3)cc2)no1
Product: CS(=O)(=O)[O-]
Yield: 95 %

Procedure:
3-(6-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenylcarbamoyl)pyridin-3-yloxy)-1-(2-(methylsulfonyl)ethyl)pyrrolidinium methanesulfonate (150 mg, 95%) was prepared using a procedure analogous to that described in Example 27, substituting N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yloxy)picolinamide from Step 1 of this example for N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpiperidin-4-yloxy)picolinamide used in Step 2 of Example 27. LC-MS (ESI) m/z 571 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.51 (s, 1H), 8.83 (s, 1H), 8.39 (br. s., 1H), 8.14 (d, J=8.67 Hz, 1H), 7.81 (d, J=8.29 Hz, 2H), 7.67 (d, J=8.29 Hz, 1H), 7.43 (d, J=8.48 Hz, 2H), 6.50 (s, 1H), 5.39 (br. s., 1H), 3.66 (br. s., 7H), 3.12 (s, 3H), 2.70 (d, J=16.39 Hz, 1H), 2.42-2.29 (overlapping m, 1H), 2.35 (s, 3H), 2.15 (d, J=10.17 Hz, 1H), 1.30 (s, 9H).