Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][CH2:10]Cl>>[CH3:7][O:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COCCCl
Product: COCCN1CCOCC1
Reaction time: 48 h

Procedure:
In an autoclave of 100 mL, morpholine (45.0 g, 517 mmol) was made reacted with chloroethyl methyl ether (25.0 g, 265 mmol) at 130 deg C. for 48 hours. Solid salt that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 25 cm. Then 1H-NMR measurement of obtained amine is performed, and it was confirmed that chemical shifts, δ (ppm), are 3.53-3.55(m, 4H), 3.33-3.35(m, 2H), 3.17(s, 3H), and 2.36-2.32 (m, 6H), and that N-2-methoxyethylmorpholine was synthesized.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCCC(=O)NCCNC(=O)OC(C)(C)C)cc1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(CCCCNCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of {2-[4-(4-methoxy-phenyl)-butyrylamino]-ethyl}-carbamic acid tert-butyl ester (6 g, 17.88 mmol) in dry THF (60 ml) under an inert atmosphere of Argon is treated carefully with borane. THF complex (53.88 ml, 1M Borane in THF). The reaction mixture is heated at reflux for 2 hours and then allowed to cool to room temperature overnight. The mixture is quenched by addition of MeOH and then heated to 70° C. for a further 2 hours. After cooling to room temperature, the solvent is removed in vacuo to afford {2-[4-(4-Methoxy-phenyl)-butylamino]-ethyl}-carbamic acid tert-butyl ester as a viscous oil; [M+H]+ 323
Reaction SMILES: [Cl:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.[O-][Cl:12].[Na+]>CO>[Cl:12][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:6][C:2]=1[Cl:1]
Reactant: FC(F)(F)c1cc(Cl)[nH]n1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1n[nH]c(Cl)c1Cl

Procedure:
A solution of 5-chloro-3-trifluoromethylpyrazole (190.0 g, 1.11 mol) in 400 ml of methanol is treated with liquid bleach (5.25% NaOCl) for 3 hr. The reaction mixture is then extracted with ether, the combined ether extracts are acidified with HCl (300 ml), washed with brine, dried and concentrated to give 4,5-dichloro-3-trifluoromethylpyrazole, a light yellow solid, m.p. 58°-60° .
Reaction SMILES: C([C:11]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)=[O:12])(OCC1C=CC=CC=1)=O.[CH:24]1([CH2:27][N:28]2[C:36]3[N:35]=[C:34]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([NH:44][CH3:45])=[CH:40][CH:39]=4)[NH:33][C:32]=3[C:31](=[O:46])[N:30]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[C:29]2=[O:55])[CH2:26]C1>CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:11](=[O:12])[NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19](=[O:21])[N:44]([C:41]2[CH:42]=[CH:43][C:38]([CH2:37][C:34]3[NH:33][C:32]4[C:31](=[O:46])[N:30]([CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=5[F:54])[C:29](=[O:55])[N:28]([CH:27]5[CH2:24][CH2:26]5)[C:36]=4[N:35]=3)=[CH:39][CH:40]=2)[CH3:45])=[CH:22][CH:23]=1)[C:18]1[CH:22]=[CH:23][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: CN(C)c1ccncc1
Product: CN(C(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3C2CC2)cc1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that N-carbobenzyloxycarbonyl-4-aminomethylbenzoic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, 0.62 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione, and 0.68 equivalents of 4-dimethylaminopyridine added as the final reagent. The product was purified by chromatography using silica gel eluted with 95:5 chloroform/methanol followed by crystallization from acetonitrile. MS, observe m/z(M+H)=701.3 and m/z(M−H)=699.4.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNc1ccc(N)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
Step B A solution of ethyl 2-(4-(tert-butoxycarbonylamino)phenylamino)acetate (772 mg, 2.62 mmol) in dichloromethane (14 mL) was treated with TFA (7 mL)) and the reaction mixture was stirred at 0° C. for 1.5 h. The resulting mixture was concentrated in vacuo and the residue was treated with EtOAc (200 ml) and washed with sat. aqueous Na2CO3, brine, dried over Na2SO4 and concentrated in vacuo to give ethyl 2-(4-aminophenylamino)acetate as a brown oil (483 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([CH2:29][CH2:30][CH3:31])[C:14]([NH:16][C:17]2[N:18]=[CH:19][N:20]([CH2:22][CH2:23]OS(C)(=O)=O)[CH:21]=2)=[O:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:32]([O:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH3:33]>>[CH2:32]([O:34][CH2:35][CH2:36][CH2:37][NH:38][CH2:23][CH2:22][N:20]1[CH:21]=[C:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:29][CH2:30][CH3:31])[N:18]=[CH:19]1)[CH3:33]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCOS(C)(=O)=O)cn1
Reactant: CCOCCCN
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCNCCCOCC)cn1

