Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH3:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[OH:13])=O.C(O)(=O)C>[Ni].O>[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[OH:13])[CH3:4]
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1ccc(O)cc1O

Procedure:
In a three necked round bottom flask (equipped with a condensor, additional funnel and mechanical stirrer) was added 15.2 g of a combination of Raney Nickel and Ni supported on silica. (50:50). 100 ml of a mixture of 50:50 ethanol:water was added and the reaction was heated at reflux conditions. 15.2 g of 2,4-dihydroxy acetophenone in 100 ml of water:ethanol and 10 ml of acetic acid was placed in the additional funnel and slowly added to the mixture (dropwise). The reaction was filtered through a milipore filter to give a pale yellow solution. Concentration of this solution in vacuo gave a solid. This solid was crystalized from 1,2-dichloroethane to give 4-ethyl resorcinol in 80% isolated yield. The unreacted 2,4-dihydroxy acetophenone was recovered (−17%) form the reaction mixture and was recycled. The structure of 4-ethyl resorcinol and 2,4-dihydroxy acetophenone were characterized by NMR, Gas Chromatography, IR and Mass spectroscopy
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].[H-].[Na+]>C1COCC1.O>[C:3]([S:6][C:3]([CH3:5])([CH3:4])[CH3:2])([CH3:5])([CH3:4])[CH3:2]
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)SC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a 50 mL round bottom flask containing 0.9 grams (8.82 mmole) of the sodium salt of 2-methyl-2-propanethiol was added 0.25 grams of sodium hydride (11.3 mmole) and the resulting mixture placed under vacuum and then under a nitrogen atmosphere. To the mixture was then added 15 mL of anhydrous tetrahydrofuran and the mixture cooled to 0° C. To the cooled mixture was added 1.5 grams (5.84 mmole) of 9 dissolved in 15 mL of anhydrous THF over a period of 10 minutes. After addition, the reaction mixture was allowed to stir, at room temperature and under a nitrogen atmosphere for 18 hours. After 18 hours the volatile components of the reaction mixture were removed under reduced pressure to give a brown solid. The brown solid was dissolved in 80 mL of H2O and aqueous washed with 100 mL of diethyl ether. The aqueous layer was then acidified with 1 mL of concentrated HCl (pH=1) and then extracted (2×100 mL) with diethyl ether and organic layers combined, dried over MgSO4, filtered and volatile components removed under reduced pressure to give 1.75 grams of the t-butyl thioether product which was used without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:72][C:73](=[O:93])[C:74]2[CH:79]=[CH:78][C:77]([N:80]3[CH2:85][CH2:84][N:83]([C:86](=[O:91])[C:87]([CH3:90])([CH3:89])[CH3:88])[CH2:82][C@H:81]3[CH3:92])=[N:76][CH:75]=2)=[CH:46][C:47]([O:67][C:68]([F:71])([F:70])[F:69])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([CH3:66])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([CH3:66])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:54]=[CH:55][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:72][C:73]([C:74]4[CH:75]=[N:76][C:77]([N:80]5[CH2:85][CH2:84][N:83]([C:86](=[O:91])[C:87]([CH3:90])([CH3:89])[CH3:88])[CH2:82][C@H:81]5[CH3:92])=[CH:78][CH:79]=4)=[O:93])=[CH:46][C:47]=3[O:67][C:68]([F:70])([F:71])[F:69])=[CH:51][CH:52]=2)[N:57]=1)=[O:9]
Reactant: C[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (9.4 mg, 0.046 mmol; Preparation 29) in DMA (5 mL) was added HATU (45.3 mg, 0.12 mmol). The reaction mixture was stirred at RT for 15 min, and N-{5-chloro-4′-[2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide tri-HCl (30.0 mg, 0.036 mmol; Preparation 31 was added followed by DIPEA (86.4 μL, 0.50 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (14 mg, 37% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O7 923.38. found 923.8.
