Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([C:24]#[N:25])[N:6]=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c1ccc(=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol), glycine (448 mg, 6.0 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The organic layer was dried over MgSO4 and concentrated. The residue was taken up in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound as a pale pink solid. MS: (−) m/z 377.31 (M−1).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[N:18]=[C:17]([CH:19]3[CH:23]([C:24](=[O:27])[NH:25][CH3:26])[CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[CH:16]=[C:15]([CH3:35])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:8]1([C:13]2[N:18]=[C:17]([CH:19]3[CH:23]([C:24]([NH:25][CH3:26])=[O:27])[CH2:22][CH2:21][NH:20]3)[CH:16]=[C:15]([CH3:35])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CNC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C1CCNC1c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
2,2,2-Trifluoroacetic acid (20.0 mL, 269 mmol) was added dropwise over 5 minutes to a 0° C. solution of tert-butyl 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidine-1-carboxylate (720 mg, 1.86 mmol) in CH2Cl2 (20 mL). The reaction mixture was warmed to rt over 30 minutes then brought to pH=8 with Na2CO3 (400 mL, sat. aqueous solution). The mixture was extracted with CH2Cl2 (5×30 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-N-methylpyrrolidine-3-carboxamide (230 mg, 43%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:5]=1[C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([OH:17])[C:9]=1[OH:18])=[O:7].I[CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[CH2:25]([O:18][C:9]1[C:10]([O:17][CH2:22][CH2:4][CH2:5][CH3:6])=[C:11]([O:15][CH3:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[C:6](=[O:7])[C:5]1[C:4]([Cl:3])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:23])[CH2:26][CH2:27][CH3:28]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(O)c1O
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1c(OC)cc(C)c(C(=O)c2c(Cl)cccc2Cl)c1OCCCC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Sodiumhydride (0.4 g; 60%; 10 mmol) is added with stirring to a solution of 2,6-dichloro-2',3'-dihydroxy-4'-methoxy-6'-methyl-benzophenone (1.64 g; 5 mmol) in tetrahydrofurane. The solvent is evaporated and the residue dissolved in 30 ml of dimethylformamide. 1-iodo-n-butane (4.6 g; 25 mmol) is added, the mixture is stirred at 100° C. for 8 hours and then the solvent is evaporated. The residue is shaken with toluene/2N hydrochloric acid, the organic layer separated, washed with water and the solvent evaporated. The residue is purified by chromatography (flash column filled with 35 g of silicagel; elution with 500 ml of petrolether containing 2% of ethylacetate); yellow oil (0.7 g; 32% y).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1)=[O:4].C([O-])(O)=O.[Na+]>CC(O)=O.O.O=[Pt]=O>[F:17][C:2]([F:1])([F:16])[C:3]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:7]1)=[O:4]
Reactant: O=C(Nc1cncc2ccccc12)C(F)(F)F
Agent: O=[Pt]=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NC1CNCc2ccccc21)C(F)(F)F
Reaction time: 10 h
Yield: 104.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(isoquinolin-4-yl)acetamide (1.0 g, 1.49 mmol) in AcOH (20 mL) was adde PtO2 (0.2 g) was added under nitrogen atmosphere. The reaction mixture placed under an atmosphere of hydrogen at rt for 10 h. The reaction mixture was filtered through a pad of celite, washed several times with MeOH. The filtrate was concentrated in vacuo to give a residue that was diluted with water, neutralized with NaHCO3, extracted with EtOAc (100 mL×3), the combined EtOAc layer was washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in EtOAc) to give (0.380 g, 33%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 9.72 (s, 1H), 7.24-7.07 (m, 4H), 4.98 (s, 1H), 3.89 (d, J=16.4 Hz, 1H), 3.82 (d, J=16.4 Hz, 1H), 3.10 (dd, J=4.8, 12.8 Hz, 1H), 2.88 (dd, J=6.8 Hz, 12.8 Hz, 1H), 2.50 (m, 1H). LCMS: M/z: (M+1):245
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:31])[CH2:28][C:27]2[C:22](=[CH:23][C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:28][C:27]2[C:22](=[CH:23][C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2cc(C)c(C)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2cc(C)c(C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (300 mg, 1.54 mmol), 2-amino-5,6-dimethyl-indan-2-carboxylic acid ethyl ester (432 mg, 1.85 mmol), HATU 878 g, 2.31 mmol) in anhydrous DMF (10 mL) is added DIPEA (382 μL, 2.31 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-40% EtOAc in heptane) to give a pure product (90) as white solid (591 mg, 94%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])([O-:14])=[O:13]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccccc1[N+](=O)[O-]

