Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:24][CH2:25][C:26]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:27]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCO
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCCOC(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To erucyl alcohol (2) (101.5 g, 310.8 mmol) in 200 ml of toluene was added chloroacetyl chloride (38.6 g, 341.9 mmol). The reaction mixture was stirred at 25° C. for 3 hours. The reaction mixture was then washed with water (100 ml) and the aqueous and organic layers separated The organic layer was dried over sodium sulphate and the solvent removed in vacuo to yield erucyl 2-chloroacetate (3) (118.7 g, 94.3%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]([S:58]([CH3:61])(=[O:60])=[O:59])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:57])[C@H:28]([NH:37][C:38]([C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][N:41]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:39])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:23][CH2:22]1.CCO.ClCCCl.NN>CCOC(C)=O>[NH2:3][CH2:12][CH2:13][N:14]([S:58]([CH3:61])(=[O:59])=[O:60])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:57])[C@H:28]([NH:37][C:38]([C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][N:41]2[C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])=[O:39])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN2C(=O)c3ccccc3C2=O)S(C)(=O)=O)CC1
Agent: NN
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN)S(C)(=O)=O)CC1
Yield: 94.5 %

Procedure:
To a 50 mL round-bottomed flask equipped with stirring was added a solution of tert-butyl 3-(N-((1R)-2-[4-(2-{[2-(1,3-dioxoisoindolin-2-yl)ethyl](methylsulfonyl)-amino}phenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step e) (433.5 mg, 0.5 mmol) in 3:1 EtOH:1,2-dichloroethane (15 mL) followed by hydrazine (Aldrich) (49 mg, 1.5 mmol). The reaction mixture was stirred at 60° C. for 12 h. The organic solvents were removed in vacuo to provide a white solid which was dissolved in EtOAc (20 mL) and washed with satd NaHCO3 (20 mL) and satd NaCl (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (349 mg). MS (ESI, pos. ion) m/z: 738 (M+1); MS (ESI, neg. ion) m/z: 736 (M−1). Calc'd for C38H48ClN5O6S: 737.30.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:26][CH2:25][CH2:24][N:23]([CH2:27][CH3:28])[CH2:21][CH3:22])=[O:18])=[CH:19][CH:20]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Reactant: CCN(CC)CCN
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: CCN(CC)CCNC(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Yield: 69 %

