Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH:21][C:22]([NH2:24])=[S:23])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:26][CH:27]=O>CN(C=O)C>[CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH:21][C:22]3[S:23][CH:26]=[CH:27][N:24]=3)=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CCCl
Reactant: NC(=S)Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Solvent: CN(C)C=O
Product: c1ccc(Oc2cnc(Nc3nccs3)c(OCC3CCCC3)c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
(3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiourea (0.68 mmol) is dissolved in DMF (3 ml) and chloro-acetaldehyde (1.0 eq., 55% in water) is added and stirred three hours at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine (“A29”) is obtained after reversed phase column chromatography (acetonitrile/water+0.1% TFA) as yellow solid in a yield of 43%. HPLC (method C): 2.03 min; LC-MS (method A): 2.22 min, 368.15 (MH+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 7.705 (d, 1H, J=2.1 Hz), 7.509 (d, 1H, J=3.9 Hz), 7.387 (t, 2H, J=7.9 Hz), 7.32 (d, 1H, J=2.1 Hz), 7.143-7.119 (m, 2H), 7.029 (d, 2H, J=7.9 Hz), 3.992 (d, 2H, J=7.1 Hz), 3.787 (br, 1H), 2A49-2.389 (m, 1H), 1.853-1.829 (m, 2H), 1.619-1.547 (m, 4H), 1.371-1.320 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:13][C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])[CH2:15][CH3:16]>C1COCC1>[CH3:17][C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:8]3[CH:9]=[CH:10][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:13])[CH2:15][CH3:16]
Reactant: CCNC(=O)c1cc[nH]c1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)CC)n3CC2CCOCC2)c1
Yield: 40.1 %

Procedure:
Following the same procedure in Example 29, using N-ethyl-1H-pyrrole-3-carboxamide (166 mg, 1.2 mmol) (see the step B in example 31 for preparation), sodium hydride (240 mg, 60%, 6.0 mmol) and 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (385 mg, 1.0 mmol) in THF (20 mL). The crude product was purified by MPLC using EtOAc on silica gel to give 195 mg (40%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.78 (t, J=7.42 Hz, 3 H), 1.13 (t, J=7.23 Hz, 3 H), 1.41-1.56 (m, 4 H), 1.59 (s, 6 H), 1.95 (q, J=7.49 Hz, 2 H), 2.21-2.35 (m, 1 H), 3.24-3.34 (m, 4 H), 3.85-3.94 (m, 2 H), 4.42 (d, J=7.62 Hz, 2 H), 6.65 (dd, J=3.32, 1.76 Hz, 1 H), 7.29 (dd, J=3.32, 2.34 Hz, 1 H), 7.78-7.82 (m, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.96 (dd, J=8.8, 1.8 Hz, 1 H), 8.27 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=487.0; Anal. Calcd for C25H34N4O4S+110 TFA+0.1H2O (602.46): C, 53.83; H, 5.89; N, 9.30. Found: C, 53.79; H, 6.00; N, 9.19.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=CC=C[CH:3]=1.[F:32]C1(CO)CC1>>[F:32][C:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][C:17]4[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=4[N:31]=3)=[CH:11][CH:10]=2)[CH2:3][CH2:7]1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1
Reactant: OCC1(F)CC1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4(F)CC4)cc3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (1-fluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][C:23]3[C:32]([CH3:33])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][C:24]=3[CH3:34])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][C:23]3[C:24]([CH3:34])=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][C:32]=3[CH3:33])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:8][CH2:9]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O)CC3)nc3ccccc23)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1cc(N2CCC(O)CC2)nc2ccccc12
Reaction time: 5 h
Yield: 39.7 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 4-(2-(4-hydroxypiperidin-1-yl)quinoline-4-carboxamido)-3,5-dimethylbenzoate (0.13 g, 0.0003 mol) in THF:MeOH (5 ml:2 ml). After 5 h at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water acidified to pH 6 with aqueous 1N HCl and extracted with ethyl acetate (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and diethyl ether and filtered to afford the title compound as a light yellow solid (0.05 g, 40%). Mass spectrum (m/z): 420.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[S:5][CH:6]=1.[N:10]1([CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)=[O:22])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:16]3[CH2:15][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:22])=[CH:24][CH:25]=2)[S:5][CH:6]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Product: Cc1csc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 4-Methyl-2-thiophene boronic acid and 4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl bromide to give 70 mg (67%). MS (ES+) 355.2
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](OS(OCC)(=O)=O)[CH3:15].C(N(CC)CC)C>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH2:14][CH3:15])=[O:5]
Reactant: CCOS(=O)(=O)OCC
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(N)cccc1[N+](=O)[O-]

