Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6](C)[CH2:7][CH2:8][CH2:9][CH2:10]O)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.NCCCCC[CH2:25][OH:26].C1(=O)OC(=O)C2=CC=CC=C12>>[C:4]1(=[O:13])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:25][OH:26])[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]12
Reactant: NCCCCCCO
Reactant: CC(CCCCO)N1C(=O)c2ccccc2C1=O
Agent: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCCCCCO
Yield: 91 %

Procedure:
This compound was prepared in the same manner as 5-phthalimidohexanol from 6-aminohexanol (3.51 g, 30.0 mmol) and phthalic anhydride (4.44 g, 30.0 mmol) to give the product as brown oil: yield 91%; 1H NMR (CDCl3) δ 1.3-1.8 (m, 8H), 3.6-3.7 (m, 4H), 4.3 (t, J=6.5 Hz, 1H), 7.7 (m, 2H), 7.8 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][C:7](=[O:9])[CH:6]=[CH:5][CH2:4]1.[C:10](Cl)(=[O:12])[CH3:11].O>ClCCl>[C:10]([O:1][CH2:2][C@H:3]1[CH2:8][C:7](=[O:9])[CH:6]=[CH:5][CH2:4]1)(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: O=C1C=CC[C@@H](CO)C1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@@H]1CC=CC(=O)C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
76 cm3 of triethylmmine are added to a solution, cooled to +5° C., of 62 g of (R)-5-hydroxymethylcyclohex-2-en-1-one [prepared according to the method described by Kenji Mori et al., Tetrahedron, Vol. 48, No. 24, 8075-8082 (1990) incorporated herein by reference] in 600 cm3 of dry dichloromethane, and then 38.4 cm3 of acetyl chloride are run in over the course of 30 minutes. After stirring at +5° C. for one hour and at 20° C. for one hour, 1 liter of water is added slowly to the mixture. The separated organic phase is washed with 1 liter of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 80 g of (R)-5-acetoxymetylcyclohex-2-en-1-one are obtained in the form of an orange-coloured oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:41](O)=[O:42])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29].[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1>C(Cl)Cl>[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49]2)[C:41]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:42])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29]
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
A solution of triphenylphosphine (98 mg, 0.37 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (67 mg, 0.37 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 75, 100 mg, 0.31mmol). The resulting reaction mixture was stirred at 0° C. for. 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (64 mg, 0.68 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (94.5 mg, 76%) as a yellow foam: mp 87-90° C. (foam-to gel); EI-HRMS m/e calcd for C21H23N3O3S (M+) 397.1460, found 397.1460.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=O.[NH3:14]>>[NH2:13][C:7]1[N:6]=[C:5]([C:3]([NH2:14])=[O:2])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1
Reactant: COC(=O)c1cc(OC)cc(N)n1
Reactant: N
Product: COc1cc(N)nc(C(N)=O)c1

Procedure:
In analogy to example 103b, by replacing 2,6-diaminoisonicotinic acid ethyl ester with 6-amino-4-methoxy-pyridine-2-carboxylic acid methyl ester and using 25% aqueous ammonia instead of methylamine, the title compound was obtained as white solid. MS (ISP) M+H+=168.4
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C@@H:11](C)[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=CC=1.C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)CC=C.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][NH2:51])[CH:45]=1>>[CH2:6]([N:7]1[CH2:11][CH2:10][N:9]([C:13]2[S:14][C:15]([C:19]([NH:51][CH2:50][C:46]3[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[C:8]1=[O:22])[CH2:5][CH:23]=[CH2:24]
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: C=CCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: C=CCCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 62 %

Procedure:
Following the procedure as described in Example 2, making variations as required to replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(but-3-enyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as an off-white solid in 62% yield: mp 144-145° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.57-8.52 (m, 2H), 8.45 (d, J=3.8 Hz, 1H), 7.70 (ddd, J=7.8, 7.8, 1.8 Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz, 1H), 5.85-5.72 (m, 1H), 5.15-5.01 (m, 2H), 4.39 (d, J=5.8 Hz, 2H), 3.98 (d, J=9.0, 7.1 Hz, 2H), 3.59-3.54 (m, 2H), 3.31 (t, J=7.0 Hz, 2H), 2.47 (s, 3H), 2.32-2.25 (m, 2H); 13C NMR (75 MHz, DMSO-d6) 8161.9, 157.4, 154.9, 151.2, 148.8, 148.0, 135.5, 135.1, 135.1, 123.4, 117.3, 116.8, 42.4, 41.9, 41.6, 40.4, 31.1, 17.1; MS (ES+) m/z 372.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:9]([CH3:11])=[CH:10][C:3]=12.C([Li])(CC)C.C1CCCCC1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:33]([O:34][CH2:35][CH3:36])=[O:37])=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])[C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: Cc1cc2c(Cl)ccnc2n1[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(cc(C)n2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C