Reaction SMILES: [F:1][C:2](S(C1C=CC=CC=1)(=O)=O)=[CH:3][C:4]([CH3:13])([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([SnH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].N(C(C)(C)C#N)=NC(C)(C)C#N>C1CCCCC1>[F:1][C:2]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)([CH3:5])[CH3:13]
Reactant: CC(C)(C=C(F)S(=O)(=O)c1ccccc1)c1ccc(Cl)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCCCC1
Product: CCCC[Sn](CCCC)(CCCC)C(F)=CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirring solution of 22.7 grams (0.067 mole) of 1-fluoro-1-phenylsulfonyl-3-methyl-3-(4-chlorophenyl)-1-butene, 42.0 grams (0.14 mole) of tributyltin hydride, and 0.5 gram (catalyst) of azobis-isobutyronitrile in 700 mL of cyclohexane is heated at reflux for about three hours. After this time the reaction mixture is cooled to ambient temperature, and 125 mL of silica gel is added. The mixture is concentrated under reduced pressure, and the residue is subjected to column chromatography. The product-containing fractions are combined and concentrated under reduced pressure, yielding 1-fluoro-3-(4-chlorophenyl)-3-methyl-1-tributylstannyl-1-butene.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[F:31][C:28]([F:29])([F:30])[CH2:27][CH2:26][O:25][CH:23]1[CH2:24][NH:21][CH2:22]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: FC(F)(F)CCOC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCO
Solvent: ClCCl
Product: Cl
Product: FC(F)(F)CCOC1CNC1
Reaction time: 1 h

Procedure:
1-Chloroethyl chloroformate (136 μL, 1.25 mmol) was added to a solution of 1-benzhydryl-3-(3,3,3-trifluoropropoxy)-azetidine (400 mg, 1.19 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture was stirred for 1 hour. Ethanol (10 mL) was added and the reaction mixture was stirred for 1 hour at room temperature and for 2 hours at 45° C. After concentration to dryness, the crude mixture was triturated in petroleum ether (2×20 mL) to give a yellow oil (245 mg, quantitative) which was used in the next step without further purification.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1/[C:11](/[CH2:35][CH3:36])=[C:12](\[C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=1)/[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.Cl>O.CCO>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1/[C:11](/[CH2:35][CH3:36])=[C:12](\[C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=1)/[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(Cl)cc2Cl)c2ccc3[nH]ncc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of LiOH (0.23 g, 9.6 mmol) in water (3.2 mL) was added to a solution of (E)-ethyl 3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (2.37 g, 4.8 mmol; Compound 112) in EtOH (20 mL) at room temperature. The resulting mixture was stirred overnight. Upon completion, 1N aqueous HCl was added until the pH was 3. The mixture was diluted with water and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (50 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified on a preparative reversed-phased HPLC column using 80-95% acetonitrile in water in the presence of 0.1% TFA to give the title compound (1.3 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.11 (s, 1H), 12.36 (br, 1H), 8.11 (d, 1H), 7.69 (s, 1H), 7.57-7.53 (m, 2H), 7.44-7.35 (m, 5H), 7.19 (dd, 1H), 6.97 (d, 2H), 6.39 (d, 1H), 2.39 (q, 2H), 0.90 (t, 3H); LCMS: 463 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:13]=1
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(CNc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 4-fluoro-3-[[3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2-methyl-phenol (324 mg, 0.95 mmol, 1.0 eq) in DMF (15 mL) was added Cs2CO3 (467 mg, 1.43 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 30 min, then isopropyl bromoacetate (207 mg, 1.15 mmol, 1.2 eq) was added and stirring continued for a further 1 h. Water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 40:1) to give the title compound as a colorless oil (317 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:32])[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28](SC)=[NH:29])=[CH:23][CH:22]=2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.[CH2:33]([NH2:36])[CH2:34]N.[C:37](O)(=O)C>CO.C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:32])[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28](=[NH:29])[NH:36][CH2:33][CH2:34][CH3:37])=[CH:23][CH:22]=2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: CC(=O)O
Reactant: CSC(=N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCNC(=N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g (3.1 mmol) of methyl 2-{4-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}ethaneimidothioate are suspended in 190 ml of methanol, and 280 mg (4.65.mmol) of ethylenediamine and 370 mg (6.2 mmol) of acetic acid are added. The mixture is stirred at room temperature overnight, diluted with methanol and methylene chloride until a clear solution is formed and adsorbed on silica gel. Chromatography on silica gel (CH2Cl2/EtOH=10/1 to 3/1) gives 570 mg (31% of theory) of the desired compound. The product is dissolved in methanol and methylene chloride, and trifluoroacetic acid is added. Removal of the solvent under reduced pressure gives the product as trifluoroacetic acid salt. Alternatively, the purification can also be carried out by chromatography on an RP8 silica gel column (water/acetonitrile=4/1+0.1% trifluoroacetic acid to 1/1+0.1% trifluoroacetic acid).