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-nitroaniline to yield 2-[(2-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[I-:12].[Na+].[I-].O>C(O)CCC.[Cu]>[I:12][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: [I-]
Reactant: Brc1ccc2ncccc2c1
Agent: [Cu]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: Ic1ccc2ncccc2c1
Temperature: 120 °C
Yield: 80 %

Procedure:
6-bromoquinoline (80.1 g, 0.385 mol) is dissolved in n-butanol (0.8 L). Copper catalyst CuI (3.7 g, 0.019 mol), a copper-ligand N,N′-dimethylethylenediamine (3.4 g, 0.0385 mol) and an iodide source NaI (115.5 g, 0.770 mol) are added and the mixture is heated in a heating jacket, under inert atmosphere to 120° C. After work-up (0.8 L water is added to the reaction mixture, the organic layer is separated off and evaporated) and purification (the crude evaporation residue was crystallized from 150 mL diisopropylether), 6-iodoquinoline was obtained in 80% yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=O)=O.[C:25]([C:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([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)=CC=1.CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:8]2[C:7]([C:26]#[C:25][C:27]3([OH:35])[CH:32]4[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]4)[CH2:28]3)=[CH:12][CH:11]=[C:10]([CH3:13])[N:9]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cc2nc(C)ccc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cc2nc(C)ccc2C#CC2(O)CN3CCC2CC3)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of 230 mg of 2-(4-methoxybenzyl)-6-methyl-3-pyridyl trifluoromethane sulfonate, 116 mg of 3-ethynyl-3-quinuclidinol, 147 mg of tetrakis(triphenylphosphine)palladium(0), 24 mg of cuprous iodide, 266 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 80° C. for 3 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and the mixture was extracted with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 192 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>C(OCC)(=O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(C=O)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(C)cc1
Yield: 47 %

Procedure:
Upon heating a solution of 6 g of 4-methylbenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6 hours, 2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 119° C (ethyl acetate/petroleumether) is obtained.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18]CC)=[O:17])=[CH:8]1.[OH-].[Na+]>O1CCCC1>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]1
Reactant: CCOC(=O)c1cn(-c2ccccc2C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1-n1cc(C(=O)O)c2ccccc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A mixture of ethyl 1-(o-tolyl)-1H-indole-3-carboxylate (0.789 g, 2.82 mmol), 4N sodium hydroxide aqueous (20 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 18 hours. Most solvent was removed and the rest was acidified with 10% hydrochloric acid aqueous to adjust to pH=5. Pale yellow precipitate formed and was collected by filtration. The solid was washed with petroleum ether, dried in vacuo to give 1-(o-tolyl)-1H-indole-3-carboxylic acid as a pale yellow solid (0.675 g, 95%). LRMS (M+H+) m/z: calcd 251.09. found 251.
Reaction SMILES: BrBr.C[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13]C)[CH:8]=[O:9].S([O-])([O-])(=O)=S.[Na+].[Na+].[C:22](=[O:25])(O)[O-].[Na+]>C(O)(=O)C>[OH:13][C:12]1[C:5]([OH:4])=[CH:6][C:7]2[C:8](=[O:9])[CH2:10][C:11]3[CH:12]=[CH:5][CH:6]=[CH:7][C:22]=3[O:25][C:10]=2[CH:11]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C([O-])O
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2Oc2cc(O)c(O)cc21
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of bromine (0.96 g) in acetic acid (10 ml) was dropped into a solution of 3,4-dimethoxybenzaldehyde (1.0 g) in acetic acid (4 ml) and the mixture was stirred for three hours. Sodium thiosulfate was added to the reaction mixture, then sodium bicarbonate was added thereto and the mixture was filtered. The crude crystals collected by the filtration were recrystallized from chloroform-ether to give the title compound (0.83 g, 56%). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:69])[C@H:4]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:5][C:6](=[O:61])[C@H:7]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=1)[NH:8][C:9](=[O:52])[C@H:10]([CH2:31][S:32][C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:11]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:69])[C@H:4]([CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)[NH:5][C:6](=[O:61])[C@H:7]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=1)[NH:8][C:9](=[O:52])[C@H:10]([CH2:31][S:32][C:33]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:11]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
Water (445 ml) is added dropwise to a solution of N,S-ditrityl-cysteinyl-tyrosyl-phenylalanine methyl ester (21.9 g, 23.5 mmoles, described in Example 1) in glacial acetic acid (1780 ml) at room temperature. The solution is stirred at 45° C for 1.5 hour and diluted with water (2200 ml). The precipitate is removed by filtration and the filtrate is evaporated. The last traces of acetic acid are removed by repeated evaporation with benzene to give (S-trityl)cysteinyl-tyrosyl-phenylalanine methyl ester.
Reaction SMILES: [CH:1]([C:3](O)([CH3:5])[CH3:4])=[CH2:2].[C:7](OC)([O:11]C)([O:9][CH3:10])[CH3:8]>C(O)(=O)CC>[CH3:4][C:3]([CH3:5])=[CH:1][CH2:2][CH2:8][C:7]([O:9][CH3:10])=[O:11]
Reactant: C=CC(C)(C)O
Reactant: COC(C)(OC)OC
Solvent: CCC(=O)O
Product: COC(=O)CCC=C(C)C
Temperature: 115 °C
Reaction time: 12 h
Yield: 271.5 %

