Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.Br[CH2:27][O:28][C:29](=[O:31])[CH3:30].O>CN(C)C=O>[CH3:27][O:28][C:29](=[O:31])[CH2:30][N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1
Reactant: CC(=O)OCBr
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (60 mg, 0.17 mmol, Example 59) and bromomethylacetate (60 mg, 0.39 mmol, Aldrich) in dimethylformamide (1.5 mL) was stirred at room temperature for 6 hours. The solution was poured into water and extracted into methylene chloride (2×). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give [4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin- 1-yl]-acetic acid methyl ester as a white solid. HRMS, observed: 418.1888; Calcd for M+: 418.1885.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)=[O:8].Cl>C(OCC)C.O1CCCC1>[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[O:21])=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)(=[O:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (0.23 ml of a 3M solution in diethyl ether) was added dropwise to a stirred solution of N6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide (from Example 103, 174 mg, 0.32 mmol) in anhydrous tetrahydrofuran (5 ml) at −70° C. under a nitrogen atmosphere. The mixture was stirred at −70° C. for an additional 2 hours before warming to room temperature. Aqueous hydrochloric acid (5 ml of 1M solution) was slowly added to the mixture, and then it was extracted with ethyl acetate (100 ml). The organic phase was separated and washed with brine, dried (magnesium sulphate) and the solvent were removed in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give the title compound (18 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])C2C=CC=CC=2Cl)[CH:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[O:19][CH3:20].CC(C)([O-:24])C.[K+].O>COCCOC>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[O:19][CH3:20])[C:8]([OH:16])=[O:24]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)cc(Br)c1OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCc1cc(C(=O)O)cc(Br)c1OC
Reaction time: 6 h
Yield: 73.5 %

Procedure:
At ambient temperature, to a stirred mixture containing 2-bromo-4-(2-chlorobenzoyl)-6-ethylanisole (10.0 g, 28.2 mmol) and potassium t-butoxide (31.7 g, 0.283 mol) in ethylene glycol dimethyl ether (157 mL) was added H2O (1.52 mL). After 6 h, the reaction solids were collected by filtration and washed with ether (2×). The crude product was dissolved in H2O (200 mL), acidified with 2N HCl (pH <2) and stirred for 7 h. The precipitate was collected by filtration, washed with H2O (2×) and dried to give 5.37 g (73%) of the title compound. 1H NMR: consistent. mass spectrum (EI) m/z 258 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:23][CH:22]=1)[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(I)=CC=1[Cl:44]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[C:23]([Cl:44])[CH:22]=1)[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cc(I)ccc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Product: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1)C(=O)OC1CCCC1

Procedure:
Synthesised by analogous methods to Intermediate 5a, using 4-bromo-3-chloro-iodobenzene at Stage 2 of Scheme 4. m/z 520 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:30]3[CH2:31][CH2:32][N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1oc2ccc(CN3CCN(c4ccccc4)CC3)cc2c1-c1ccccc1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with N-phenylpiperazine in ethanol to provide yellow needles of 4-(2-nitro-3-phenyl-5-benzofuranylmethyl)-1-phenylpiperazine, m.p. 155°-157° C., having the structure
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21]/[CH:22]=[CH:23]/[CH2:24][CH3:25].CC([O-])(C)C.[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21]/[CH:22]=[CH:23]/[CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CC/C=C/CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC/C=C/CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 37.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.47 g) is alkylated using (E)-1-bromo-2-pentene (1 g; 6.71 mmol) and KOtBu (0.75 g; 6.71 mmol) at RT for 20 h. After aqueous work-up and flash chromatography on silica gel eluting with light petroleum/EtOAc (2.5:1) the pure alkylated acetamide (0.85 g; 2.58 mmol) is de-acetylated under reflux conditions using DBU (0.6 ml) in MeOH (60 ml). (E)-5-amino-3,3-dimethyl-6-nitro-1-(pent-2-enyl)-1,3-dihydro-indol-2-one (0.6 g) is obtained after an aqueous work-up.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](C(O)=O)=[O:14].S(Cl)([Cl:20])=O>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([Cl:20])=[O:14]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1onc(-c2ccccc2)c1C(=O)Cl

Procedure:
A mixture of 111.76 g of 5-methyl-3-phenyl-4-isoxazoloyl carboxylic acid, 6 drops of pyridine and 29.5 ml of thionyl chloride is stirred under reflux for 4 hrs. The excess thionyl chloride is evaporated in vacuo. Distillation of the residue yields 113.74 g of yellow liquid.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:11]#[N:12])=[CH:7][NH:8][C:9]=1[CH3:10])[CH2:2][CH2:3][CH3:4].[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([N:8]2[CH:7]=[C:6]([C:11]#[N:12])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:9]2[CH3:10])=[CH:19][CH:18]=1)[CH3:14]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CCCCc1c(C#N)c[nH]c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1c(C#N)cn(-c2ccc(C(=O)OCC)cc2)c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A suspension of 4-butyl-5-methyl-1H-pyrrole-3-carbonitrile (0.081 g), 4-fluoro-benzoic acid ethyl ester (0.10 g) and cesium carbonate (0.21 g) in N,N-dimethylformamide (3 mL) was stirred at 70° C. overnight. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/6) to give the title compound (0.032 g).
Reaction SMILES: [NH2:1][CH:2]1[C:22]2[C:17](=[C:18]([Br:23])[CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:30](ON1C(=O)CCC1=O)([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31]>C1COCC1.CCOCC>[Br:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[C:4]1([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH2:3][CH:2]2[NH:1][C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1cccc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(NC(=O)OCC[Si](C)(C)C)c1cccc(Br)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.4 %