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[C@H:7]([C:23](O)=[O:24])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:32][NH:33][C:34]1[CH:42]=[CH:41][C:37](C(O)=O)=[CH:36][CH:35]=1.[C:43]([O-:46])([O-])=[O:44].[K+].[K+].OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1.C1COCC1>[C:1]([S:4][C@H:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)(=[O:11])=[O:12])[C@H:7]([C:23]([N:33]([CH3:32])[C:34]2[CH:35]=[CH:36][C:37]([C:43]([OH:46])=[O:44])=[CH:41][CH:42]=2)=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@@H]1C[C@@H](C(=O)O)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reactant: O=C([O-])[O-]
Reactant: CNc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1C[C@@H](C(=O)N(C)c2ccc(C(=O)O)cc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To 200 mg (0.52 mmol) (2S,4R)-4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid in 10 ml toluene and 4 ml THF were added 226 μl (2.6 mmol, 5eq) oxalyl chloride and the solution was stirred at RT for 2 h, and was concentrated. The residue was dissolved in 8 ml THF, and the solution was added at 0° C. to a suspension of 180 mg (1.19 mmol, 2.2 eq) 4-methylamino benzoic acid and 360 mg (2.6 mmol, 5eq) K2CO3 in 8 ml THF. After 2.5 h the solution was acidified by 1M KHSO4 and extracted with EtOAc, the organic phase was washed with brine and dried over Na2SO4. Column chromatography yielded 91 mg (35%) (2S,4R)-4-[[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-methyl-amino]-benzoic acid as white solid, MS: 513 (MH+).
Reaction SMILES: Cl.[OH:2][C@@H:3]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](OCCCC#N)[CH:22]=2)[N:17]=[CH:16][CH:15]=1)[C@@H:4]1[N:9]2[CH2:10][CH2:11][C@H:6]([C@@H:7]([CH:12]=[CH2:13])[CH2:8]2)[CH2:5]1.[CH3:30][OH:31]>>[CH3:30][O:31][C:8](=[NH:9])[CH:7]([C:21]1[CH:22]=[C:23]2[C:18]([N:17]=[CH:16][CH:15]=[C:14]2[CH:3]([OH:2])[C@@H:4]2[N:9]3[CH2:10][CH2:11][C@H:6]([C@@H:7]([CH:12]=[CH2:13])[CH2:8]3)[CH2:5]2)=[CH:19][CH:20]=1)[CH2:6][CH3:5]
Reactant: CO
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCC#N)cc12
Agent: Cl
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2C(O)c1ccnc2ccc(C(CC)C(=N)OC)cc12
Reaction time: 96 h

Procedure:
Hydrochloric acid gas was bubbled through a solution of 200 mg (0.52 mmol) of (9S)-4-[(9-hydroxycinchonan-6'-yl)oxy]butanenitrile (2) in 5 ml of anhydrous methanol at -10° C. for a period of 15 minutes. The reaction mixture was stoppered and left at 4° C. for 4 days, concentrated to dryness and yielded 220 mg (0.49 mmol, 93%) of (9S)-4-[(9-hydroxycinchonan-6'-yl)butanimidic acid methyl ester (3) as solids. HNMR indicated the purity of (9S)-4-[(9-Hydroxycinchonan-6'-yl)butanimidic acid methyl ester (3) was 75% with the remaining 25% as the hydrolyzed compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:26])=[C:13]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19](C)[CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[CH2:28]([O:30][CH:31]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:29].[CH2:56]1CCN2C(=NCCC2)CC1>>[CH2:35]([O:34][C:32](=[O:33])/[C:31](/[O:30][CH2:28][CH3:29])=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:15][C:13]2[N:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[O:11][C:12]=2[CH3:26])=[CH:18][C:19]=1[CH3:56])[CH3:36]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)ccc1C=O