Procedure:
A distillation column-provided four-necked flask having a volume of one liter, which was equipped with a dropping funnel, a thermometer, a stirring device and a reflux ratio regulator, was charged with 50.0 g (580.5 mmoles) of 2-vinyl-2-propanol, 139.5 g (1,161.0 mmoles) of trimethyl orthoacetate and 1.3 g (17.4 mmoles) of propionic acid, and the internal temperature was raised to 115° C. Heating was continued for 12 hours while removing a fraction of not higher than 65° C. from a column top of the distillation column. After confirming the disappearance of 2-vinyl-2-propanol by a gas chromatographic analysis of the reaction solution, the reaction solution was distilled in vacuo. Fractions of from 60 to 65° C./1.2 kPa were collected to obtain 62.2 g (437.1 mmoles) of methyl 5-methyl-4-hexenate. The yield was 75.3%.
Reaction SMILES: [C:1]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2].[C:14]1([CH:21]=CC=[C:17](O)[CH:16]=1)[OH:15]>CS(O)(=O)=O>[OH:15][C:14]1[CH:21]=[C:4]2[C:5]([C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=3[C:1](=[O:2])[O:3]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCCCCC1=O
Reactant: Oc1cccc(O)c1
Agent: CS(=O)(=O)O
Product: O=c1oc2cc(O)ccc2c2c1CCCCC2
Reaction time: 4 h
Yield: 78 %

