Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Br)cc1F
Yield: 92.2 %

Procedure:
Combine 4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10 mL, 0.137 mol) in toluene (10 mL) and reflux for 2 h. Evaporate the reaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g, 93%) and use for the next step without further purification. Dissolve tert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL), cool to 0° C. and add a solution of 4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol) in anhydrous DCM (10 mL). Stir the reaction mixture at 0° C. for 10 min, warm to ambient temperature and continue to stir for 30 min. Wash the reaction mixture with brine (2×10 mL), dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (1.0 g, 87%). MS (ES+) m/z: 275 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([O:30][C:31]1[C:40]2[C:35](=[CH:36][C:37](F)=[C:38]([Cl:41])[CH:39]=2)[CH:34]=[CH:33][N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CC(N(C)C)=O>[CH2:23]([O:30][C:31]1[C:40]2[C:35](=[CH:36][C:37]([O:14][C:11]3([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][CH2:9][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)=[C:38]([Cl:41])[CH:39]=2)[CH:34]=[CH:33][N:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1cc2c(OCc3ccccc3)nccc2cc1OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Yield: 86.2 %

Procedure:
566 mg of 1-Benzyl-4-phenyl-piperidin-4-ol (67) were dissolved in 6 ml of dry dimethyl acetamide. 48 mg of sodium hydride (95%) were added and after 1 h of stirring, 580 mg of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (61), dissolved in 6 ml of dry dimethyl acetamide were added. The course of the reaction was monitored by LCMS and 50 mg of sodium hydride were added several times until no further conversion could be observed. 10 mL of water were added. The resulting precipitate was purified by silica gel chromatography to give 930 mg of the desired product, sufficiently pure for further conversion. Rt=1.62 min (Method C). Detected mass: 536.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][NH:11][C:10](=[O:16])[CH:9]=2)[CH:7]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10](=[O:16])[CH:9]=2)[CH:7]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
5.43 g (purity 80%, 14.4 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one and 1.2 eq. of tert-butyl bromoacetate in the presence of 1.5 eq. of potassium carbonate were reacted according to General Method 4B at 100° C. Yield: 3.64 g (61% of theory)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@H:3]([CH3:31])[CH2:2][NH:1][C:34](=[O:35])[C@@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@@H]1O
Product: C[C@H](CNC(=O)[C@@H](O)CCO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 78 %

Procedure:
The procedure described in Example 63 was repeated using 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 65, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 78% yield; NMR spectrum (DMSO-d6) 1.31-1.47 (m, 4H), 1.64-1.77 (m, 1H), 3.33-3.50 (m, 3H), 3.71-3.84 (m, 1H), 3.90-4.00 (m, 1H), 4.32 (t, 1H), 4.87-4.98 (m, 1H), 5.29 (s, 2H), 5.48 (d, 1H), 7.18-7.27 (m, 2H), 7.28-7.40 (m, 2H), 7.54-7.64 (m, 2H), 7.87 (dt, 1H), 8.10-8.21 (m, 2H), 8.47 (s, 1H), 8.59 (d, 1H), 9.95 (s, 1H); Mass spectrum MH+ 537.9.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCOCC1.O>[OH:4][CH2:3][C@@H:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1
Reactant: N[C@H](CO)C[C@H]1CCCOC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@H](CO)C[C@H]1CCCOC1)OCc1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
To a solution of (5)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-1-ol (50 g, 312.5 mmol) and K2CO3 (129.375 g, 937.5 mmol) in dioxane (250 mL) and water (250 mL) at 0° C. was added CbzCl (106.6 g, 625 mmol) dropwise. The reaction mixture was stirred at room temperature until the staring material disappeared. The organic solvent was distilled and the residue was dissolved in AcOEt (200 mL). The organic phase was separated and the water was extracted with AcOEt (3×100 ml). The combined organic phase was washed with water (3×50 ml), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column to give the product (26 g). 1H NMR (CD3OD) 1.1-1.3 (m, 2H), 1.4-1.5 (m, 1H), 1.5-1.7 (m, 3H), 1.8-1.9 (m, 1H), 2.6-2.8 (m, 1H), 3.0-3.1 (t, 1H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 1H), 3.6-3.8 (m, 2H), 3.8-3.9 (m, 2H), 5.0-5.1 (s, 2H), 7.3-7.4 (m, 5H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=S)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Yield: 69.5 %

Procedure:
To a solution of 14.6 g (110 mmol) of rhodanine and 25.7 g (110 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 150 ml of ethanol, 1.08 ml (11.0 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 26.71 g of the desired compound (69.7% yield, pale yellow crystals).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: Cc1ncc([N+](=O)[O-])cc1C(=O)O
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc([N+](=O)[O-])cc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-5-nitronicotinic acid (364 mg, 2 mmol), aniline (186 mg, 2 mmol) and DIEA (774 mg, 6 mmol) in DMF (6 mL) is added HATU (798 mg, 2.1 mmol). The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed by rotary evaporation and the crude product is purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to afford -methyl-5-nitro-N-phenylnicotinamide as a light green solid. MS m/z 258.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][C:24]3[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=3)=[CH:29][CH:30]=2)=[CH:9][CH:10]=1)[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: Ic1ccc(Cc2ccccc2)cc1
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(Cc3ccccc3)cc2)cc1
Yield: 50 %

