Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.C1C=CC=CC=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C(N(CC)CC)C>[CH2:19]([NH:21][C:22]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: ON=C1CCOc2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCNC(=O)ON=C1CCOc2ccccc21
Reaction time: 8 h

Procedure:
4-Chromanone oxime (20 g, 0.12 mole) was added to benzene (260 ml) and refluxed for 45 min. in a flask equipped with a Dean-Stark trap. The solution was cooled to 25°-30°, triethylamine (0.5 ml) was added, followed by ethyl isocyanate (8.5 g, 0.12 mole). The solution was refluxed for 3 hrs. and stored overnight at room temperature. The mixture was filtered and the filtrate was stripped of solvent under reduced pressure. Anhydrous ether (100 ml) was added to the residue and the mixture was cooled for 3 hrs. The product was collected by filtration, yield: 20 g (79%). A sample was recrystallized from isopropanol, m.p. 110°-111°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH3:11])(=[O:9])=[O:8].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1COCC1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7](=[O:9])(=[O:8])[NH:10][CH3:11])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNS(=O)(=O)CCCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 10 h
Yield: 41 %

Procedure:
To a solution of 5-hydroxy-N-methylpentane-1-sulfonamide (Example 21; 6.4 mmol) and triethyl amine (19.2 mmol) in THF (15 ml) was added para toluenesulfonyl chloride (5.9 mmol) in THF (5 ml) at room temperature and the reaction mixture was stirred for 10 hours. The reaction mixture was washed by saturated NaHCO3 solution and then brine. The organic layer was dried over MgSO4, filtered off and concentrated. The residue was purified by flash column chromatography (SiO2; eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to give the pure title compound (0.9 gr; 41% yield.
Reaction SMILES: [C:1]([Si:5]([CH3:27])([CH3:26])[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([OH:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl[C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49]Br>C(#N)C.CN(C=O)C>[CH2:49]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:10]2[CH:9]=[C:8]([CH3:25])[C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:27])[CH3:26])=[C:12]([CH3:13])[CH:11]=2)([OH:24])[C:15]1=[O:23])[C:48]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:47]=1
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: Clc1ccccc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Yield: 81.1 %

Procedure:
Using a method similar to Preparation 17 with 3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (3.83 g, 10 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (3.5 ml, 12 mmol) and 2-chlorobenzyl bromide (1.56 mL, 12 mmol) in acetonitrile/DMF (60 mL/20 mL) gives 5.9 g of a crude yellow gum. Purify by flash chromatography (CH2Cl2 to 10% EtOAc/CH2Cl2) gives 3.84 g (76%) of the title compound as a white solid. Mp 147.1° C. MS (ES): m/z=490 (M+1−H2O); 1H NMR(DMSO-d6): δ7.52 (dd, J=1.7, 1.4 Hz, J=7.7, 7.4 Hz, 1H), 7.37-7.14 (m, 5H), 7.05 (t, J=7.7 Hz, 1H), 6.93 (s, 2H), 6.86 (d, J=7.7 Hz, 1H), 6.73 (s, 1H), 4.96 (abq, 2H), 2.11 (s, 6H), 0.98 (s, 9H), 0.16 (s, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]([CH3:17])=[O:16]>>[S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:14]/[C:15](=[O:16])[CH3:17])=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)/C=C/c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.6 g of 3-thiophenecarboxaldehyde was dissolved in 30 ml of acetone, and 20 g of potassium carbonate was added. The mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was worked up in a customary manner. The resulting alcohol compound was dissolved in 10 ml of methylene chloride, and 1.1 ml of methanesulfonyl chloride and 2.3 ml of triethylamine were added. The mixture was stirred overnight at room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=40/1] to give 650 mg of the captioned compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])(CC)C.[C:26](=O)([O:30]CC)[O:27][CH2:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[C:26]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:7]=[CH:6]2)([O:27][CH2:28][CH3:29])=[O:30]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(F)cc21
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a solution of 760 mg (2.61 mmol) of 6-fluoro-1-triisopropylsilylindole dissolved in 6 ml of anhydrous tetrahydrofuran are added dropwise at −78° C. under argon 2.01 ml of a sec-butyllithium solution (1.3M in cyclohexane, 2.01 mmol). The reaction mixture is stirred for 2 h at −78° C. then 500 μL (3.15 mmol) of diethyl carbonate are added dropwise at −78° C. to the reaction mixture. This mixture is stirred for 5 h with a gentle temperature rise then an ammonium chloride saturated aqueous solution is added. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 97:3) to yield 445 mg (46%) of 5-carboethoxy-6-fluoro-1-triisopropylsilylindole in the form of a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.C(=O)(O)[O-].[Na+]>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]2[CH2:34][CH2:35][N:30]([C:25]3[N:24]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)[S:7][C:8]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CN1CCN(c2ncccn2)CC1)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
Compound 262 (300 mg, 0.860 mmol) was dissolved in THF (5.0 mL), and 1-(2-pyrimidinyl)piperazine (0.370 mL, 2.58 mmol) was added thereto, followed by stirring at room temperature for 16 hours. Further, 1-(2-pyrimidinyl)piperazine (0.370 mL, 2.58 mmol) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water and aqueous saturated sodium bicarbonate solution were added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=1:2) to afford the entitled Compound 278 (345 mg, 84%) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][CH3:33])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:29](O)=[O:30])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>>[F:34][C:35]([F:39])([F:38])[CH2:36][NH:37][C:29]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:32][CH3:33])=[O:30]
Reactant: NCC(F)(F)F
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)NCC(F)(F)F