Procedure:
In the same way as described in for Compound 90, step 3, using 4-(5-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (0.593 g 1.78 mmol), N,N diethylethane-1,2-diamine (0.30 mL, 2.14 mmol), DIPEA (0.48 mL, 2.68 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.68 g, 1.78 mmol) in DMF. The title compound (0.53 g, 69%) is obtained after purification by silica gel column chromatography eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH). LCMS: Rt 2.21 min (96%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:13][S:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:21]([N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:10]2([CH2:13][S:12][CH2:11]2)[CH2:9]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: Brc1ccc2c(c1)NCC21CSC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC2(CSC2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cooled solution of 6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] (0.25 g, 0.96 mmol), 4-dimethylaminopyridine (5.89 mg, 0.048 mmol), and triethylamine (0.269 mL, 1.928 mmol) in DCM (9.64 mL) was added acetyl chloride (0.137 mL, 1.928 mmol). The solution was stirred for 5 min at this temperature, the ice bath was removed and the solution was stirred at rt for 3 h. The reaction was poured into 2N HCl aqueous solution and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give 1-acetyl-6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] as a yellow solid. Mass Spectrum (ESI) m/e=297.9 [(M+1) (79Br)] and 300.0 [(M+1) (81Br)].
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[C:35]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][C:46](O)=[O:47])[CH2:40][CH2:39]1)(=[O:37])[CH3:36].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[C:35]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][C:46]([NH:1][CH2:2][C:3]([N:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]3[C:24]4[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[C:20]=4[CH:19]=[CH:18][CH:17]=3)[C:8]=2[Cl:34])[CH3:6])=[O:4])=[O:47])[CH2:40][CH2:39]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCN(CCC(=O)O)CC1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCN4CCN(C(C)=O)CC4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 3-(4-acetylpiperazin-1-yl)propanoic acid were used to prepare 16 as described for compound 1. LCMS (+ESI) 668 (M). 1H-NMR (CDCl3, δ): 8.58 (m, 1H), 7.84 (bt, 1H), 7.58 (t, J=2.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.82 (m, 2 H), 5.68 (d, J=4.0 Hz, 2H), 5.28 (s, 2H), 4.21 (s, 3H), 3.89 (dd, 1H), 3.69 (m, 2H), 3.25 (s, 3H), 2.53 (m, 4H), 2.04 (s, 3H). Calcd. for C33H37Cl2N7O5+1H2O: C, 56.57; H, 5.61; N, 13.99. Found: C, 56.33; H, 5.48; N, 14.21.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH:31]=[O:32])[N:23]=[C:22]2[CH2:33][CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([Mg]Br)([CH3:39])([CH3:38])[CH3:37]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH:31]([OH:32])[C:36]([CH3:39])([CH3:38])[CH3:37])[N:23]=[C:22]2[CH2:33][CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc(C=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)[Mg]Br
Solvent: C1CCOC1
Product: CCCc1nc(C(O)C(C)(C)C)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 59(b), 1.14 g of ethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-formyl-2-propylimidazole-5-carboxylate [prepared as described in step (c) above] was reacted with 2.4 ml of a 2M solution of t-butylmagnesium bromide in tetrahydrofuran, to afford 0.78 g of the title compound as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]=[CH:5]2
Reactant: CCCCCCCI
Reactant: Oc1ccc2cc(Br)ccc2n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCOc1ccc2cc(Br)ccc2n1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-bromoquinolin-2-ol (352 mg1.57 mmol) and silver carbonate (863 mg, 3.14 mmol, 2.0 eq.) in toluene (20 mL) was added 1-iodoheptane (355 mg, 1.57 mmol, 1.0 eq.) and stirred for 3 h at 110° C. The reaction mixture was evaporated under reduced pressure to remove most of solvent, then filtered, and washed with ethyl acetate. The filtrate was concentrated to give crude the title compound. The crude product was purified by flash chromatography using PE/EA (20/1) as eluent to give product as a red oil (300 mg, 60%). ESI-MS: 323.8 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 7.84-7.83 (m, 2H), 7.70-7.68 (m, 2H), 6.89 (d, 1H), 4.43 (t, 2H), 1.81 (q, 2H), 1.51-1.28 (m, 8H), 0.90 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17](Br)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[C:39](F)(F)F.C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[C:25]([CH3:39])[CH:26]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Reactant: CC1(C)OB(c2ccc(F)c(C(F)(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2cn(CCO)c(C3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[4-Bromo-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (2000.00 mg; 5.34 mmol; 1.00 eq.), 2-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1233.97 mg; 8.02 mmol; 1.50 eq.), mg; 0.53 mmol; 0.10 eq.) and Cs2CO3 (3483 mg, 10.69 mmol) in dioxane 15 ml and water 1.5 ml was purged with argon, added Pd(0)(tBu3)2 (273 mg, 0.53 mmol), stirred at 50° C. for overnight. LC-MS showed desired as major product. Diluted reaction solution with EA 70 ml, washed with brine 30mIX2, separated out organic layer, dried, removed off solvent, got crude product, which was subjected to biotage NASP column (100 g), elated with 40-100% EA in hexane and contained 0.5% TEA in EA, collected title compound 1650 mg, 76%
Reaction SMILES: [F:1][C:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C1C=CC=CC=1.CCCCC>[Br:30][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([CH3:10])[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(F)CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCC
Product: CC(C)(F)CCCCCBr
Temperature: 0 °C
Yield: 72.4 %

Procedure:
A stirred solution of the product from Step II (0.427 g, 0.00288 mol) in benzene (5.2 ml) was mixed with triphenylphosphine (0.83 g, 0400317 mol) cooled in an ice bath and treated, portion-wise, during 26 minutes with N-bromosuccinimide (0.56 g, 0.00317 mol). The mixture was kept in the ice bath for 30 minutes and at ambient temperature for 3.5 hours; it was then diluted with pentane (20 ml), cooled in an ice bath for a few minutes and filtered. The solid was washed with pentane and the filtrate was concentrated. A mixture of the residue and pentane was cooled in an ice bath for a few minutes and again filtered. The filtrate was mixed with Et2O and washed successively with cold 5% aqueous sodium thiosulfate, 0.5N NaOH and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 1-3% EtOAc-hexane to give 0.440 g of 1-bromo-6-fluoro-6-methylheptane.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O>C1C=CC=CC=1>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[NH:5][CH2:1][CH2:2][CH2:3][NH:4]1
Reactant: O=Cc1ccccn1
Reactant: NCCCN
Solvent: c1ccccc1
Product: c1ccc(C2NCCCN2)nc1
Yield: 98 %