Procedure:
A solution of 2-amino-6-nitrobenzoic acid (29.2 g, 0.16 mol), diethylsulfate (24.7 g, 0.160 mol) and triethylamine (16.2 g, 0.160 mol) in N-dimethylformamide (250 ml) was stirred at 20°-25° for 20 hours. After removing DMF at 60° and 0.2 mm pressure, the residue was flash chromotographed over silica gel and the ethyl ester (10.8 g) eluted first with toluene then with 50% toluene -50% chloroform.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[CH:20]1[CH2:25][CH2:24][CH:23]([O:26][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:22][CH2:21]1)=[O:4]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.5 %

Procedure:
3-[(4-Hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (62 mg, 0.136 mmol) was dissolved in benzene (0.7 ml) and then p-nitrobenzoic acid (27 mg, 0.163 mmol) and triphenylphosphine (43 mg, 0.163 mmol) were added. The resulting solution was cooled in an ice bath and diethyl azodicarboxylate (26 ul, 0.163 mmol) was added. After stirring at room temperature for 22 hours, the solvents were removed and the residue was purified by preparative chromatography (30% EtOAc/Hexane) to obtain 44 mg (54%) of 3-{(4-Methyl-cyclohexanecarbonyl)-[4-(4-nitro-benzoyloxy)-cyclohexyl]-amino}-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([N:23]=[N+]=[N-])([O:21][CH3:22])[C:19](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[H][H].C>O1CCOCC1.[Pt]=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([NH2:23])([O:21][CH3:22])[C:19](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])(=[O:3])[CH3:2]
Reactant: CO[C@@]1(N=[N+]=[N-])C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1COCCO1
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21

Procedure:
A solution of t-butyl (6R,7R and S[5:1])-3-acetoxymethyl-7-azido-7-bromoceph-3-em-4-carboxylate (17.255 g, 39.8 mmole), pyridine (3.24 ml, 40 mmole), silver tetrafluoroborate (8.55 g, 43.8 mmole) in methylene chloride (160 ml), and methanol (320 ml) was stirred at +20° to +25° for 16 hours (a grey precipitate appeared within 1 to 2 minutes, but t.l.c. indicated that the long reaction-time was necessary). The mixture was filtered through Celite and the filtrate was evaporated and chromatographed on silica gel (250 g) in 5% ethyl acetate in benzene. A mixture of t-butyl (6R,7R and S[1:5])-3-acetoxymethyl-7-azido-7-methoxyceph-3-em-4-carboxylates was obtained as a pale-yellow viscous oil which slowly crystallised (13.910 g, 36.2 mmole, 90.5%), λmax 248.5 nm, inflexion at 265 nm (ε7,500 and 7,060 respectively). The n.m.r. spectrum indicated the assigned isomer ratio. Crystallisation of a sample from ether and petroleum-ether (b.p. 60° to 80°) provided a sample of t-butyl(6R,7S)-3-acetoxymethyl-7-azido-7-methoxyceph-3-em-4-carboxylate as a white crystalline solid m.p. 77.5° to 78.5°(dec); [α]D -33.2°; t.l.c. Rf 0.51: λmax 247.5 nm, inflexion at 264.5 nm (ε 8,180 and 7,600 respectively). c)(i) A suspension of platinum oxide (99.4 mg) in dry dioxan (10 ml) was stirred under a dry nitrogen atmosphere. A slow stream of hydrogen was then bubbled through the suspension for 3 minutes. A solution of t-butyl (6R,7S)-3-acetoxymethyl-7-azido-7-methoxyceph3-em-4-carboxylate (98.7 mg, 0.257 mmole) in dry dioxan (5 ml) was added to the suspension and stirring continued for a total of 25 hours; the stream of hydrogen was passed for the first 71/2 hours and the last 2 hours of this period. The black solution-suspension was stirred with charcoal (2 g) for 10 minutes and then filtered through a bed of charcoal on kieselgel G (Merck) on Celite. The filtrate was evaporated to give a crude sample of the title compound, t.l.c. Rf 0.13.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[CH:17]=[C:18]([C:28](=[O:30])[CH3:29])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([N:25]1[CH2:24][CH2:23][N:22]([C:21]2[CH:20]=[CH:19][C:18]([C:28](=[O:30])[CH3:29])=[CH:17][C:16]=2[F:15])[CH2:27][CH2:26]1)=[O:6]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3c(Cl)ccc([N+](=O)[O-])c3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 2,6-dichloro-3-nitro-benzoic acid (CAS: 55775-97-8; commercial) and 1-(3-fluoro-4-piperazin-1-yl-phenyl)-ethanone: colourless solid, m.p. 209-211° C., MS (ISP): 440.1 MH+.
Reaction SMILES: C(O[C:5](=O)[CH3:6])(=O)C.S(=O)(=O)(O)O.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:5]2([CH3:6])[CH2:18][CH2:19][CH2:14][CH2:15][CH2:16]2)[CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC1(c2cc(Br)ccc2O)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
There are then slowly added 10.8 ml (117 mmoles) of acetic anhydride and the reaction mixture is stirred at ambient temperature for 18 hours. 2.7 ml (50 mmoles) of concentrated sulfuric acid are then added and in small portions 17.3 g (100 mmoles) of 4-bromophenol. The reaction mixture is stirred at ambient temperature for 24 hours, evaporated to dryness and taken up in 200 ml of water. The pH is adjusted to 7 with sodium bicarbonate and extracted with ethylether. The organic phase is decanted, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a silica column by using as the eluant a 40/60 mixture of dichloromethane and hexane. The solvents are evaporated and 8.97 g (33% yield) of 4-bromo-2-(1-methylcyclohexyl) phenol in the form of a yellowish oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:34]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CO[C@H]1CC[C@H](CCNS(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CO[C@H]1CC[C@H](CCN(C(=O)c2ccccc2)S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C