Procedure:
This compound was prepared from 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2-(R/S)-carboxylic acid and trifluoroethylamine as described in Example 15.
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:25]=2[C:26]#[N:27])=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[C:4]([OH:32])[CH:3]=1.[O:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40]O)[CH:35]=[N:34]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:19]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:25]=2[C:26]#[N:27])=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[C:4]([O:32][CH2:40][CH2:39][CH2:38][C:36]2[CH:35]=[N:34][O:33][CH:37]=2)[CH:3]=1
Reactant: OCCCc1cnoc1
Reactant: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCc1cnoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (30 mg, 0.065 mmol) in THF (700 μL), 3-isoxazol-4-yl-propan-1-ol (9 mg, 0.071 mmol), triphenylphosphine (26 mg, 0.089 mmol) and DIAD (20 μL, 0.098 mmol) were added. The mixture was stirred at rt overnight, concentrated, diluted with 1 mL MeOH and purified by prep HPLC to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(3-isoxazol-4-yl-propoxy)-N-(2-methoxyphenyl)-N-methyl-benzamide 46-1. MS: 571.2 (M+H)+, tR=6.12 min (method 3).
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH3:13]>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[F:12][C:6]1[CH:5]=[C:4]([CH3:13])[C:3]([O:2][C:1]([O:14][CH3:15])=[O:16])=[CH:8][C:7]=1[NH2:9]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(F)cc1C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
A mixture of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (8 g, 35 mmol), (EP 0307777 A2), and platinum(IV)oxide (174 mg) in ethanol (100 ml) and ethyl acetate (70 ml) was stirred under hydrogen at 1.3 atmospheres pressure for 1.5 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate (7/3) to give 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (6.56 g, 94%) as an oil which crystallised. 1H NMR Spectrum (CDCl3): 2.09(s, 3H); 3.66(br s, 2H); 3.90(s, 3H); 6.54(d, 1H); 6.83(d, 1H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:37])[CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:27].C(N(CC)CC)C>CO>[CH2:26]([O:28][C:29](=[O:37])[CH2:30][CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CC1CCN(c2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc(OC)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (100 mg, 0.29 mmol) and ethyl-2-(piperidin-4-yl)acetate hydrochloride (63 mg, 0.30 mmol) in 3 ml of methanol was treated with triethylamine (0.13 ml, 0.92 mmol). The mixture was stirred for 3 hours at room temperature, concentrated and the product purified by chromatography on silica gel using ethyl acetate as an eluent. The title compound was isolated as a colorless solid (137 mg, 99%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([CH3:34])[C:22]=1[CH3:35]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([CH3:34])[C:22]=3[CH3:35])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1)#[CH:19]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: C#Cc1ccc(-c2nscc2COS(C)(=O)=O)cc1
Product: C#Cc1ccc(-c2nscc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-ethynylphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.31 (m, 4H), 6.86 (t, J=7.0 Hz, 1H), 6.62 (t, J=7.0 Hz, 1H), 5.21 (s, 2H), 2.95 (t, J=6.1 Hz, 2H), 2.68 (m, 4H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[OH:15].C[O:17][C:18](O[Si](C)(C)C)=[C:19]([CH3:21])[CH3:20].Cl>CN(C=O)C.F[Zn]F>[C:8]([C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]2[O:15][C:18](=[O:17])[C:19]([CH3:21])([CH3:20])[C:2]=2[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl
Agent: F[Zn]F
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(cc1[N+](=O)[O-])OC(=O)C2(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Difluorozinc (6.093 g, 58.92 mmol) was added to a round bottomed flask, which was flushed with nitrogen. Pd(tBu3P)2 (2 g, 3.835 mmol) was then added under nitrogen stream. 2-Bromo-4-tert-butyl-5-nitro-phenol (16.15 g, 58.92 mmol) dissolved in DMF (80.75 mL) was then added to the flask. The reaction mixture was an orange suspension. (1-Methoxy-2-methyl-prop-1-enoxy)trimethylsilane (21.61 g, 25.13 mL, 117.8 mmol) was added to the mixture and the resulting mixture was heated to 80° C. and stirred for 16 h. When complete, the reaction mixture was cooled to ambient temperature and filtered through Celite®. The filter cake was washed with MTBE (536.0 mL) and water (893.3 mL) was added to the filtrate. The mixture was stirred for 15 min and settled for another 15 min. The layers were separated and 0.5M HCl (500 mL, 250.0 mmol) was added to the organic phase. The layers were separated and the organic layer was washed with water (500 mL). The layers were separated and the organic layer was washed with NaCl (500 mL; 8 wt %). The organic layer was separated and the solvent removed in vacuo. The crude product was obtained as a brown crystalline solid and was then purified through a silica plug, using hexane:MTBE 20:1-10:1 as an eluent. The fractions containing product were combined and the solvent removed in vacuo to give the pure product as a white crystalline solid. 1H-NMR (400 MHZ, DMSO-d6) δ 7.80 (s, 1H); 7.62 (s, 1H); 1.49 (s, 6H); 1.34 (s, 9H)
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[CH2:3][NH:4]C(=O)OC(C)(C)C.ClS([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:27](=[O:28])([O:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21])[CH2:3][NH2:4])[NH2:26]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCC(OC(N)=O)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A solution of 420 mg (1.38 mmol) of the compound of Example 36A in 100 ml of acetonitrile was cooled to −15° C., and a solution of 168 μl (1.93 mmol) of chlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwise. After 5 min, 50 ml of water were added and the reaction mixture was stirred further at 60° C. overnight. After cooling to RT, 50 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (321 mg, about 90% pure, 85% of theory) corresponded to the title compound and was reacted further without additional purification.
Reaction SMILES: [CH3:1][C:2]1([C:10]([OH:12])=O)[CH2:5][C:4]([F:7])([F:6])[C:3]1([F:9])[Cl:8].S(Cl)([Cl:15])=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][C:2]1([C:10]([Cl:15])=[O:12])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:8])[F:9]
Reactant: CC1(C(=O)O)CC(F)(F)C1(F)Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C(=O)Cl)CC(F)(F)C1(F)Cl
Yield: 75.4 %