Procedure:
To a stirred solution of 1,3-propanediamine (0.37 g, 0.005 mol) in dry benzene (25) mL) was added dropwise at room temperature pyridine-2-carboxaldehyde (2) (0.535 g. 0.005 mol) in dry benzene (5 mL). The resulting cloudy solution was heated under reflux, using a Dean-Stark trap to remove water during 2 hr. The solvent was then completely removed by distillation to give about a quantatitive yield (0.80 g) of compound (9), having an N--CH(2-pyr)--N resonance at 4.1 ppm).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:10][CH:8]([CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])(=[O:23])=[O:22]
Reactant: CC(O)COc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COc1ccc(Cl)cc1)OS(C)(=O)=O
Temperature: -8 °C
Reaction time: 1 h

Procedure:
To a solution of 37.4 g of 3-(p-chlorophenoxy)propan-2-ol and 41 ml of triethylamine in 500 ml of dichloromethane stirred and chilled at -8° C. is added dropwise 18.7 ml of methanesulfonyl chloride in 50 ml of dichloromethane. After stirring at -8° C. for 1 hour, the solution is washed with 350 ml portions of ice cold water, 1N HCl, saturated NaCl, saturated NaHCO3 and saturated NaCl. The organic layer is dried (MgSO4) and the solvent removed under reduced pressure to give 54 g of product as white crystals, mp 72°-78° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([C:23](=[O:39])[NH:24][CH:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:23](=[O:39])[NH:24][CH:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OCC(NC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OCC(NC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.4 %

Procedure:
4-[3-(2-tert-Butoxy-1-tert-butoxycarbonyl-ethylcarbamoyl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (10 g) was dissolved in 250 mL of methanol. This solution was treated with 1.2 g of 10% (wt/wt) palladium on carbon catalyst under nitrogen atmosphere. The mixture was then degassed before stirring under 1 atmosphere of hydrogen gas at room temperature for approximately 2.5 hours. At this time, the reaction mixture was filtered through celite and washed with copious volumes of methanol. The dark filtrate was concentrated in vacuo and the residue was further dried over phosphorous pentaoxide. In this manner, 9.49 g of the expected product was obtained as a grey-purple solid. H1-NMR spectroscopy indicated a spectrum consistent with 4-[4-amino-3-(2-tert-butoxy-1-tert-butoxycarbonyl-ethylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:19](O)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)C1C=CC=CC=1>C1C=CC=CC=1>[C:20]1([CH:19]2[N:13]([CH2:12][CH2:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:14][CH:15]([CH2:16][OH:17])[O:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(CCNCC(O)CO)cc1OC
Reactant: O=C(O)c1ccccc1
Solvent: O=Cc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(CCN2CC(CO)OC2c2ccccc2)cc1OC
Yield: 2750 %

Procedure:
A solution of 3 (195 g, 0.76 mol), benzoic acid (3.0 g), benzaldehyde (270 ml), C6H6 (180 ml) was heated to reflux while collecting the H2O in a Dean-Stark trap. After 21/2 hours, 13 ml of H2O was collected and the solution cooled, washed with saturated Na2CO3. The aqueous layer was washed with CHCl3 (2X) and the combined extracts dried, filtered and concentrated to dryness to yield 232 g of 5 which contains 26 mol % benzaldehyde. This corresponds to 209 g of 5; 'H NMR (CDCl3) δ 2.6 (6H, m), 3.4 (2H, m), 3.75 (7H, d, m), 4.3 (1H, m), 4.8 (1H, d), 6.7 (3H, m), 7.4 (5H, bs). ##STR150##
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=O)OCC)C.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.O>CN(C)C=O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
2.63 g of sodium hydride are added to 50 ml of dimethylformamide. The mixture is cooled to 0° C. and 16 g (58.6 mmol) of (4-nitro-benzyl)-phosphonic acid diethyl ester is added portionwise. The solution is stirred at room temperature for 1.5 h, then cooled to −10°. A solution of 6.09 g (50 mmol)4-fluoro-benzaldehyde in 10 ml dimethylformamide is slowly added to the mixture at −10°. Stirring at room temperature for 45 min followed by additon of 250 ml water yields a precipitate which is filtered and recrystallised from ethanol/water 85:15 to yield 10.81 g (91%) of a yellow solid. MS: m/e=243.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])[C:5]([NH:28][C@H:26]([C:24]1[NH:23][C:22]2[CH:29]=[CH:30][C:19]([Cl:18])=[CH:20][C:21]=2[N:25]=1)[CH3:27])=[O:7]
Reactant: O=C(O)c1ccc(N2CCCNC2=O)c(Cl)c1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)c1ccc(N2CCCNC2=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 0 °C