Procedure:
Methanesulfonic acid 2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-ethyl ester was reacted with 3-ethoxypropyl amine to provide the title compound: MS 446.2 m/z (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Li]CCCC.Cl[Si:21]([CH3:32])([CH3:31])[CH:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]1[CH3:30]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[C:5]([NH:6][Si:21]([CH3:31])([CH3:32])[CH:22]2[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]2[CH3:30])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C(C)C)cc(Br)cc2C(C)C)C(C)=C1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of 13.8 g (53 mmol) of 4-bromo-2,6-diisopropylaniline in 170 ml of THF, 21.0 ml of 2.5 M (53 mmol) of nBuLi in hexanes were added dropwise at −80° C. This mixture was additionally stirred for 30 minutes at ambient temperature and then added to a solution of 11.4 g (53 nimol) of chloro(dimethyl)(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane in 70 ml of THF. The resulting mixture was stirred overnight and then evaporated to dryness. The residue was suspended in 100 ml of toluene. This suspension was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow oil, b.p. 156-162° C./0.15 mm Hg. Yield 12.8 g (55%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][C:34](OC)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:33][C:34]1[NH:22][C:20](=[O:21])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: CC(O)C(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: COc1ccc(Cc2nc3c(nnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1OC

Procedure:
Analogously to the procedure of Example 29, the title compound is prepared from 10 mg (0.024 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-[1,2,3]triazole-4-carboxamide and 20 mg (0.107 mmol) of methyl 3,4-dimethoxyphenylacetate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1.[Cl:12][C:13]1[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C1COCC1>[Cl:12][C:13]1[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([NH:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([C:2]([F:10])([F:11])[F:1])[CH2:8][CH2:7]1)=[O:16]
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of trans-4-trifluoromethyl-cyclohexylamine (4.8 g) and TEA (8.3 mL, 59.4 mmol) in THF (150 mL) is stirred for 20 min at rt. 2,6-Dichloro-nicotinoyl chloride (5.0 g, 23.8 mmol) in THF (50 mL) is added dropwise under cooling and the mixture is stirred at rt for 2 h. The reaction mixture is filtered and the filtrate is concentrated. The residue is treated with water, filtered off, washed with water and dried to give the sub-title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(C)cc3c2ccc2nnc(C)n23)c1
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.043 g, 1.1 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (200.0 mg, 1.074 mmol, from Example 2, Step 5) in DMF (20 mL). After 10 minutes, methyl 3-(bromomethyl)benzoate (0.25 g, 1.1 mmol, Alfa Aesar) was added. After 45 minutes, the reaction mixture was poured into pH 7 buffer and the product was extracted with three portions of EtOAc. The combined organic extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:19]([C:12]2[C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:10][CH:11]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Product: O=C(NC1CC1)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Yield: 81.4 %

Procedure:
In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (35 mg) and cyclopropylamine (9 mg, ex Lancaster) afforded the title compound (32 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C(C)C)=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)OC(=O)c1cnc(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reaction time: 3 h
Yield: 97.1 %