Procedure:
To an ice-cold mixture of 4.0 g. (10 mMol) ethyl trans-4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-cyclohexyloxyacetate, 50 ml. methylene chloride and 1.5 g. (15 mMol) triethylamine is added dropwise a mixture of 1.4 g. (10 mMol) benzoyl chloride and 30 ml. methylene chloride. The reaction mixture is maintained for 4 hours at reflux temperature, cooled, filtered and the filtrate washed with dilute hydrochloric acid and water. It is then dried with anhydrous sodium sulphate and evaporated After purification over silica gel/ cyclohexane/diethyl ether (2:1 v/v), there is obtained a yield of 1.7 g (67% of theory); m.p. 81°-82° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.[F:29][C:30]([F:47])([F:46])[C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37](N2C=CN=C2)=[O:38])=[CH:33][CH:32]=1.Cl>C(OCC)(=O)C.O>[F:29][C:30]([F:46])([F:47])[C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]3[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=3)[CH2:2]2)=[O:38])=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)n1ccnc1
Reactant: CCOC(=O)c1cc([C@H]2CCCNC2)ccc1C
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc([C@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
(R)-Ethyl 5-(3-piperidinyl)-2-methylbenzoate-D-tartaric acid (2.02 g, 5.08 mmol) was dissolved in 100 mL ethyl acetate and washed with 100 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 10 mL toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (1.37 g, 5.08 mmol) was added. The reaction was stirred for 72 h at room temperature under nitrogen. The reaction was diluted with water (200 mL), acidified with 1N aqueous hydrochloric acid and extracted with diethyl ether (2×150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 2.12 g (93%) of the desired (R)-3-(3-ethoxycarbonyl-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C1C=CC(N2CCN(S(CC(C(C)C)C(O)=O)(=O)=O)CC2)=CC=1.[OH:29][NH:30][C:31]([C:33]1([CH2:39][S:40]([N:43]2[CH2:48][CH2:47][N:46]([C:49]3[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=3)[CH2:45][CH2:44]2)(=[O:42])=[O:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32].O1C=CC=C1B(O)O>>[OH:29][NH:30][C:31]([C:33]1([CH2:39][S:40]([N:43]2[CH2:48][CH2:47][N:46]([C:49]3[CH:54]=[CH:53][C:52]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[CH:51][CH:50]=3)[CH2:45][CH2:44]2)(=[O:42])=[O:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3ccco3)cc2)CC1)C(=O)O
Reactant: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Agent: OB(O)c1ccco1
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ccc(-c4ccco4)cc3)CC2)CCOCC1
Yield: 14 %

