Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9]2)[CH:4]([OH:15])[CH2:3][CH2:2]1.Cl.Cl[CH2:18][C:19]([CH3:25])([CH3:24])[CH2:20][N:21]([CH3:23])[CH3:22]>>[CH3:18][C:19]([CH3:25])([CH2:20][N:21]([CH3:23])[CH3:22])[CH2:24][O:15][CH:4]1[CH:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9][CH:10]2[CH2:1][CH2:2][CH2:3]1
Reactant: OC1CCCC2Oc3ccccc3OC12
Reactant: CN(C)CC(C)(C)CCl
Agent: Cl
Product: CN(C)CC(C)(C)COC1CCCC2Oc3ccccc3OC12
Yield: 58.5 %

Procedure:
In an analogous manner as described in Example 5, but starting with 10 g (0.048 mole) of the alcohol of Example 1 and 8.6 g (0.046 mole) of 1-chloro-2,2-dimethyl-3-dimethylaminopropane hydrochloride, there were obtained 8.6 g of the title-compound of boiling point 135° C. at a pressure of 6.5 Pa, having the elementary analysis:
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[C:9]1([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Oc1cccnc1-c1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
To a 1 liter round bottom flask equipped with a nitrogen inlet and a condenser was introduced 25 gm. (143.68 mmol) 2-bromo-3-hydroxypyridine, 19.27 gm. (156 mmol) phenylboronic acid, 5 gm (4.31 mmol) tetrakistriphenylphosphine palladium (0). The contents were dissolved in 300 ml of benzene and 100 ml of 2M aqueous sodium carbonate solution. The reaction mixture was heated under reflux for a period of 18 hours. The mixture was allowed to cool to room temperature and extracted with ethyl acetate (4×100 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was taken up in chloroform followed by treatment with ether to afford a solid precipitate. Upon filtration there was obtained 10.4 gm (42%) of 2-phenyl-3-hydroxypyridine. 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H), 7.71 (d, 2H), 7.51–7.40 (m, 2H), 7.22 (d, 2H), 7.15 (m, 1H) ppm. Mass spectrum APCI m/z 172 (p+1).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][OH:29]>CCCCCC.C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1ccc(-c2cnc(OCc3ccc(Cl)c(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 3,4-dichlorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(3,4-dichlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC). HPLC/MS: m/e=511 (M+); Rt=5.07 min; 1H-NMR 500 MHz (CDCl3): δ 5.47 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.21 (d, J=9 Hz,1H), 7.22-7.30 (m, 3H), 7.38 (m, 2H), 7.43 (d, J=9 Hz, 1H), 7.66 (d, J=2 Hz,1H), 8.61 (s, 1H). 2-(3,4-Dichlorobenzyloxy)-4-(2-chloro-4-thiomethyl-phenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf product which was the by-product of the thiomethyl anion displacement of the 4-chloro substituent on the 4-(2,4-dichlorophenyl) ring. HPLC/MS: m/e=523 (M+1); Rt=4.93 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.48 (s, 2H), 7.0-7.10 (m, 1H), 7.15-7.21 (m, 2H), 7.24-7.30 (m, 3H), 7.40-7.60 (m, 3H), 7.68 (d, J=2 Hz,1H), 860 (s, 1H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:12][NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[CH3:15])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:26][C:25]1[CH:24]=[CH:23][C:11]([CH2:12][NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH3:15])=[CH:10][C:9]=1[OH:8]
