Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])=O.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH2:1][C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:4]=1[CH3:30])[CH3:33]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CNC
Product: Cc1c(CN(C)C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 37 %

Procedure:
Using N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 20 and dimethylamine, the title compound was synthesized in the same manner as in Example 26. Yield: 37%. Amorphous substance.
Reaction SMILES: O[C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.S(=O)(=O)(O)O.[CH:18]([OH:20])=[O:19]>>[C:2]12([C:18]([OH:20])=[O:19])[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1
Reactant: OC12CCCC(C1)C1CCC2C1
Reactant: O=CO
Agent: O=S(=O)(O)O
Product: O=C(O)C12CCCC(C1)C1CCC2C1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
5 g of 1-hydroxytricyclo[4.3.1.12,5 ]undecane dissolved in 20 ml of formic acid was added dropwise with stirring to 40 ml of conc. sulfuric acid over a period of 1.5 hours while the temperature was kept at 0° to 10° C. The mixture was further stirred for 1 hour and allowed to stand. Separated solids were collected by filtration and dried to afford 5.7 g (yield: 97.5%) of tricyclo[4.3.1.12,5 ]undecane-1-carboxylic acid of the formula (1a). The data on the melting point, elemental analysis, IR, MS and 13C NMR spectra were in complete agreement with that in Example 1.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])=[O:7])(C)(C)C.ClC1C=CC=CC=1Cl.[OH-].[Na+]>CCOCC>[CH3:17][C:11]1[S:10][C:9]([S:6](=[O:8])(=[O:7])[NH2:5])=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=1
Reactant: Cc1cc(C(=O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: Cc1cc(C(=O)O)c(S(N)(=O)=O)s1
Temperature: 140 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A mixture of 5.0 gm (18 millimols) of 2-(N-tert. butyl)sulfamoyl-5-methyl-thiophene-3-carboxylic acid and 20 ml of o-dichloro-benzene was heated, while stirring, for 4 hours at 140° C. After cooling, the reaction mixture was taken up in a mixture of ether and the equivalent amount of dilute aqueous sodium hydroxide. After separation of the ether phase, the aqueous phase was acidified with hydrochloric acid, and the precipitated material was suction-filtered off. The filter cake was recrystallized from ethyl acetate/cyclohexane, yielding 3.3 gm (83% of theory) of 5-methyl-2-sulfamoylthiophene-3-carboxylic acid.
Reaction SMILES: S(O[C:6]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(C)(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[CH3:17][C:14]1[CH:13]=[C:7]([CH:6]=[CH:16][CH:15]=1)[CH:8]([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1ccc(OS(C)(=O)=O)c(C(C)C(=O)O)c1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(C(C)C(=O)O)c1

Procedure:
To a solution of 1.29 g. of 2-mesyloxy-5-methyl-hydratropic acid in 25 ml. of methanol 1.4 ml. of triethylamine and 0.2 g. of a 5% palladium-on-charcoal catalyst are added. The mixture is hydrogenated at 25° C., under atmospheric pressure until the calculated amount of hydrogen is used up. The catalyst is filtered off and the solution is evaporated. The evaporation residue is taken up in water, acidified with a 20% aqueous hydrochloric acid solution and shaken with ether. Ether is distilled off to give 3-methyl-hydratropic acid as an oily residue. The corresponding cyclohexylamine salt melts at 168° C. to 169° C.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:29][CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:22]([N:29]([CH2:30][CH3:31])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNCc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.296 g, 1.00 mmol) and N-benzyl-N-ethylamine (0.149 g, 1.10 mmol) in methylene chloride (10 mL) were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.353 g, 1.10 mmol) and the reaction mixture was stirred at room temperature for three days. The resulting solution was diluted with methylene chloride (90 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.129 g (31%) of a whitish oil.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]1)=O)(C)(C)C.[CH3:17][Si:18]([CH3:29])([CH3:28])[C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1>>[CH3:28][Si:18]([CH3:17])([CH3:29])[C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)C#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)n1cnc(CCCO)c1
Product: C[Si](C)(C)C#Cc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 4-(3-hydroxypropyl)-1H-imidazole-1-carboxylic acid tert-butyl ester and 5 mmol of 4-(2-(trimethylsilyl)-1-ethynyl)phenol (for the preparation see the literature mentioned in Example 122) are treated as described in Example 122.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([CH2:43][CH2:44][N:45]4[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 42.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (108 mg, 0.23 mmol), 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 131, step D) (52 mg, 0.21 mmol), and p-toluenesulfonic acid (107 mg, 0.56 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and neutralized with 1 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (61 mg, 0.09 mmol, 37%). 1H NMR (400 MHz, CDCl3) δ ppm 9.47 (d, J=6.97 Hz, 1H), 8.27-8.31 (m, 2H), 8.26 (d, J=5.50 Hz, 1H), 7.98-8.06 (m, 2H), 7.81 (d, J=8.07 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.80 Hz, 1H), 7.51 (t, J=7.70 Hz, 1H), 7.32-7.40 (m, 1H), 7.18-7.26 (m, 1H), 6.98 (t, J=8.25 Hz, 2H), 6.89 (t, J=6.78 Hz, 1H), 6.78-6.84 (m, 2H), 6.60 (d, J=5.50 Hz, 1H), 3.93 (s, 3H), 2.76-2.85 (m, 2H), 2.43-2.75 (m, 10H), 2.32 (s, 3H). MS (ESI): 675 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][N:18](CC2C=CC=CC=2)[CH2:17]1)=[O:15].O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:19][N:18]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[O:15]
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1[C@H](C)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@H](C)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Benzyloxycarbonyl chloride (3.25 mL, 22.8 mmol) was added to a solution of 1-benzyl-4-[(S)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-3-carboxylic acid methyl ester (2.97 g, 7.58 mmol) in dichloromethane (20 mL), and the mixture was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction mixture. The organic layer was separated, dried over magnesium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3.1 g (96%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[CH:9]([F:11])[F:10].[CH2:12]([S-:14])[CH3:13].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:14][CH2:12][CH3:13])=[CH:4][C:3]=1[CH:9]([F:11])[F:10]
Reactant: Fc1ccc(Br)c(C(F)F)c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1ccc(Br)c(C(F)F)c1
Yield: 28.4 %