Procedure:
Prepared according to the method for the preparation 2-[4-(4-furan-2-ylphenyl)-piperazine-1-sulfonylmethyl]-3-methylbutyric acid, from 4-[4-(4-bromophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid hydroxyamide (0.249 g) and furan-2-boronic acid (0.066 g), to give the title compound as a cream solid (0.034 g, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)=[C:4]([F:19])[CH:3]=1.[Cl-].[NH4+]>CO.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([NH2:16])[CH:9]=2)=[C:4]([F:19])[CH:3]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1N
Temperature: 25 °C
Yield: 96 %

Procedure:
4′-chloro-4-ethyl-2′-fluoro-3-nitrobiphenyl (1.795 g, 6.45 mmol) is suspended in a mixture of methanol (20 ml) and water (4 ml). To this mixture is added zinc dust (2.95 g, 45 mmol) and a solution of ammonium chloride (1.04 g, 19 mmol) in water (4 ml), and once the addition is complete the mixture is heated at reflux for 3 hours. The mixture is cooled to room temperature, and filtered through a plug of diatomaceous earth. The filtrate is partitioned between ethyl acetate and water, and the organic extract is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 4′-chloro-4-ethyl-2′-fluorobiphen-3-ylamine (1.546 g), used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11](Cl)=[N:12][OH:13])[C:5]=1[F:15].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].NC1C=CC=CC=1>C1COCC1>[Cl:10][C:9]1[C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([F:15])[C:6]([C:11](=[N:12][OH:13])[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1c(Cl)ccc(C(Cl)=NO)c1F
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: COC(=O)c1c(Cl)ccc(C(=NO)Nc2cccc(C(F)(F)F)c2)c1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl-6-chloro-3-(chloro(hydroxyimino)methyl)-2-fluorobenzoate (1.2 g, 4.3 mmol) in THF (10 ml) at 0° C. was added 3-(trifluoromethyl)aniline (2.7 ml, 22 mmol). After stirring at 0° C. for 10 min, the reaction was allowed to warm to RT and stir for 3 h, then heat at 50° C. in an oil bath overnight. Added more of the aniline (5 mL) and heated at 50° C. for another 5 h. After cooling to RT, the solvent was evaporated and solid formed was filtered off. The filtrate was dissolved in DCM and purified by chromatography through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 5% to 25% EtOAc in hexane, to provide methyl 6-chloro-2-fluoro-3-(N′-hydroxy-N-(3-(trifluoromethyl)phenyl)carbamimidoyl)benzoate as off-white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.FC(F)(F)S(O[C:26]1[CH2:27][CH2:28][O:29][CH2:30][CH:31]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:29]1[CH2:28][CH:27]=[C:26]([C:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH:10]=2)[CH2:31][CH2:30]1
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C1=C(C2=CCC3(CC2)OCCO3)CCOC1
Temperature: 100 °C

Procedure:
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (prepared as described in PCT Int. Appl. WO2006064189, 1.57 g, 5.90 mmol), commercially available 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (5.23 mmol), and tetrakis (triphenylphosphino)palladium(0) (302 mg, 0.262 mmol) were dissolved in 1,4-dioxane (20 mL), treated with 2M aqueous Na2CO3 (14 mL, 28 mmol), bubbled with argon for a few minutes, and heated to 100° C. under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. This was purified by flash chromatography (silica gel, EtOAc) to give the title compound as a colorless crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: Cc1ccc(I)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(I)ccc1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Fluoro-4-iodo-1-methylbenzene (2.0 g, 8.6 mmol) was dissovled in carbon tetrachloride (10 mL), treated with N-bromosuccinimide (1.5 g, 8.6 mmol, 1 equiv) and benzoyl peroxide (9.0 mg, 0.004 equiv) and placed into an oil bath preheated to 80° C. for 3 hours. The mixture was cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo, providing the titled compound.