Reactant: C[C@@H](NCc1ccc(Cl)c(O[Si](C)(C)C(C)(C)C)c1)c1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of (R)—N-(3-(tert-butyldimethylsilyloxy)-4-chlorobenzyl)-1-(3-chlorophenyl)ethanamine 82 (540 mg, 1316 μmol) in THF was added tetra-butylammonium fluoride (1M soln in THF, 1381 μL, 1381 μmol). The solution was stirred at room temperature under N2 for 3 h and then checked by TLC for completion. The reaction solution was concentrated and the crude material was purified by silica gel chromatography using a 5% to 60% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 83 (200 mg, 91% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J=6.46 Hz, 3H) 3.50-3.61 (m, 2H) 3.77 (q, J=6.52 Hz, 1H) 6.78 (dd, J=8.22, 1.37 Hz, 1H) 6.96 (d, J=1.37 Hz, 1H) 7.20-7.29 (m, 4H) 7.34 (s, 1H). Mass spectrum: calculated for C15H15Cl2NO 296.2. found 297.3 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([N:15]1[CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17](=[O:21])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CN(Cc2ccccc2)CCN1
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CN(Cc2ccccc2)CCN1c1ccccc1
Temperature: 220 °C
Yield: 35 %

Procedure:
To a 25 mL microwave vessel was added 4-bromobenzene (6.1 g, 39.0 mmol), 4-benzylpiperazin-2-one (5.0 g, 36.3 mmol), potassium carbonate (3.6 g, 26.3 mmol), and copper(I) iodide (500 mg, 2.6 mmol). The reaction vessel was sealed and purged with nitrogen. Anhydrous NMP (8.0 mL) was added via syringe. The vessel was heated via microwave at 220° C. for 40 minutes. The mixture was filtered through a bed of celite followed by CH2Cl2 (20 mL). The filtrate was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the desired piperazinone as a white solid (3.4 g, 12.7 mmol, 50% yield). 1H NMR (400 MHz, CDCl3) δ 7.42-7.24 (m, 10H), 3.69 (t, J=5.4 Hz, 1H), 3.63 (s, 1H), 3.40-3.31 (m, 2H), 2.84 (s, 1H), 2.81 (t, J=5.2 Hz, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=267.3; tR=1.63 min.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccccc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.81 (1H, d, J=1.6 Hz), 7.09-7.20 (2H, m), 7.36-7.41 (2H, m), 7.48-7.51 (1H, m), 7.58 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H11FN4O, 295. Found, 295.
Reaction SMILES: C(N=[CH:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[CH:9][C:8]=1[CH:21]1[CH2:23][CH2:22]1)CCC.Cl.[OH2:25]>>[CH:21]1([C:8]2[CH:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[C:7]=2[CH:6]=[O:25])[CH2:23][CH2:22]1
Reactant: CCCCN=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: O
Agent: Cl
Product: O=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
Crude butyl-[1-(2-cyclopropyl-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine (intermediate AL, 3.54 g, 10.5 mmol) was dissolved in 8 mL water. Hydrochloric acid (25%, 0.49 mL) was added and the mixture was refluxed for 2 h. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude material, brown oil (1.01 g, 34%) was used without further purification.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH:7][C:6]1=[O:16].[CH3:17][O:18][C:19]([S:21]Cl)=[O:20]>CO>[CH3:17][O:18][C:19]([S:21][S:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH:7][C:6]1=[O:16])=[O:20]
Reactant: COC(=O)SCl
Reactant: O=C1NCC(c2ccccc2)N1CCCS
Solvent: CO
Product: COC(=O)SSCCCN1C(=O)NCC1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.7 g of 1-(3-mercaptopropyl-5-phenyl-2-imidazolidinone in 70 ml of methanol, cooled to 0°, there is added dropwise 3.9 g of methoxy carbonylsulfenyl chloride over a fifteen minute period. The solution is allowed to stir at 0° for 1 hour and at room temperature for four hours. The reaction is concentrated in vacuo and the residual oil eluted on a silica gel column with ethyl acetate. The product is purified further by recrystallization from isopropyl ether, m.p. 98°-100° C.