Procedure:
1-methylethyl 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylate (D60) (1.6 g, 6.21 mmol) in isopropanol (70 ml) and water (35.0 ml) was treated with 2N sodium hydroxide (6.21 ml, 12.42 mmol) and stirred for 3 hours to give a single product. Evaporated off the IPA, acidified with glacial acetic acid and extracted product into EtOAc (100 ml). Dried over MgSO4 and evaporated off the solvent to yield 1.30 g of the title compound as a white solid. MS (ES) C9H1035ClNO3 requires 215; found 214 (M−H+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13].[CH:18]1([O:23][C:24]2[CH:25]=[C:26]3[CH:32]=[CH:31][NH:30][C:27]3=[N:28][CH:29]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[K+].O>CO>[CH:18]1([O:23][C:24]2[CH:25]=[C:26]3[C:32]([CH:8]([OH:9])[C:7]4[C:2]([F:1])=[C:3]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:4]=[CH:5][C:6]=4[F:10])=[CH:31][NH:30][C:27]3=[N:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: c1cc2cc(OC3CCCC3)cnc2[nH]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(OC4CCCC4)cc23)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (10, 102 mg, 0.32 mmol) in methanol (1.5 mL) was added 5-cyclopentyloxy-1H-pyrrolo[2,3-b]pyridine (P-0001, 65 mg, 0.32 mmol, prepared as described in Example 12) and potassium hydroxide (54 mg, 0.96 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give a solid (11, 102 mg, 68%). MS (ESI) [M+H+]+=466.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[C:14]([F:22])[CH:13]=2)=[N:4][C:5]([CH:8]2[CH2:11][O:10][CH2:9]2)=[CH:6][N:7]=1.[Li+].[OH-]>CO.C1COCC1>[NH2:1][C:2]1[C:3]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[C:14]([F:22])[CH:13]=2)=[N:4][C:5]([CH:8]2[CH2:11][O:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3COC3)cnc2N)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(C2COC2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 4-(3-amino-6-(oxetan-3-yl)pyrazin-2-yl)-2-fluorobenzoate (13 mg, 0.043 mmol) in MeOH (1 mL) and THF (2 mL) was added LiOH (0.128 mL, 0.128 mmol). The reaction mixture was stirred 2 h at room temperature. The reaction mixtures was adjusted to acidic (pH˜3) and solvent was evaporated on rotovap. The crude was azeotrope with toluene and proceed for next step. LCMS (m/z): 290.1 (MH+), 0.46 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]12[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=[C:15]1[C:14]1[C:9](=[CH:10][C:11]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[C:12]([Cl:22])[C:13]=1[Cl:21])[CH2:8]2)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:41]([CH3:46])([CH3:45])[C:42]([OH:44])=[O:43]>O1CCCC1>[C:1]([O:4][CH2:5][CH2:6][C:7]12[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=[C:15]1[C:14]1[C:9](=[CH:10][C:11]([O:23][CH2:24][C:25]([O:27][C:41]([C:42]([OH:44])=[O:43])([CH3:46])[CH3:45])=[O:26])=[C:12]([Cl:22])[C:13]=1[Cl:21])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(C)(O)C(=O)O
Reactant: CC(=O)OCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)OCCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC(C)(C)C(=O)O)c(Cl)c1Cl)C2
Temperature: 20 °C

Procedure:
{[9a-(Acetoxyethyl)-5,6-dichloro-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}acetic acid (4.13 g, 10 mMole) is dissolved in dry tetrahydrofuran (20 ml). 1,1'-Carbonyldiimidazole (3.2 g, 10 mMole) is added and the mixture stirred at 20° C. for an hour. 2-Hydroxy-2-methylpropionic acid (1.05 g, 10 mMole) is added and the mixture stirred for 18 hours at 20° C. The solvent is removed by evaporation in vacuo. The residue is dissolved in methylene chloride, washed with water and dried over MgSO4. The solvent is removed by evaporation in vacuo and the residue purified by chromatography using a silica gel column with methylene chloride/tetrahydrofuran/acetic acid 100/2/1 (V.V.V.) as the eluent. Selecting the appropriate cuts gave the desired compound upon evaporation of the solvent in vacuo.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.ClCCl.COCCN(S(F)(F)[F:31])CCOC.C(=O)(O)[O-].[Na+]>O>[F:31][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(F)CC1
Temperature: 25 °C