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then pouring into ice water, adding conc. ammonia solution, filtering, washing with water and purifying by chromatography on silica gel (eluting gradient ethyl acetate/(methanol/conc. ammonia solution 19:1)=98:2->90:10) with subsequent filtration through activated charcoal, trituration with ether and drying in the drying pistol at 70° C.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1)[CH2:24][C:23]2=[O:37]>>[OH:36][C:32]1[CH:31]=[C:30]([CH:25]2[CH2:24][CH:23]([OH:37])[C:22]3[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=3)[O:26]2)[CH:35]=[CH:34][CH:33]=1
Reactant: O=C1CC(c2cccc(O)c2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1cccc(C2CC(O)c3cc(O)ccc3O2)c1

Procedure:
2-(3-Hydroxyphenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 6-hydroxy-2-(3-hydroxyphenyl)chroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 9.43 (bs, 1H), 8.88 (bs, 1H), 7.19-7.15 (m, 1H), 6.87 (d, 1H, J 2.7 Hz), 6.84-6.82 (m, 2H), 6.72-6.69 (m, 1H), 6.58 (d, 1H, J 8.7 Hz), 6.53 (dd, 1H, J 2.7, 8.7), 5.01 (d, 1H, J 11.3 Hz), 4.86 (dd, 1H, J 6.2, 10.8 Hz), 2.25-2.19 (m, 1H), 1.88-1.75 (m, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:13][C:14]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH3:24])[C:15](OCCCCCC)=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[CH2:26]([O:25][C:14]([O:13][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:24])[CH2:15][OH:16])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCOC(C)(CO)OCCCCCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 96.1 %

Procedure:
To a mixture of LiAlH4 (3.44 g, 90.5 mmol) in Et2O (200 mL) is added a solution of ester 3 (29.5 g, 82.3 mmol) in Et2O (100 mL). After addition, the mixture is refluxed for 6 hours. The reaction mixture is cooled to 0° C. and quenched with ethyl acetate (20 mL) and H2O (20 mL). The mixture is added to saturated potassium sodium tartrate (300 mL) and stirred at 23° C. for 12 hours. The mixture is extracted with Et2O (2×200 mL) and the combined organic layers are dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propan-1-ol 4 (20.6 g, 94%) as a colorless oil: Rf (15% EtOAc/hexane)=0.20; IR (thin film, cm−1) 3430, 2955, 2929, 2859, 1467, 1378, 1244, 1155, 1112, 1064, 876; 1H NMR (600 MHz, C6D6) δ 3.58 (d, J=6.6 Hz, 2H), 3.43 (t, J=6.6 Hz, 4H), 1.58 (t, J=6.6 Hz, 1H), 1.53 (m, 4H), 1.36 (s, 3H), 1.34-1.22 (m, 12H), 0.88 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, C6D6) δ 101.0, 66.2, 61.3, 32.5, 30.9, 26.8, 23.4, 21.3, 14.6.
Reaction SMILES: [F-].[K+].[Cl:3][C:4]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([F:17])[C:10]([Si](C)(C)C)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>O.O1CCCC1>[Cl:3][C:4]1[C:12]([C:13]([F:14])([F:15])[F:16])=[C:11]([F:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: C[Si](C)(C)c1cc(C(=O)O)c(Cl)c(C(F)(F)F)c1F
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(C(F)(F)F)c1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of potassium fluoride (0.367 g, 9.55 mmol) in water (15 ml) was added to a solution of 2-chloro-4-fluoro-3-(trifluoromethyl)-5-(trimethylsilyl)benzoic acid (1 g, 3.18 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at 100° C. overnight. An additional aliquot of water (15 ml) and potassium fluoride (0.370 g, 9.62 mmol) was added and heating at 100° C. was continued for a further 4 hrs. The tetrahydrofuran was evaporated in vacuo and replaced with enough dimethylformamide to dissolve all solids. The mixture was heated overnight at 100° C. but starting material still remained so more potassium fluoride (0.367 g, 9.55 mmol) was added and heating at 100° C. continued for 7 days. At this stage almost all of the starting material had disappeared so the reaction was evaporated to dryness under vacuum and taken up in 2N aqueous hydrogen chloride (75 ml) and diethyl ether (50 ml). The aqueous layer was separated and extracted with more diethyl ether (2×50 ml) and then the combined organic fractions were dried over sodium sulphate and evaporated to give crude product as a white solid. This was purified by recrystallisation from toluene to give pure 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid (0.566 g) as a white solid.