Procedure:
1-Bromo-2-(difluoromethyl)-4-fluorobenzene (Preparation 50, 772 mg, 3.43 mmol) and sodium ethanethiolate (352.7 mg, 3.77 mmol) in DMSO (5 mL) was heated at 50° C. for 18 hours. On cooling, water (70 mL) was added to the reaction mixture, the product was extracted with EtOAc (20 mL×3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel column chromatography eluting with heptane to afford the title compound as a colourless oil (260 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[N:10]=[N:9]2)=[C:4]([CH:17]2[CH2:19][CH2:18]2)[CH:3]=1.[NH2:20][C:21]1[C:22](=[O:34])[N:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH3:27])[C:25]=1[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:20][C:21]3[C:22](=[O:34])[N:23]([CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)[N:24]([CH3:27])[C:25]=3[CH3:26])=[O:16])[N:10]=[N:9]2)=[C:4]([CH:17]2[CH2:19][CH2:18]2)[CH:3]=1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1C1CC1
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)nnn1-c1ccc(Cl)cc1C1CC1

Procedure:
The title compound was prepared from 1-(4-chloro-2-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Example 13, step 5) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A) analogously to Example 1, step 3.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3].[CH2:23](O)[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCOCCCCCc1ccc(-c2ncc(O)cn2)cc1
Reactant: CCCC/C=C\CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC/C=C\CCOc1cnc(-c2ccc(CCCCCOCCC)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-hydroxypyrimidine, 0.3 g of (Z)-3-octen-1-ol, 0.4 g of diethyl azodicarboxylate, 0.6 g of triphenylphosphine and 25 ml of absolute tetrahydrofuran was stirred at room temperature overnight and then concentrated. The residue was suspended with 50 ml of hot hexane and filtered. The filtrate was concentrated. Chromatography of the residue on silica gel with toluene/hexane (vol. 1:1) and recrystallization from methanol gave pure 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-([(Z)-3-octenyl]oxy)pyrimidine, m.p. (C-I) 38° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:16])[CH2:15][CH2:14][CH2:13]2)=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18])=O.CO.C(=O)([O-])[O-].[K+].[K+].O>>[CH3:16][C:12]1([C:9]2[CH:10]=[CH:11][C:6]([NH2:5])=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=2)[CH2:13][CH2:14][CH2:15]1
Reactant: CC1(c2ccc(NC(=O)C(F)(F)F)c([N+](=O)[O-])c2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(c2ccc(N)c([N+](=O)[O-])c2)CCC1
Temperature: 45 °C
Yield: 102.1 %

Procedure:
A solution of 2,2,2-trifluoro-N-[4-(1-methylcyclobutyl)-2-nitrophenyl]acetamide (580 mg. 1.9 mmol) in Methanol (18 ml, 440 mmol) was treated with a solution of Potassium carbonate (788 mg, 5.70 mmol) in Water (4.5 ml, 250 mmol) and the mixture was heated at 45° C. for 50 minutes The reaction mixture was cooled to RT and the methanol was removed in vacuo. The remaining aqueous phase was diluted with 10 ml H2O and extracted with three 20 ml portions of EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to yield an oil. The material was placed on high vacuum where upon it solidified giving the desired compound (400 mg). The material was used directly in the next step 1H NMR (400 MHz. CDCl3) d ppm 7.90 (d, J=2.07 Hz, 1H), 7.23 (dd, J=8.50, 2.28 Hz, 1H), 6.77 (d, J=8.71 Hz, 1H), 5.96 (br. s., 2H), 2.33 (m, 2H), 2.13 (m, 1H), 2.04 (m, 2H), 1.84 (m, 1H), 1.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].[CH2:27](Br)[CH:28]=[CH2:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:29]([N:4]1[C:5]2[CH:6]=[C:7]3[N:22]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[NH:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:26])([CH3:1])[C:3]1=[O:25])[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4ccc(OC)cc4)nc3cc21
Temperature: 150 °C