Procedure:
A 1-L, round bottom flask was charged with 12.64 g (51.4 mmol) of benzyl 4-oxo-1-piperidinecarboxylate and 300 mL of dichloromethane. To the stirring solution at −78° C. was added 19 mL (102.8 mmol) of [bis(2-methoxyethyl)amino]sulfur trifluoride via addition funnel over a period of about 1 h. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was added portionwise with caution to a large extractor containing water and saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate solution, twice with 10% aqueous hydrochloric acid solution and saturated aqueous brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography on a Biotage® system (gradient, hexane to 65% ethyl acetate/hexane) afforded the desired product. LC/MS 242.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:47][O:48][CH:49]1[CH2:53][CH2:52][N:51]([CH2:54][C:55]2[CH:63]=[CH:62][C:58]([CH2:59][NH:60][CH3:61])=[CH:57][CH:56]=2)[CH2:50]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:60]([CH2:59][C:58]3[CH:57]=[CH:56][C:55]([CH2:54][N:51]4[CH2:52][CH2:53][CH:49]([O:48][CH3:47])[CH2:50]4)=[CH:63][CH:62]=3)[CH3:61])=[O:23])[N:20]=2)[CH3:14])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(OC)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol) DIPEA (0.04 mL, 0.21 mmol), [4-(3-methoxy-pyrrolidin-1-ylmethyl)-benzyl]-methyl-amine hydrochloride (37 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]=[CH2:19])[C:11]=1[O:20][CH3:21])[CH3:9])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]2[CH2:19][O:31]2)[C:11]=1[O:20][CH3:21])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Solvent: ClCCl
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]carbamate (460 mg, 1.4 mmol, from Example 189, Step 1) was stirred in methylene chloride (4.6 mL) and m-chloroperbenzoic acid (2.1 g, 8.5 mmol) was added. The mixture was stirred overnight at room temperature. The suspension was filtered and the collected solids were washed with methylene chloride. The filtrates were evaporated to give the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
61.5 g (205 mmol) of tert-butyl (3-bromobenzyl)-N-methylcarbamate, 40 g (260 mmol) of 4-formylbenzeneboronic acid and 800 ml of toluene are introduced into a three-necked flask and under argon. 205 ml of an aqueous potassium carbonate solution (2 M) are added dropwise, the reaction medium is degassed with argon and 7 g of tetrakis(triphenylphosphine)-palladium(0) chloride are added and the mixture is heated at 90° C. for 24 hours. The reaction medium is poured into water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulphate and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (70-30) mixture. After evaporation of the solvents, 38 g (57%) of the expected product are recovered.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([C:25]([C:13](=[CH:12][NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH3:3])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(=O)C=CNc1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNc1ccccc1OC)C(=O)C1CCCCC1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
50% Sodium hydride (4.8 g, 0.1 mol) was washed with petroleum ether then stirred in dry tetrahydrofuran (50 ml) under nitrogen at -20° C. Ethyl 3-(2-methoxyphenylamino)acrylate (17.4 g, 0.1 mol) in dry tetrahydrofuran (100 ml) was added dropwise, keeping the temperature to -20° C. Cooling was removed and the mixture was stirred until a dark red colour was achieved. The mixture was recooled to -20° C. and cyclohexylcarbonyl chloride (14.0 ml, 0.1 mol) in dry tetrahydrofuran (50 ml) was added dropwise. The mixture was allowed to warm to room temperature and was stirred for a further 3 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and 2M HCl. The organic layer was washed with water and brine, dried and evaporated to an oil which was chromatographed (silica gel, dichloromethane-hexane) to afford ethyl 2-cyclohexylcarbonyl-3-(2-methoxyphenylamino)acrylate as a yellow oil (23.3 g, 70%).