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([CH:12]1[N:17]2[C:18](=[O:40])[C@@H:19]([NH:20][C:21](=[O:39])/[C:22](/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=3)=[CH:23]\[CH2:24][CH3:25])[C@H:16]2[S:15][CH:14]=[C:13]1[Cl:41])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:50])C=1>ClCCl.C(=O)([O-])O.[Na+]>[C:1]([O:7][CH2:8][O:9][C:10]([C:12]1[N:17]2[C:18](=[O:40])[C@@H:19]([NH:20][C:21](=[O:39])/[C:22](/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=3)=[CH:23]\[CH2:24][CH3:25])[C@H:16]2[S:15](=[O:50])[CH2:14][C:13]=1[Cl:41])=[O:11])(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)C(Cl)=CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(Cl)CS(=O)[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
To a solution of 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-chloro-2-cephem-4-carboxylic acid pivaloyloxymethyl ester (410 mg) in dichloromethane (3 ml) is added dropwise a solution of m-chloroperbenzoic acid (47.4 mg) in dichloromethane (1 ml) with stirring at 0° C. After stirring at the same temperature for 20 minutes, the reaction mixture is diluted with aqueous sodium hydrogen carbonate. The organic layer is separated, washed with water, dried, and concentrated. The resulting residue is purified by silica gel column chromatography to give 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-chloro-3-cephem-4-carboxylic acid 1-oxide pivaloyloxymethyl ester (135 mg) as crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=5)[CH2:20][CH2:19]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:3]=1.[NH3:40]>O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:19][CH2:20][CH:21]([C:24]5[CH:32]=[CH:31][C:27]([C:28]([NH2:40])=[O:30])=[CH:26][CH:25]=5)[CH2:22][CH2:23]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(N5CCC(c6ccc(C(=O)O)cc6)CC5)cc4C3)nc(N)n2)CC1
Reactant: N
Solvent: O
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCC(c6ccc(C(N)=O)cc6)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 4-(1-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidin-4-yl)benzoic acid and ammonia solution in water. LCMS (M+H)+: m/z=527.3.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=485.1, tR (minutes, Method G)=2.63. [α]D20=+27.63 (c=1.52 mg/mL,CHCl3)
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Br:42]Br>C(#N)C.C(OCC)C>[Br:42][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCBr)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 2-(4-(tert-butyldimethylsilyloxy)phenyl)ethanol (1250 mg, 4.95 mmol) in acetonitrile (50 mL) and diethyl ether (25 mL) was sequentially added triphenylphosphine (3.44 mL, 14.8 mmol), 1H-imidazole (1011 mg, 14.8 μmol), and bromine (765 μl, 14.8 mmol). The clear solution was stirred at 23° C. for 18 h. The mixture was concentrated directly onto silica (20 g) under reduced pressure then purified on 120 grams of silica eluting with 0-5% EtOAc/Hexane. MS (ESI pos. ion) m/z (MH+): 315/317. Calc'd exact mass for C14H23BrOSi: 314. 1H NMR (400 MHz, Chloroform-d) δ ppm 0.19 (s, 6 H) 0.98 (s, 9 H) 3.08 (t, J=7.78 Hz, 2 H) 3.47-3.57 (m, 2 H) 6.78 (d, J=8.53 Hz, 2 H) 7.05 (d, J=8.53 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([OH:15])[C:8]=3[C:6]=2[CH:7]=1.[Br:16]Br.O>CC(O)=O>[Br:16][C:12]1[C:13]2[S:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[C:8]=2[C:9]([OH:15])=[N:10][CH:11]=1
Reactant: BrBr
Reactant: Oc1nccc2sc3ccc(Cl)cc3c12
Solvent: CC(=O)O
Solvent: O
Product: Oc1ncc(Br)c2sc3ccc(Cl)cc3c12
Temperature: 120 °C

Procedure:
To 8-chloro[1]benzothieno[3,2-c]pyridine-1-ol in AcOH (0.3 M) was added Br2 (1.1 equiv). The resulting mixture was heated at 120° C. for 1 h, cooled to room temperature, poured into H2O and filtered. The solid was suspended in acetone, sonicated and filtered to provide the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([C:21]([CH3:24])([CH3:23])[CH3:22])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13]CC1C=CC=CC=1>CO.[Pd]>[Si:2]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:25])[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCCCCCOCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 13,13,14,14-tetramethyl-1-phenyl-2,5,12-trioxa-13-silapentadecane (intermediate 15; 3.1 g, 0.008 mol) in methanol (74 mL) was added palladium on charcoal (10%, 0.3 g). The mixture was stirred overnight at room temperature under hydrogen (balloon pressure). The catalyst was filtered and the filtrate was evaporated under reduced pressure giving crude, which was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 9:1 to 4:1) to give the title compound as a colourless oil (77%).