Procedure:
To a stirred solution of crude (±)-tert-butyl 3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (264 mg, 0.69 mmol) in THF (5 mL) was added 10% aq K2CO3 (10 mL), followed by Teoc-OSu (269 mg, 1.04 mmol). The mixture was stirred at rt for 3 d, diluted with ether (80 mL), washed with brine (25 mL) and dried over MgSO4. Removal of the solvent left an oil (240 mg) which was purified chromatography on a 12-g silica cartridge, eluted with a 0-50% EtOAc in hexanes gradient to afford (±)-tert-butyl 7-bromo-3-((2-(trimethylsilyl)ethoxy)carbonylamino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (85 mg, 31% for 2 steps). LC-MS Method 1 tR=2.35 min, m/z=425, 427, 547, 549.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:8]=[C:9]([F:11])[CH:10]=1.[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:35]([NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(F)cc(CC(=O)OC)c1
Reactant: O=C=NCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(F)cc(CC(=O)OC)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-ethylaminomethyl-5-fluoro-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl isocyanate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:50][O:51][CH2:52]CCO>>[CH2:26]([C:16]1[N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:18]=[C:13]2[C:12](=[O:28])[NH:11][C:10]([C:9]3[C:4]([O:3][CH2:1][CH2:2][CH2:50][O:51][CH3:52])=[N:5][CH:6]=[C:7]([S:29]([N:32]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]4)(=[O:30])=[O:31])[CH:8]=3)=[N:15][C:14]=12)[CH3:27]
Reactant: COCCCO
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCCOC)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
A mixture of the title compound of Example 1 (200 mg, 0.36 mmol), potassium bis(trimethylsilyl)amide (361 mg, 1.81 mmol) and 3-methoxypropan-1-ol (1.5 ml) was stirred at 90° C. for 18 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (97:3 to 95:5), to give the title compound (81 mg, 38%) as a foam. Found: C, 55.36; H, 6.11; N, 18.18. C28H36N8O5S; 0.50 H2O requires C, 55.52; H, 6.16; N, 18.50%. δ (CDCl3): 1.01 (3H,t), 1.29 (3H,t), 2.19 (2H,m), 2.40 (2H,q), 2.54 (4H,m), 3.02 (2H,q), 3.12 (4H,m), 3.39 (3H,s), 3.65 (2H,t), 4.76 (2H,t), 5.68 (2H,s), 7.09 (1H,d), 7.21 (1H,m), 7.62 (1H,m), 8.56 (1H,d), 8.62 (1H,s), 8.93 (1H,s), 10.84 (1H,s). LRMS: m/z 597 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
Ethyl 2-[4-(trifluoromethyl)phenyl]thiazole-5-carboxylate (28 mg, 0.09 mmol.) and LiOH (5.0 mg, 0.12 mmol) were diluted with THF/H2O=1:1 (1 mL), and then stirred for 3 hrs at room temperature. The mixture was acidified with 1N HCl, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield the crude title compound as a yellow solid (23 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32][C:33]1[S:37][C:36]([C:38](O)=[O:39])=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:38]([C:36]4[S:37][C:33]([CH2:32][O:31][CH3:30])=[CH:34][CH:35]=4)=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCc1ccc(C(=O)O)s1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COCc1ccc(C(=O)N[C@@H](C)[C@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)c2cccc(OC)c2)s1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-(methoxymethyl)thiophene-2-carboxylic acid (26 mg, 0.15 mmol).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1ccc(Br)cc1Br
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Br)cc1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4-Dibromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,4-dibromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]2=[N:10]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:26](=[O:30])[C:27]([CH3:29])=[CH2:28])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]2=[N:10]1
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Nc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reaction time: 1 h