Procedure:
A solution of 4-chloro-2-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (525 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under nitrogen atmosphere, and to the reaction mixture was added 0.99M sec-butyllithium/cyclohexane solution (4.1 ml) dropwise. After the mixture was stirred at −78° C., ethyl chlorocarbonate (389 μl) was added dropwise. The reaction solution was stirred at −78° C. for 30 minutes, saturated aqueous ammonium chloride (20 ml) was added, and the temperature was returned to ambient temperature. The reaction solution was transferred into a separating funnel and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain ethyl 4-chloro-2-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (645 mg) as a colorless viscous liquid.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1.CSC1C=CC(C=O)=CC=1.FC1C=CC(CCl)=CC=1>C1(C)C=CC=CC=1.CC(O)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[NH:7][C:17]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cc2ccc(F)cc2)cc1
Reactant: NNc1ccccc1
Agent: CSc1ccc(C=O)cc1
Agent: Fc1ccc(CCl)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2[nH]c3ccccc3c2-c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
To phenylhydrazine (50 uL) in toluene-HOAc (2:1, 2 mL) was added 2-(4-fluorophenyl)-1-(4-(methylsulfonyl)phenyl)ethanone (105 mg) (prepared from 4-(methylthio)benzaldehyde and 4-fluorobenzyl chloride by the same method as described in Step 1 of Example 4). After 1 hr at 85° C., the reaction mixture was extracted with EtOAc and HCl. After drying over NaSO4 and evaporation in vacuo the title compound was purified by flash chromatography (67 mg).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([NH:16][C:17]1[CH:26]=[C:25]([C:27]#[CH:28])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:8]([NH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1
Reactant: C#Cc1ccc(C(=O)OC)c(NC(=O)c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#Cc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 mL of toluene suspension containing 0.15 g of methyl 2-(benzamido)-4-ethynylbenzoate, 0.090 mL of iodinated benzene, 5 mg of copper(I) iodide, 20 mg of bis(triphenylphosphine)palladium(II) chloride and 0.15 mL of triethylamine was stirred under nitrogen atmosphere at room temperature for 2 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 0.13 g of methyl 2-(benzamido)-4-(phenylethynyl)benzoate as white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:17])[C:9]=1[SH:18].I[CH2:20][CH3:21].Cl>C(#N)C.O>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:17])[C:9]=1[S:18][CH2:20][CH3:21]
Reactant: CCI
Reactant: Cc1c(C(=O)O)ccc(Cl)c1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCSc1c(Cl)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
3.71 g (11.3 mmol) of cesium carbonate were added to 1.10 g (5.42 mmol) of 4-chloro-3-mercapto-2-methylbenzoic acid in 20 ml of acetonitrile. The reaction mixture was stirred at RT for 10 min, and 1.02 g (6.51 mmol) of iodoethane were then slowly added dropwise. The reaction mixture was then stirred at RT for 16 h. The solvent was then removed, and a mixture of 20 ml of methanol and 2 ml of 20% strength aqueous sodium hydroxide solution was then added to the reaction mixture. For the hydrolysis of the ethyl ester formed, the mixture was stirred at RT for 16 h and then freed from the solvents. The residue was taken up in water and acidified with diluted HCl, and the mixture was stirred at RT for 10 min and then filtered. The residue was washed with water and sucked dry. 1.15 g of clean product were isolated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51]3)[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K61) (274 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (410 mg, 82%).
Reaction SMILES: Br[C:2]1[C:15]2[C@:14]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36].CN(C=O)C.C(NC(C)C)(C)C>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.[Cu]I>[NH2:20][C:17]1[O:18][CH2:19][C@@:14]2([N:16]=1)[C:15]1[C:2]([C:38]#[C:37][C:35]([CH3:36])([OH:39])[CH3:34])=[C:3]([O:27][CH2:28][C:29]3([CH3:33])[CH2:32][O:31][CH2:30]3)[CH:4]=[CH:5][C:6]=1[O:7][C:8]1[C:13]2=[CH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: C#CC(C)(C)O
Reactant: CC1(COc2ccc3c(c2Br)[C@]2(COC(N)=N2)c2cc(-c4cccnc4)ccc2O3)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1c(OCC2(C)COC2)ccc2c1[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 90 °C