Reaction SMILES: C(O)=O.C(O[CH:7](OCC)[CH2:8][CH:9]([O:14][CH3:15])[CH2:10][CH2:11][CH:12]=[CH2:13])C.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH3:15][O:14][CH:9]([CH2:10][CH2:11][CH:12]=[CH2:13])[CH2:8][CH:7]=[N:25][OH:26]
Reactant: NO
Reactant: C=CCCC(CC(OCC)OCC)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: C=CCCC(CC=NO)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 80% formic acid solution (30 mL) was added to 7,7-diethoxy-5-methoxyhept-1-ene obtained in Preparation Example 57-(2) (2.98 g), and the mixture was stirred at room temperature for 10 minutes. After further adding a 75% ethanol solution (64 mL), sodium acetate (3.75 g) and hydroxylamine hydrochloride (1.92 g) were added, followed by further stirring for one hour and 20 minutes. The solvent was concentrated to about 40 mL under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution (three times), water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.95 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][C@@H:28]([CH:31]([CH3:33])[CH3:32])[CH2:29][OH:30]>>[OH:30][CH2:29][C@@H:28]([NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26])[CH:31]([CH3:33])[CH3:32]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: CC(C)[C@H](N)CO
Product: CC(C)[C@@H](CO)NC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and (S)-(+)-2-amino-3-methyl-1-butanol in a manner similar to that described in Example 11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:28]([O-])=O)=[C:6]([CH:27]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]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)=[CH:10][CH:9]=1>[C].[Pd].C(OCC)(=O)C>[NH2:28][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]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)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3cc(Cl)ccc3[N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3cc(Cl)ccc3N)cc2)CC1
Yield: 76.2 %

Procedure:
5% carbon-palladium (1.3 g) was added to an ethyl acetate (100 ml) solution of tert-butyl 4-[4-(5-chloro-2-nitrophenoxy)phenyl]piperazine-1-carboxylate (5.64 g, 13 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give a crystal of tert-butyl 4-[4-(2-amino-5-chlorophenoxy)phenyl]piperazine-1-carboxylate (4.0 g, 76%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:9])[CH3:8].[C:10]([O:14][C:15]([N:17]1[C@@H:21]([C@H:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:19][C@H:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:30]([O:29][C@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:21]1[CH2:20][CH2:19][C@@H:18]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:42](=[O:43])[NH:9][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:8])=[CH:45][CH:46]=2)[N:17]1[C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(N)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
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: CC(NC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
1-Pyridin-2-yl-ethylamine (77 mg, 0.628 mmol) was added to a stirred, room temperature mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (300 mg, 0.571 mmol), HATU (260 mg, 0.685 mmol, 1.2 equivalents) and DIPEA (470 μL, 2.69 mmol, 4.7 equivalents) in DMF (1.2 mL). The reaction was stirred at room temperature for 16 hours before being loaded directly onto a silica column and purified by normal phase flash chromatography using silica gel (20-100% hexanes/ethyl acetate). The product fractions were collected and concentrated in vacuo to afford the title compound as a colorless gum (350 mg, 97%). LC-MS=630.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:25])[CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:27]1([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:24][CH2:23][CH2:22][N:21]([CH3:25])[C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]2[CH:7]=[CH:8][C:9]3[NH:10][C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34](=[O:35])[NH:33][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:43][CH:42]=4)=[N:1][C:4]=3[CH:5]=2)=[O:26])=[CH:16][CH:17]=1
Reactant: CN(CCO)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(C(=O)Nc5ccccc5)cc4)nc3c2)cc1

Procedure:
Compound 214 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(N-methyl-N-2-hydroxyethylamino)benzamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C30H27N5O3: 506.22; found: 506.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].O.NN>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.5 g of (+/−)-cis-1,2-dimethoxy-4-(2-nitrocyclohexyl)benzene are dissolved in 400 ml of methanol and treated with 7 ml of hydrazine hydrate and 2.5 g of Raney nickel in portions at RT in the course of 8 h. After stirring overnight at RT, the reaction mixture is filtered, the filtrate is concentrated and the residue is chromatog raphed on silica gel using a mixture of toluene/ethyl acetate/triethylamine=4/2/0.5. The title compound is obtained as an oil.