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)4-methoxy-benzamide (200 mg), allyl bromide (78 mg; 0.65 mmol) and K2CO3 (233 mg; 1.69 mmol) in acetone (3.2 ml) and N,N-dimethylformamide (1.6 ml) is stirred at 50° C. for 48 h. The mixture is filtered and concentrated in vacuo. The residue is suspended in acetic acid (3 ml), iron (150 mg; powder) is added and the resulting mixture is heated in a microwave apparatus at 150° C. for 900 s. After re-cooling the mixture is filtered and concentrated in vacuo. The desired compound is obtained by preparative RP-HPLC.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6].N1C=CC=CC=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:1][C@@H:2]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH:4]([C:5]#[N:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: N#CC(C[C@@H](O)COCc1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)O[C@@H](COCc2ccccc2)CC(C#N)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
(4R)-4-hydroxy-2-phenyl-5-[(phenylmethyl)oxy]pentanenitrile (16.0 g, 57 mmol), accessed via the method of preparation 1, was dissolved in 116 mL CHCl3 and 116 mL Pyridine (25 eq) with DMAP (0.70 g, 5.7 mmol, 0.1 eq) and cooled to 0° C. 4-methylbenzenesulfonyl chloride (43.5 g, 228 mmol, 4 eq) was added to the reaction mixture and stirred 3 days at 0° C. The reaction mixture was washed successively with 1N HCl (4×250 mL) and brine, dried over MgSO4, filtered and concentrated to a red oil. The crude material was purified by flash chromatography (SiO2, 10→25% EtOAc/Hexanes) to give the diastereomeric product as a yellow oil (14.88 g, 34.2 mmol, 60%). ES-LCMS m/z 458.36 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[CH:27][CH:28]=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>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To a solution of 1.10 g of 3,5-dichloro-4-(3-hydroxypropoxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.56 g of 3-trifluoromethoxyphenol and 0.83 g of triphenylphosphine dissolved in 20 ml of tetrahydrofuran was added dropwise a solution of 0.64 g of diisopropylazodicarboxylate dissolved in 10 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 1.03 g of 3,5-dichloro-4-(3-(4-trifluoromethoxyphenoxy) propoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (64% yield), nD23.4 1.5343.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:27]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[C:31]=2[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[CH:27]1[C:36]2[C:31](=[C:32]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)C1CCN(Cc2cc3nc(-c4cccc5cnccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C
Yield: 49.7 %

Procedure:
A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.630 g, 1.59 mmol), isoquinoline-5-boronic acid (0.331 g, 1.91 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol), 1 N aqueous sodium carbonate solution (2.5 mL) and acetonitrile (7.5 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in methanol and filtered through celite. The filtrates were concentrated then purified by chromatography (C-18 reverse phase column, 5 to 95% acetonitrile in water containing 0.1% TFA). The fractions containing the desired product were concentrated then dissolved in MeOH/dichloromethane, basified with solid sodium carbonate then filtered and concentrated to furnish 109 (0.386 g, 50%) as a white foam. MS m/e 489 [M+H]; 1H NMR (300 MHz, MeOH-d4) δ ppm 1.61-1.91 (m, 2 H) 1.99-2.15 (m, 2H) 2.17-2.36 (m, 2 H) 2.88 (s, 6 H) 3.04-3.28 (m, 3 H) 3.73-3.87 (m, 4 H) 3.91 (s, 2 H) 3.96-4.07 (m, 4 H) 7.33 (s, 1 H) 7.69-7.83 (m, 1 H) 8.18 (d, J=8.3 Hz, 1 H) 8.30 (d, J=7.2 Hz, 1 H) 8.43 (d, J=6.4 Hz, 1 H) 8.57 (d, J=6.0 Hz, 1 H) 9.28 (s, 1 H)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:33])[NH:31][CH3:32])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1.CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:33])[NH:31][CH3:32])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.80 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 5.70 ml of 4-methoxybenzyl mercaptan dissolved in 100 ml of dry tetrahydrofuran, and the mixture was then stirred at 0° to 5° C. for 30 minutes. At the end of this time, a solution of 11.00 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-methanesulfonyloxy-2-methylcarbamoylpyrrolidine [prepared as described in step (2) above] in 80 ml of dry dimethylformamide was added to the mixture, and the mixture was stirred at 34° C. for 4.5 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 by volume mixture of ethyl acetate and hexane) to afford 4.35 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
A mixture of (4-amino-phenyl)-acetic acid (25 g) in acetic acid (200 mL) was treated with acetic anhydride (31.3 mL). The mixture was heated on a steam bath for 4 hours, then cooled, then treated with water (20 mL) and then evaporated. The residue was dried under vacuum to give the title compound (30.4 g) as a beige coloured solid.