Procedure:
A resealable tube was charged with (S)-1′-bromo-2′-((3-methyloxetan-3-yl)methoxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (300 mg, 0.590 mmol), 2-methyl-3-butyn-2-ol (248 mg, 2.95 mmol), tetrakis(triphenylphosphine)palladium (68.2 mg, 0.059 mmol) and copper(i) iodide (22.48 mg, 0.118 mmol). To this were added DMF (1180 μL, 0.590 mmol) and diisopropylamine (1241 μL, 8.85 mmol). The reaction was flushed with argon, sealed and heated at 90° C. for 1.5 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% CH2Cl2 to 10:1 methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-4-(2-amino-2′-((3-methyloxetan-3-yl)methoxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-1′-yl)-2-methylbut-3-yn-2-ol as a light yellow solid. MS m/z=512.2 [M+H].
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]2([NH2:44])[CH2:43][CH2:42]2)[N:36]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:37]3[N:36]=[C:35]([CH3:34])[CH:40]=[CH:39][N:38]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: Cc1ccnc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.022 g (42%). 1H NMR (400 MHz, CD3OD): δ 8.54 (d, J=5.6 Hz, 1H), 7.97-7.94 (m, 2H), 7.90 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 4H), 7.19 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.55 (s, 3H), 2.31 (s, 3H), 1.89-1.86 (m, 2H), 1.59-1.56 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −77.65 (TFA), −112.33, −122.77 LCMS: (ES+) m/z=583.2 (M+H)+
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19](N(OC)C)=[O:20])#[N:2].[CH3:25][Mg]Br.CCOCC>O1CCCC1>[C:19]([C:4]1[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:6]2[C:11]([C:3]=1[C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:20])[CH3:25]
Reactant: CON(C)C(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 3-cyano-1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-indole-2-carboxamide (90 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added 3.0 M methylmagnesium bromide in ether (0.93 mL, 2.8 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-15% EtOAc/hexane) to give the desired product (43 mg, 56%). LCMS calculated for C17H12FN2O(M+H)+: m/z=279.1. Found: 279.0.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([NH:20][C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12])=[O:19]
Reactant: NC(=O)c1cc(F)ccc1Cl
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1cc(F)ccc1Cl)Nc1ccc(OC(F)(F)F)cc1
Yield: 82.3 %

Procedure:
A solution of 4.06 g (0.02 mol) of 4-trifluoromethoxy-phenyl isocyanate in 10 ml of dry toluene is added to 3.48 g (0.02 mol) of 2-chloro-5-fluorobenzamide in 100 ml of dry toluene, at 100° C., in the absence of moisture. The mixture is boiled under reflux for 10 hours. After it has been cooled, the precipitated product is filtered off under suction and rinsed with methanol. 6.2 g (82.5% of theory) of 1-(2-chloro-5-fluoro-benzoyl)-3-(4-trifluoromethoxyphenyl)-urea of melting point 199° C. are obtained. The compound is identical to the compound prepared by process variant (a).
Reaction SMILES: Cl.[F:2][C:3]1[C:9]([Cl:10])=[C:8]([F:11])[C:7]([Cl:12])=[CH:6][C:4]=1[NH2:5].[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[F:2][C:3]1[C:9]([Cl:10])=[C:8]([F:11])[C:7]([Cl:12])=[CH:6][C:4]=1[N:5]=[C:13]=[O:14]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)c(F)c(Cl)c1F
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(Cl)c(F)c(Cl)c1F
Reaction time: 2 h

Procedure:
Hydrogen chloride was passed into a well-stirred solution of 39.6 gm (0.20 mol) of 2,4-difluoro-3,5-dichloroaniline in 400 ml of toluene until a precipitate no longer separated out. The heterogeneous mixture thus obtained was cooled to 5° to 10° C. At this temperature, 40 gm (0.4 mol) of phosgene were passed in, with stirring. The mixture was then heated slowly, with stirring, so that after about two hours a temperature of 100° to 105° C. was reached. Stirring was then continued for seven hours at this temperature. During this time, a clear solution was formed, and hydrogen chloride was liberated. Nitrogen was then passed into the mixture for one hour at the same temperature to drive off the excess phosgene. Thereafter the solvent was distilled off, in vacuo at the end. The crude product which remained was distilled in a water pump vacuum.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[N:10]=1.O>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[C:13]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]=[C:11]([Cl:16])[N:10]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(OCC2CC2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
109 mg of cyclopropylcarbinol was dissolved in 2 ml of dimethylformamide, and 60 mg of 60% sodium hydride was added thereto under ice water cooling, and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added 400 mg of 2,4,6-trichloropyridine, and stirred at room temperature for 30 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 133 mg of the objective compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1.O>N1C=CC=CC=1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:63]([CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:69])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)CCC(=O)O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reaction time: 3 h

Procedure:
After 3 hours at room temperature, a solution of 500 mg (0.59 mmole) of taxol, 900 mg (7.6 mmole) of succinic anhydride in 12 mL of pyridine is evaporated to dryness in vacuo. The residue is treated with 20 mL of water, stirred for 20 min. and filtered. The precipitate is dissolved in acetone, water slowly added, and the fine crystals collected. This yields 490 mg (86%) of title compound which showed: mp 178°-80° C.; [a] -42.1° (c=1.1 EtOH); Anal. (C H NO H O) C,H,N.