Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cc2)CCN1
Reaction time: 2.5 h
Yield: 102.7 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[({4-[(3-fluorophenyl)amino]-1-piperidinyl}carbonyl) (methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D33) (9.337 g, 17.322 mmol) was dissolved in DCM (144 mL) and cooled in an ice bath. TFA (36 mL) was added slowly and the mixture was allowed to stir for 2.5 h under argon. The solvent was removed under vacuum and the residue partitioned between DCM and saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer extracted twice with DCM. The combined organic extracts were dried and concentrated to give the title compound as a cream coloured foam (7.82 g). MS (ES): MH+ 440.3.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH2:14])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>C1COCC1>[CH2:26]([NH:14][C:11]1[N:10]=[CH:9][C:8]2[CH2:7][CH2:6][C:5]3[N:15]=[C:2]([CH3:1])[S:3][C:4]=3[C:13]=2[N:12]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1nc2c(s1)-c1nc(N)ncc1CC2
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2c(s1)-c1nc(NCc3ccccc3)ncc1CC2
Temperature: -78 °C
Yield: 19.7 %

Procedure:
To 2-methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-ylamine (100 mg, 0.46 mmol) in dry THF (10 mL), cooled to −78° C., was added LiHMDS (458 μL, 0.46 mmol). The mixture was stirred for 15 min before benzyl bromide (65 μL, 94 mg, 0.55 mmol) was added. The solution was stirred at −78° C. and allowed to warm to room temperature over a period of 16 h. Ammonium chloride solution was added (100 mL) and the product was extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, dried, filtered, and concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) followed by crystallisation from EtOH gave the title product as orange crystals (28 mg, 20%): mp 152-154° C. 1H-NMR (CDCl3): δ 8.07 (s, 1H, Py-H), 7.40-7.25 (m, 5H, Ph-H), 5.47 (brs, 1H, NH), 4.64 (d, 2H, J 5.8, CH2), 2.98 (m, 4H, CH2—CH2), 2.75 (s, 3H, CH3). MS (ESI+): m/z 309.11 (M+H)+. Anal. (C17H16N4S)C, H, N.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:21]#[N:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])O.[K+].O>ClCCl>[C:21]([C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][CH2:13][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][CH2:10]1)#[N:22]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccccc1C1(C#N)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C#N)(c2ccccc2C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
1-Benzyl-4-cyano-4-(2-methylphenyl)piperidine (406 mg) was dissolved in dichloromethane (8 ml), added with ethyl chloroformate (0.16 ml) and potassium hydrogencarbonate (168 mg) and stirred at room temperature for 24 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=5:1→4:1) to obtain 381 mg of the title compound. Yield: 100%.
Reaction SMILES: [OH:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[CH:3][C:4](=O)[CH:5]([O:7][CH3:8])[CH3:6].C([O-])(=O)C.[NH4+:24]>>[NH2:24][C:4]([CH:5]([O:7][CH3:8])[CH3:6])=[CH:3][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:1]
Reactant: [NH4+]
Reactant: COC(C)C(=O)C=C(O)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Product: COC(C)C(N)=CC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
10.0 g 1-Hydroxy-4-methoxy-1-(4-trifluoromethyl-phenyl)-pent-1-en-3-one are dissolved in 100 ml ethanole. 4.7 g of Ammonium acetate are added and the mixture is heated for four hours to reflux. Then the solvent is evaporated in vacuo, the residue is partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The phases are separated and the aqueous phase is twice extracted with dichloromethane. The combined organic phases are dried with magnesium sulphate, the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 90:10 to 50:50).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:12][C:11](=[O:13])/[CH:10]=[CH:9]/[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=C(O)/C=C/C=C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccccc1)c1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
As in Example 115, (E)-5,5-diphenyl-2,4-pentadienoic acid (lg) and 4-nitrophenol (0.7 g) in dichloromethane (10 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.824 g). The mixture was stirred at 0°-5° C. for 10 minutes, then at room temperature for 45 minutes. After the usual work up, the ester was crystallized from 2-propanol to yield 1.1 g of (E)-5,5-diphenyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 113°-115° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@@H:15]([CH2:18][O:19][CH3:20])[CH2:16][CH3:17])[C:9]=2[N+:21]([O-])=O)[CH:7]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[F:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@@H:15]([CH2:18][O:19][CH3:20])[CH2:16][CH3:17])[C:9]=2[NH2:21])[CH:7]=1