Procedure:
The title compound was prepared from the product from step 1 (1.3 g, 4.6 mmol) and 4-iododiphenylmethane (2.0 g, 6.9 mmol) using the Step 4 procedure of example 1 with 50% yield (1.1 g). 1HNMR (CDCl3) 1.43 (s, 9H), 3.73 (s, 3H), 3.97 (s, 2H), 5.29 (m, 1H), 5.50 (m, 1H), 6.94 (m, 4H), 7.15 (d, J=6.8 Hz, 2H), 7.20 (m, 3H), 7.30 (m, 4H), MS m/z 448 (M+1).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([O:23]CC=C)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].N1CCOCC1>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)CC1(CNC(=O)OC(C)OC(=O)C(C)C)CCCCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1COCCN1
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of compound (15) (1 g, 2.7 mmol) in acetonitrile (10 mL) under nitrogen was added (10 mg, 0.008 mmol) of tetrakis(triphenylphosphine) palladium (0) followed by morpholine (0.28 mL, 0.28 g, 3.2 mmol). After one hour, the solvent was removed in vacuo. The resulting oil was dissolved in diethyl ether (50 mL) and the organic phase was washed with 2N HCl (20 mL), water (20 mL) and brine (20 mL). The ether layer was dried over anhydrous sodium sulfate and concentrated to give an oil, which was purified by column chromatography on silica gel, eluting with 30% ethyl acetate:hexane. The desired product (11) was isolated as a white crystalline solid (0.75 g, 84% yield), m.p 63–64° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].Br[Mg][CH:17]1[CH2:26][CH2:25][C:20]2([O:24][CH2:23][CH2:22][O:21]2)[CH2:19][CH2:18]1.O1CCCC1.Cl.O>O1CCCC1>[O:21]1[C:20]2([CH2:25][CH2:26][CH:17]([CH:7]([C:6]3[CH:5]=[C:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:3][C:2]=3[CH3:1])[OH:8])[CH2:18][CH2:19]2)[O:24][CH2:23][CH2:22]1
Reactant: Br[Mg]C1CCC2(CC1)OCCO2
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(O)C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-3-carbaldehyde (2.4 g) in tetrahydrofuran (30 mL) was added dropwise 0.4N bromo(1,4-dioxaspiro[4.5]dec-8-yl)magnesium-tetrahydrofuran solution (33.5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give the title compound (3.9 g, 91%) as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][N:7]1[C:11]([C:12]2[S:24][C:15]3[N:16]=[CH:17][N:18]=[C:19](S(C)(=O)=O)[C:14]=3[CH:13]=2)=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=[CH:8]1.C[N:37]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][N:7]1[C:11]([C:12]2[S:24][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:37])[C:14]=3[CH:13]=2)=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=[CH:8]1
Reactant: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(S(C)(=O)=O)ncnc3s2)cc1OC
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(N)ncnc3s2)cc1OC