Procedure:
One drop of dimethylformamide is added to a mixture 91.2 g (0.45 mol) of 1-methyl-2,3,3-trifluoro-2-chloro-cyclobutane-1-carboxylic acid and 450 ml of chloroform. After this, 80.3 g (0.675 mol) of thionyl chloride are added dropwise at 25°-30° C. with stirring, and the stirred mixture is heated to the boil. After 6 hours the mixture is cooled, the solvent is stripped off, and the residue is subjected to fractional distillation under reduced pressure. 75 g (75% of theory) of 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carbonyl chloride are obtained in form of a liquid of boiling point 65 - 70° C. at 20 mbar. ##STR61## 108.3 g (0.5 mol) of methyl 1-methyl-2-th(oro-2,3,3-trifluoro-cyclobutane-1-carboxylate are added dropwise at 20°-25° C. in the course of 15 minutes to a stirred solution of 127.3 g of potassium hydroxide in 540 ml of methanol. Stirring is continued for 12 hours at 20°-25° C., and part of the methanol is then stripped off under reduced pressure. The residue is diluted with water, and the mixture is extracted using methylene chloride. The aqueous phase is acidified using dilute hydrochloric acid and extracted using methylene chloride. The combined organic phases are dried and concentrated under reduced pressure. 93.3 g of an oil are obtained which consists of 99% 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carboxylic acid. The yield is thus calculated at 90% of theory. 174 g (1.74 mol) of methyl methacrylate and 1.5 g o& hydroquinone are initially introduced into an autoclave, and 200 g (1.74 mol) of trifluorochloroethylene are added at -70° C. 7 bar of nitrogen are injected, and the mixture is then heated to 140° C. The pressure which is established at this temperature is increased to 28 bar by injecting more nitrogen. The mixture is maintained at 140° C. for 17 hours and then allowed to cool, the pressure is released, and the mixture is distilled. In this process, 203 g (54% of theory) of methyl 1-methyl-2-chloro-2,3,3 -trifluoro-cyclobutane-1-carboxylate are obtained in form of a liquid of boiling point 57° C. at 17 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].CC([O-])=O.[Na+].[Br:21]Br>CC(O)=O.C(OCC)C>[Br:21][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1c(Br)cc(C(=O)O)c(OC)c1OC
Temperature: 80 °C