Reactant: CC[C@H](COC)Nc1nccc(-c2cc(F)c(OC)cc2C)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC[C@H](COC)Nc1nccc(-c2cc(F)c(OC)cc2C)c1N
Yield: 102.3 %

Procedure:
(R)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.16 g, 0.44 mmol) and Na2S2O4 (1.15 g, 6.6 mmol) were treated as in Part E of Example 9 to give 0.15 g (98%) crude (R)-4-(5-Fluoro-4-methoxy-2-methyl-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine. MS (AP) m/z 334.3 [(M+H)+, 100].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: BrCc1ccccc1Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1Br
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2-Bromobenzyl bromide (5.25 g, 21.0 mmol) was dissolved in dry DMF (200 mL) and potassium phthalimide (3.89 g, 21.0 mmol) was added. The suspension was stirred at 70° C. for 5 h. The mixture was cooled to room temperature and poured into ice water (200 mL). After 30 min the mixture was filtered and the crystalline compound was dried overnight. Recrystallisation from DCM/petroleum ether afforded the title compound as colourless crystals.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=1.[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:29][C@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH:28]=1)[C:25](O)=[O:26])(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:29][C@H:30]([CH3:35])[C:31]([F:32])([F:33])[F:34])=[C:24]([C:25]([N:9]2[CH2:8][CH2:7][C:6]3[N:5]=[C:4]([C:3]([F:2])([F:14])[F:15])[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[O:26])[CH:28]=1)(=[O:19])=[O:18]
Reactant: FC(F)(F)c1ccc2c(n1)CCNC2
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ccc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine hydrochloride (CA [741736-98-1]; WO2004069162) and 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.3).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:19])[CH2:13][C:14](OCC)=[O:15])=[C:8]([CH:20]=[CH2:21])[CH:7]=1)=[O:4].[BH4-].[Li+].O.Cl>O1CCCC1>[CH3:22][N:2]([CH3:1])[C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:19])[CH2:13][CH2:14][OH:15])=[C:8]([CH:20]=[CH2:21])[CH:7]=1
Reactant: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CCO
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of ethyl 3-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-hydroxy-propionate (5.28 g, 17.2 mmol) obtained in step (d) of Example 192 in tetrahydrofuran (50 ml) was added lithium tetrahydroborate (544 mg, 25.0 mmol) at −20° C. with stirring, and the reaction temperature was raised gradually to ambient temperature over one hour under a nitrogen atmosphere. To the reaction mixture were added successively water (20 ml) and 1N hydrochloric acid (20 ml), and the resulting mixture was extracted with ethyl acetate (40 ml×2). The organic layer was dried over anhydrous sodium sulfate, filtered; and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using mixed solvents of hexane and ethyl acetate (1:1-0:1) and ethyl acetate and methanol (5:1 successively as the eluents to afford the title compound (4.44 g, yield: 97%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=2[C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:26]1)[CH3:24]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([CH2:31][N:28]4[CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:30][CH2:29]4)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(C(=O)O)cc1/C=C/c1csc2c(N)ncnc12
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(C)c(/C=C/c4csc5c(N)ncnc45)c3)cc2C(F)(F)F)CC1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using (E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid and 4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>ClCCl.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 46 h

Procedure:
After (S)-1-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (772.5 mg, 2.95 mmol), 4-nitrobenzoic acid (494 mg, 2.95 mmol), and dichloromethane (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (693 mg, 2.95 mmol) dissolved in dichloromethane (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 46 hours. Water (10 mL) was added, and separation was carried out. Then, the aqueous layer was extracted using dichloromethane (10 mL,×1). The resulting organic layer was collectively washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (496 mg, yield: 74%/(S)-1-phenylethyl alcohol).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:12]2[CH:18]=[N:17][N:16](CC3C=CC(OC)=CC=3)[C:13]2=[N:14][CH:15]=1)=[O:9])=C>C(O)(C(F)(F)F)=O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:12]2[CH:18]=[N:17][NH:16][C:13]2=[N:14][CH:15]=1)=[O:9]