Procedure:
To 10.4 g. (0.04 mole) of 2-(2-hydroxy-5-aminophenyl)-5-chlorobenzotriazole and 4.1 g. triethylamine in 400 ml. methylene chloride (no preservative) was added at 0°-5° C., under nitrogen, with stirring, 4.2 g. methacryloyl chloride in 30 ml. methylene chloride. The dropwise addition required about 30 minutes. The mixture was stirred at 0°-5° C. for an additional 30 minutes and then at room temperature for one hour. The mixture was then washed with equal volumes of water, 5% hydrochloric acid and water. The organic phase was dried over magnesium sulfate and poured onto a 2" column of silica gel (120 g.) which had been slurry packed with methylene chloride. The column was eluted with methylene chloride and 100 ml. fractions were taken. The fractions were examined by thin layer chromatography (TLC) on silica gel plates using 1:5, ethyl acetate:chloroform as the developing solvent. The fractions containing the product (r.f. 0.36) were combined and evaporated. The residual solid was crystallized from ethanol to give 2.2 g. of product, m.p. 204°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[C@:7]1([C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16][OH:17])[O:8]1)[O:6][CH2:5]2.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C(C)=CC=CC=1C>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:17][CH2:16][C@H:9]2[O:8][C@@:7]3([C:18]4[C:4](=[CH:3][C:2]([Cl:1])=[C:20]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=5)[CH:19]=4)[CH2:5][O:6]3)[C@H:12]([OH:13])[C@@H:11]([OH:14])[C@@H:10]2[OH:15])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1cccc(C)n1
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 65.9 %

Procedure:
To a stirred solution of (1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (0.15 g, 0.356 mmol) in 3.5 mL of 2,6-lutidine was added p-toluenesulfonyl chloride (0.34 g, 1.78 mmol). After stirring for 21 h at ambient temperature, the solvent was distilled off. The residue was taken up with 30 mL of ethyl acetate, washed with 1 M hydrochloric acid and brine prior to drying over Na2SO4. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 135 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.61 (d, J=8.0 Hz, 2H), 7.35 (s, 1H), 7.21 (s, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 4H), 5.02 (d, J=12.8 Hz, 1H), 4.97 (d, J=12.8 Hz, 1H), 4.22-4.08 (m, 4H), 3.90-3.86 (m, 1H), 3.71-3.65 (m, 2H), 3.39-3.34 (m, 1H), 2.59 (q, J=7.6 Hz, 2H), 2.33 (s, 3H), 1.18 (t, J=7.6 Hz, 3H); LC-MS (m/z) 575 [(M+1)+], 619 [(M+45)−].
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH:1]1([CH2:7][C@@H:8]([C:10]([O:12][CH2:17][CH3:18])=[O:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)CC1CCCCC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
N-[N-[N-(4-(piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-L-β-cyclohexyl alanine, ethyl ester ##STR16##A. β-cyclohexyl alanine (1.5 g) is dissolved in absolute ethanol (75 ml) and the solution cooled to 0° C. Thionyl chloride (1.1 ml) is added dropwise over a period of 10-15 minutes, the solution allowed to warm to room temperature, and then stirred at room temperature for about 18 hours. The reaction mixture is evaporated in vacuo, toluene is azeotroped twice from the residue, and the residue is taken up into ethyl acetate. The ethyl acetate solution is washed with water, 1N sodium hydroxide, water, brine, dried over sodium sulfate, filtered, and evaporated in vacuo to give β-cyclohexyl alanine, ethyl ester.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([O:19][C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:29][CH:28]=2)=[O:25])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)(=O)C>[CH2:13]([O:19][C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][N:36]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:34])=[CH:31][CH:32]=2)=[O:25])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 90 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(hexyloxy)-N-[4-(hydrazinocarbonyl)phenyl]-benzamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 110 mg of the title compound (90%) as a yellow powder in 91.1% purity by HPLC (Rt: 5.86, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(N[C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH:11]([OH:13])C)=[O:5])C.Cl.[OH-].[Na+].C(=O)(O)[O-:18].[Na+]>>[OH:13][CH2:11][C:10]1[CH:9]=[CH:8][S:7][C:6]=1[C:4]([OH:5])=[O:18]
Reactant: CCNC(=O)c1sccc1C(C)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1sccc1CO
Temperature: 25 °C
Yield: 10 %

Procedure:
A solution of 3-(1-Hydroxy-ethyl)-thiophene-2-carboxylic acid ethylamide (298 mg, 1.5 mmol) in 15 ml of aqueous 6N HCl solution is heated at 100° C. for 1.5 h. The reaction mixture is cooled to room temperature and the pH is adjusted to ˜8.5 with 30% aqueous NaOH solution and saturated aqueous sodium bicarbonate solution. The resulting solution is extracted with Dichloromethane. The aqueous layer is collected and acidified with aqueous 6N HCl until the pH˜1. The resulting solution is extracted with tBuOH-Ether. The combined organic extracts are dried and concentrated to give the title compound (25 mg, 10%).
Reaction SMILES: [OH:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[F:22][C:23]([CH2:26][C:27](O)=[S:28])([F:25])[F:24]>>[F:22][C:23]([CH2:26][C:27]([O:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[S:28])([F:25])[F:24]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](O)[C@H]3SC2)s1
Reactant: OC(=S)CC(F)(F)F
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](OC(=S)CC(F)(F)F)[C@H]3SC2)s1

Procedure:
Reaction of 7β-hydroxy-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid and trifluoromethylthioacetic acid according to the procedure of Preparation 3 gives the title compound.