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[1-(3,4-dimethoxybenzyl)-4-phenyl-1H-imidazol-5-yl]-4-(methylsulfonyl)-thieno[2,3-d]pyrimidine (intermediate 19) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). White solid (35 mg, 91%);
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCCCCC>ClC(Cl)Cl>[CH3:6][O:5][C:1](=[O:4])[CH:2]([C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:3]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(S)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Dissolve 5.0 mL (55.0 mmol) methyl thioglycolate and 14.3 g (55.0 mmol) triphenylmethanol in 80 mL trichloromethane. Then slowly drop 6.9 mL (55.0 mmol) boron trifluoride ethyl ether complex into the solution and stir the solution at room temperature. Use thin layer chromatography (TLC)(chloroform:hexane=1:1) to follow the reaction. After starting material disappeared completely, wash the reaction solution with water (2×100 mL). The organic phase is dried by anhydrous sodium sulfate and then the solvent is removed by vacuum evaporation to get 18.6 g (97.5%) triphenylmethyl thioglycolic acid methyl ester (hereafter referred to as compound 1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:17][C:18]1([CH3:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH3:17][C:18]1([CH3:24])[CH2:23][CH2:22][N:21]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1
Reactant: CC1(C)CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (4.74 g, 0.03 mol) in toluene (50 mL), Na2CO3 (3.39 g, 32.0 mmol) and 4,4-dimethylpiperidine (J. Org. Chem., 47(20), 3890, (1982), 3.3 g, 0.033 mmol) were added. The resulting mixture was stirred at 50° C. for 1 h and concentrated in vacuo. Water (20 mL) and EtOAc (50 mL) were then added. The organic layer was separated, dried and concentrated to afford 4,4-dimethyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl which was directly subjected to catalytic hydrogenation as described in Example 47, step (a) to obtain 4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine (4.1 g, 67%). Mass spectrum (ESI, m/z): Calcd. for C12H19N3, 206.1 (M+H), found 206.2.
Reaction SMILES: C(OC([NH:8][C:9]1[NH:35][CH2:34][C:33]2[CH:36]=[C:37]([Cl:38])[C:30](=[C:31]([Cl:39])[CH:32]=2)[NH:29][C:28](=[O:40])[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=[CH:23][CH2:22][O:21][C:20]2[CH:48]=[CH:49][C:17](=[CH:18][CH:19]=2)[C:16]2[C:12](=[C:13]([CH3:50])[O:14][N:15]=2)[C:11](=[O:51])[N:10]=1)=O)(C)(C)C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[NH2:8][C:9]1[NH:35][CH2:34][C:33]2[CH:32]=[C:31]([Cl:39])[C:30](=[C:37]([Cl:38])[CH:36]=2)[NH:29][C:28](=[O:40])[CH2:27][NH:26][CH2:25][CH:24]=[CH:23][CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:17](=[CH:49][CH:48]=2)[C:16]2[C:12](=[C:13]([CH3:50])[O:14][N:15]=2)[C:11](=[O:51])[N:10]=1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]
Reactant: Cc1onc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CC=CCOc1ccc-2cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1onc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCC=CCOc1ccc-2cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The intermediate (24 mg) from Step 1(C) was dissolved in 2 mL of TFA and DCM mixture (1:1). The resulted solution was stirred at room temperature for 1 h. TFA and DCM were evaporated in vacuo to give a crude product, which was purified by preparative HPLC to give the title compound as a TFA salt (19.9 mg).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:18](OCC)=[O:19].[H-].[Na+].O>COCCOC>[CH:18]([CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:19]
Reactant: CCOC(=O)CCc1cccc2ccccc12
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A mixture of ethyl 3-(1-naphthyl)propionate (18.01 g) and ethyl formate (8.88 g) was added to a suspension of sodium hydride (57% dispersion in oil, 4.43 g) in 1,2-dimethoxyethane stirred at 5°, and the mixture was stirred at 5° for one hour and allowed to warm to room temperature. Water (300 ml) was added and the mixture was extracted with chloroform and the residual aqueous phase adjusted to pH 4 with hydrochloric acid: the mixture was extracted with ether and the extracts evaporated to give ethyl 2-formyl-3-(1-naphthyl)-propionate (16.05 g) as an oil.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[C:13]=2[C:15]([F:18])([F:17])[F:16])[N:8]=[C:7]([CH3:31])[C:6]=1[CH3:32])(=O)C.[OH-].[Na+].O.Cl>C(O)C>[F:17][C:15]([F:16])([F:18])[C:13]1[C:12]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:22][CH:21]=2)=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([OH:4])=[C:6]([CH3:32])[C:7]([CH3:31])=[N:8]2
Reactant: CC(=O)Oc1c(C)c(C)nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(O)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
4-Acetoxy-5-trifluoromethyl-6-(4-trifluoromethoxyphenoxy)-2,3-dimethyl-quinoline (1.5 g) prepared in Synthesis Example 2 was dissolved in 10 mL of ethanol. A 20% sodium hydroxide solution (10 mL) was added to the solution, and the mixture was stirred at 50° C. for 3 hr. This reaction mixture was added to 20 mL of water, and the mixture was neutralized with 1 N hydrochloric acid. The precipitated crystals were collected by filtration under the reduced pressure to give 1.34 g of 5-trifluoromethyl-6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline (yield 98.0%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23](Cl)(=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27].CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CCCCC(=O)Cl
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and pentanoyl chloride (0.36 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O for 18 h. The product was dried in vacuo to give pentanoic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.77 g, 35% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.71 min (95.58%); mp: 184-186° C.; 1H NMR (DMSO-d6) δ 0.81-0.95 (m, 3H, CH3), 1.28 (dq, J=7.3, 14.8 Hz, 2H, CH2), 1.41-1.64 (m, 2H, CH2), 1.97-2.13 (m, 1H, CHH), 2.17 (t, J=7.5 Hz, 2H, CH2), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-2.99 (m, 1H, CHH), 4.43 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.67-7.81 (m, 2H, Ar), 7.88 (d, J=7.7 Hz, 1H, Ar), 8.50 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.68, 21.79, 21.99, 27.37, 30.93, 34.98, 41.87, 48.99, 121.78, 123.48, 129.71, 131.59, 133.28, 147.84, 166.97, 167.12, 169.82, 172.47, 172.73; LCMS: MH=372; Anal Calcd for C19H21N3O5: C, 61.45; H, 5.70; N, 11.31. Found: C, 61.12; H, 5.54; N, 11.15.
Reaction SMILES: [SH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)(O)[O-].[Na+].Cl>CCOCC.N1C=CC=CC=1>[CH2:23]([O:22][C:20]([S:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)C(S)c1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)SC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A solution of α-mercapto-2'-chloro-4-biphenylylacetic acid 5.6 g. (0.02 moles) in 25 ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1 ml. (0.022 moles) of ethyl chloroformate. The mixture is basified with 10% sodium bicarbonate solution. The alkaline mixture is worked with ether, then acidified with 10% hydrochloric acid, washed with ether, dried and filtered. The solvent is removed and the residue is triturated with hexane to obtain α-ethoxycarbonylthio-2'-chloro-4-biphenylylacetic acid.