Reactant: C=COCCONC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Nc1ccc(I)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCCO)c1cnc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Yield: 28.8 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2-vinyloxyethoxy)-amide (346 mg, 0.57 mmol) was dissolved in TFA (5 mL) and the reaction mixture heated at 65° C. for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as a yellow solid (75 mg, 30%). LCMS (Method A): RT=6.67 min, [M+H]+=458. 1H NMR (DMSO-d6, 400 MHz) 13.51 (1H, s), 11.75 (1H, s), 10.38 (1H, s), 8.45 (1H, s), 7.80 (1H, dd, J=9.67, 1.86 Hz), 7.64-7.60 (1H, m), 7.30-7.21 (1H, m), 6.74 (1H, s), 4.71 (1H, s), 3.90 (2H, t, J=4.95 Hz), 3.61-3.56 (3H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COC(=O)C(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C(Cc1c(N)cccc1C(F)(F)F)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A suspension of 40.4 g (0.088 mol) of [2-(2-nitro-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)-ethyl] propanedioic acid, dimethyl ester (see Example 7A) in methanol was treated with a cold suspension of 5% palladium on charcoal in methanol (under nitrogen) and placed on the Parr apparatus at 58 psi of hydrogen. The mixture was heated at 50°-55° C. for 1 hour to assure that all of the starting material had dissolved. The mixture was removed from the Parr apparatus and allowed to stand at room temperature overnight. The flask was heated to dissolve the crystallized product, and the hot solution was filtered through Celite (under nitrogen) and washed with hot methanol. The colorless filtrate was concentrated on a rotary evaporator to yield 36.9 g of the title compound, melting point 111°-113° C. A sample crystallized from methanol melted at 112°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24]Cl)[CH2:19][CH2:18]3)[C:10]3=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[C:27]=1[Br:28].[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([CH:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][N:29]4[CH2:34][CH2:33][S:32][CH2:31][CH2:30]4)[CH2:21][CH2:22]3)[C:10]3=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[C:27]=1[Br:28]
Reactant: O=C(CCl)N1CCC(C2c3ccc(Cl)c(Br)c3CCc3cc(Br)cnc32)CC1
Reactant: C1CSCCN1
Solvent: ClCCl
Solvent: O
Product: O=C(CN1CCSCC1)N1CCC(C2c3ccc(Cl)c(Br)c3CCc3cc(Br)cnc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ~0.11 g of 4-[8-Chloro-3,7-dibromo-5,6-dihydro-11H-benzo[5,6 ]cyclohepta[1,2-b]pyridin-11-yl]-1-(chloroacetyl)piperidine in 5 ml of CH2Cl2 is added 0.12 ml of thiomorpholine and the mixture is stirred at ambient temperature for 24 h, and diluted with 20 ml of distilled water. The layers are separated and the aqueous layer is back extracted with 10 ml of CH2Cl2. The combined organic layer is washed once with saturated brine, dried over Mg2SO4, filtered and evaporated to a brown residue. Flash chromatography over 20 g silica gel with 200 ml of 3% MeOH/CH2Cl2 gives 0.12 g of the title compound, yield in two steps is 93.8%. MS: 614.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](Br)[C:15]#[CH:16]>>[CH2:16]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([OH:13])=[C:4]([O:11][CH3:12])[CH:5]=1)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: COc1cc(C(=O)O)cc(Br)c1O
Product: C#CCOC(=O)c1cc(Br)c(O)c(OC)c1

Procedure:
By utilizing the procedure of Example 5, by reacting 5-bromovanillic acid with propargyl bromide, there is obtained 5-bromovanillic acid propargyl ester; M.P. 121°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([NH2:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])[CH3:25]>>[C:24]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([NH:36][C:20]([C:10]2[CH:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:21])[CH2:34][CH2:35]1)=[O:29])([CH3:23])([CH3:25])[CH3:26]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(N)CC1
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-amino-1-piperazinecarboxylic acid 1,1-dimethylethyl ester (CAN 118753-66-5) as starting materials; MS (EI) 515.2 (M+H)+.