Procedure:
The first stage consists of condensing 2-carbetoxycycloheptanone with resorcinol in methanesulphonic acid, the reaction is taken to 25° C. for 4 hours. The intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one thus formed precipitates by adding ethanol then water then it is isolated by filtration, dried under vacuum at 60° C. and a yield of 78% is obtained. In a second stage, sulphonylisocyanate chloride is converted, in toluenic solution, to sulphamoyl chloride by the action of the formic acid, then condensed with the previous intermediate dissolved in N,N-dimethylacetamide (DMA). The reaction medium is treated with water and extracted with 2-methyltetrahydrofurane (2-MeTHF). The crude compound 1 is then obtained by filtration of the precipitate obtained by adding methylcyclohexane to the organic phase. Finally, pure compound 1 is obtained by recrystallization of the crude product by dissolution in acetone while hot and precipitation by adding methylcyclohexane (the addition of the antisolvent methylcyclohexane having the main purpose of increasing the yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][CH2:6]2)#[N:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:13]([CH2:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCC1CCc2cc(C#N)ccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC1CCc2cc(C#N)ccc21)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{[(5-cyano-2,3-dihydro-1H-inden-1-yl)methyl]amino}ethyl)carbamate (184 mg, 0.58 mmol), chloro-acetyl chloride (85 mg, 0.76 mmol) and TEA (135 mg, 1.3 mmol) in 20 mL DCM was stirred at RT for 12 hours. The mixture was diluted with 50 mL DCM and then washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC (EA/PE=1:1) to give the title compound. MS m/z: 392 [M+1]+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:19]>C1COCC1>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[O:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(F)c1cc(N)on1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
3-(2-fluoropropan-2-yl)isoxazol-5-amine (11.26 g, 78.19 mmol) described in Example 42A in THF (300 mL) was treated with potassium carbonate (21.58 g, 156 mmol) and p-chlorophenyl chloroformate (14.94 g, 78.19 mmol). After stirring at rt for 1 h, additional p-chlorophenyl chloroformate (7.5 g, 39.26 mmol) was introduced, and the reaction mixture was stirred at rt overnight. The mixture was filtered through a celite pad, washed with ethyl acetate and concentrated to dryness. The residue was taken into ethyl acetate, washed with brine, and the organics dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (eluting with 10 to 50% ethyl acetate in hexanes) to give 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (16.51 g, 71%) as a cream solid. 1H NMR (300 MHz, CDCl3) δ 7.87 (brs, 1H), 7.36-7.41 (m, 2H), 7.13-7.17 (m, 2H), 6.27 (s, 1H), 1.74 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: [I:1]I.[OH-].[Na+].[C:5]([S:9]([CH2:12][C@@H:13]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:14]([NH:16][C@@H:17]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:18]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24])=[O:19])=[O:15])(=[O:11])=[O:10])([CH3:8])([CH3:7])[CH3:6]>CO.O>[C:5]([S:9]([CH2:12][C@@H:13]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:14]([NH:16][C@@H:17]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][C:41]=1[I:1])[C:18]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:26][CH2:27]1)[OH:24])=[O:19])=[O:15])(=[O:11])=[O:10])([CH3:8])([CH3:6])[CH3:7]
Reactant: II
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1nc[nH]c1I)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 0.08 h

Procedure:
10.4 ml (2.08 mmol) of a 0.2N methanolic iodine solution and 2.4 ml (0.48 mmol) of 0.2N sodium hydroxide solution are simultaneously added dropwise at 0° while stirring to a mixture of 630 mg (1 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide and 20 ml (4 mmol) of 0.2N sodium hydroxide solution in 20 ml of methanol. The colourless reaction mixture is stirred at 0° for 5 minutes and thereafter at room temperature for 2.5 hours. Subsequently, the mixture is diluted with 25 ml of water and extracted twice with 80 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue (750 mg) is chromatographed using a 15:1 mixture of methylene chloride and methanol as the eluent. There are obtained 504 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-5-iodoimidazole-4-propionamide, MS: 757 (M+H)+, and 38 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-2,5-iodoimidazole-4-propionamide, MS: 883 (M+H)+, each as a colourless solid.
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[OH:21][C:22]1[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=1)[CH2:25][NH:26][S:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:29])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:17][C:15]1[CH:14]=[C:4]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=2[F:13])[C:3]([N+:18]([O-:20])=[O:19])=[C:2]([CH:16]=1)[O:21][C:22]1[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=1)[CH2:25][NH:26][S:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:29])=[O:28]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 140.5 %

Procedure:
2.0 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 64% pure, 3.25 mmol, 1 eq.), 0.98 g tert-butyl [(3-hydroxybenzyl)sulfamoyl]carbamate (Intermediate 2A; 3.24 mmol, 1 eq.) and 1.6 g caesium carbonate (4.9 mmol, 1.5 eq.) were suspended in 25 mL DMF and stirred in a closed vial at rt for 3 days. Additional 0.4 eq. tert-butyl [(3-hydroxybenzyl)sulfamoyl]carbamate and 0.4 eq. caesium carbonate were added and stirring was continued for 2 days. The reaction mixture was partitioned between sodium chloride solution and ether, the layers were separated and the aqueous layer was reextracted with ether. The combined organic layers were dried, filtered and concentrated in vacuo to yield 3.08 g of the crude product (as a regioisomeric mixture containing some unreacted starting material), which was used in the subsequent reaction without further purification.