Procedure:
To a solution of 2,3,4-trimethoxybenzoic acid (4.7 g, 22 mmol) and NaOAc (5.5 g, 40 mmol) in 35 ml AcOH was added a solution of bromine (1.5 ml, 29 mmol) in 35 ml AcOH. The reaction became red in color, which quickly faded. The mixture was heated to 80° C. for 1 h, at which point it was cooled to ambient temperature. The material was partitioned between dichloromethane and water. The organic layer was removed and the aqueous layer was extracted once with dichloromethane. The combined organic layers were dried with Na2SO4, filtered, and concentrated to give an oil which solidified on standing. The material was dissolved in diethyl ether and hexanes. Concentration to ½ the volume resulted in precipitation of a white solid. Filtration provided the title compound as a white solid. MS m/z: 293 (M+H+); calc'd for C10H11BrO5: 291.1
Reaction SMILES: [CH2:1]([N:3]([CH2:40][CH3:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34](I)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].[CH2:42]([OH:57])[CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]#[CH:56].CCN(CC)CC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1COCC1>[CH2:1]([N:3]([CH2:40][CH3:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:56]#[C:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2]
Reactant: C#CCOCCOCCOCCOCCO
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(I)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C#CCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 13 h
Yield: 78.8 %

Procedure:
To a slurry of 2-(5-(diethylamino)-2-(3-iodobenzamido)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (385 mg, 0.57 mmol), 3,6,9,12-tetraoxapentadec-14-yn-1-ol (175 mg, 0.75 mmol), Et3N (3 mL) and THF (2 mL) was added bis(triphenylphosphine)palladium(II)dichloride (12 mg, 0.017 mmol) and CuI (10 mg, 0.053 mmol) and purged well with nitrogen. The reaction mixture was stirred for 13 hours, then concentrated under vacuum and combined with the crude product from another run (0.15 mmol scale). Purification by flash chromatography on silica gel eluting (1% to 5% MeOH in DCM) gave the title compound (349 mg). 1H NMR (400 MHz, CDCl3, ppm) δ□ 12.51 (s, 1H), 8.83 (d, J=5.3 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.21 (s, 1H), 7.99 (t, J=1.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.65 (s, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.58-7.54 (m, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 6.98 (d, J=2.6 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.48 (s, 2H), 3.82-3.80 (m, 2H), 3.72-3.70 (m, 2H), 3.67-3.63 (m, 4H), 3.60 (s, 4H), 3.53-3.51 (m, 2H), 3.32 (quar, J=7.2 Hz, 4H), 2.90 (s, 1H), 1.13 (t, J=6.8 Hz, 6H). MS (ES, m/z): 777.4 [M+H]+.