Reaction SMILES: CC(C1C=CC(O)=CC=1)=O.[H-].[Na+].ClC1C=C(Cl)C=CC=1CCl.[BH4-].[Na+].[Cl:25][C:26]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:27]=1[CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH:34](O)[CH3:35])=[CH:32][CH:31]=1.S(Cl)(Cl)=O.[NH:48]1[CH:52]=[CH:51][N:50]=[CH:49]1.[Na].N1C=CN=C1.Cl([O-])(=O)(=O)=O>C(O)C.O1CCOCC1.C(Cl)Cl.CCOCC.CN(C)C=O>[Cl:25][C:26]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:27]=1[CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH:34]([N:48]2[CH:52]=[CH:51][N:50]=[CH:49]2)[CH3:35])=[CH:32][CH:31]=1
Reactant: CC(O)c1ccc(OCc2ccc(Cl)cc2Cl)cc1
Reactant: c1c[nH]cn1
Agent: CC(=O)c1ccc(O)cc1
Agent: ClCc1ccc(Cl)cc1Cl
Agent: [BH4-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(c1ccc(OCc2ccc(Cl)cc2Cl)cc1)n1ccnc1

Procedure:
136 g. of 4-hydroxyacetophenone is etherified in 500 ml. of dimethylformamide with 30 g. of sodium hydride oil suspension (80%) and 195 g. of 2,4-dichlorobenzyl chloride analogously to Example 16. The thus-obtained 4-(2,4-dichlorobenzyloxy)-acetophenone (290 g., m.p. 89°-90° ) is reduced in 1 liter of ethanol/dioxane (2 : 1) with 50 g. of sodium borohydride analogously to Example 26, and worked up. Of the thusobtained 4-(2,4-dichlorobenzyloxy)-α-methylbenzyl alcohol (m.p. 61°-64°), 1.7 g. is stirred with 5 ml. of thionyl chloride for 1 hour at room temperature. The product remaining after a careful evaporation of the thionyl chloride is reacted according to Example 15 with a solution of sodium imidazole, prepared from 360 mg. of imidazole and 160 mg. of sodium hydride, and converted into the perchlorate as described in Example 26. Yield: 940 mg.; m.p. 103°-106° (methylene chloride/ether).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:11][CH:10]([C:12]([O:14]C(C)(C)C)=[O:13])[CH2:9]2)=[CH:4][C:3]=1[F:20]>CO.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:4][C:3]=1[F:20]
Reactant: CC(C)(C)OC(=O)C1CC(O)(c2ccc(Br)c(F)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC(O)(c2ccc(Br)c(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Into a 1000-mL round-bottom flask was placed a solution of tert-butyl 3-(4-bromo-3-fluorophenyl)-3-hydroxycyclobutane-1-carboxylate (62 g, 179.60 mmol, 1.00 equiv) in methanol/NaOH (40%) (300/300 mL). The resulting solution was stirred at room temperature for 3 h, concentrated under vacuum and extracted with 3×200 mL of ethyl acetate. The pH value of the aqueous layer was adjusted to 4 with hydrogen chloride (2 mol/L). The resulting solution was extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 1×500 mL of water and 1×500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 50 g (96%) of 3-(4-bromo-3-fluorophenyl)-3-hydroxycyclobutane-1-carboxylic acid as a yellow liquid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[S:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[C:23]([C@@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[S:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
In 1 ml of acetic acid is dissolved 0.9 g of tert-butyl 3(R)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supenatant liquid is decanted, and the precipitate is dissolved in 30 ml of 1N aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized by adding 3 ml of acetic acid, and purified by MCI-gel chromatography (water:methanol=1:2). The eluent is ccncentrated under reduced pressure, and the residue is lyophilized to give 0.43 g of 3(R)-[1(S)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.