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: CCOC(=O)/C(=C/c1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], 4-hydroxy-2-methyl-benzaldehyde (for the preparation of 4-hydroxy-2-methyl-benzaldehyde see: H. H. Hodgson, T. A. Jenkinson, J. Chem. Soc. 1929, 469, 1639-1641) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from 4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) in the presence of potassium carbonate to yield 4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-benzaldehyde. 4-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-benzaldehyde was reacted with (ethoxy-ethoxy-carbonyl-methyl)-triphenyl-phosphonium chloride [for the preparation of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride see: K. K. Bach, H. R. El-Seedi, H. M. Jensen, H. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetrahedron 1994, 50, 7543-7556] in the presence of DBU in analogy to the procedure described in example 120 c] to give 2Z-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield 2Z-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid as light green solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[O:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([S:35]([N:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)(=[O:37])=[O:36])[CH:39]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: O=S(=O)(c1cccc(B(O)O)c1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc(S(=O)(=O)N4CCOCC4)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.13 mmol) were added (3-(morpholinosulfonyl)phenyl)boronic acid (54 mg, 0.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.01 mmol) and 133 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (50 to 100%, hexane-ethyl acetate) to give 58 mg (73% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH2:26][CH3:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH2:26][CH3:27])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCCOc1cc(Cl)ccc1CO
Product: CCCOc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-propoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.01 (3H, t, J=7.2 Hz), 1.77-1.86 (2H, m), 3.98 (2H, t, J=2.4 Hz), 5.24 (2H, s), 5.78 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 6.95 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.34 (1H, d, J=8.4 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 8.05 (1H, d, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H17ClN4O2, 369. Found, 369.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[O:7][N:6]=1)=[N+]=[N-].C(N(CC)CC)C.C(S)CCS.[H-].[Na+]>CC(O)C>[F:13][C:10]([F:11])([F:12])[C:8]1[O:7][N:6]=[C:5]([CH2:4][NH2:1])[CH:9]=1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)on1
Agent: SCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: NCc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
To a solution of 6.26 g 3-(azidomethyl)-5-(trifluoromethyl)isoxazole in 100 mL 2-propanol were added 9.08 mL triethyl amine and 330 uL 1,3-propanedithiol. 2.45 g sodiumhydride were added portion wise and stirred at RT for 16 h. The reaction mixture was concentrated in vacuo. The residue was poured carefully into 180 mL 10% acetic acid and washed with diethyl ether/heptane mixture 1.1 (3×50 mL) The aqueous layer was basified with conc. NaOH to pH=12 (50 mL), saturated with NaCl and extracted with CH2Cl2 (3×250 mL). The combined organic layer was dried over Na2SO4, filtered off and concentrated in vacuo to yield 3.4 g of the title compound as yellow oil; LC-MS (UV peak area/ESI) 97.6%, 167.043 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].Br[CH2:17][C:18]#[C:19][CH3:20].[H-].[Na+]>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:17][C:18]#[C:19][CH3:20])[CH:13]([CH3:15])[CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCBr
Reactant: CC#CCOc1cc(NC(C)C)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CC#CC)C(C)C)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 164 mg of 4-(2-butynyloxy)-6-(isopropylamino)pyrimidine and 106 mg of 1-bromo-2-butyne, to which 40 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. Then, ice water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to preparative silica gel thin layer chromatography to give 155 mg of 4-(2-butynyloxy)-6-(N-(2-butynyl)-N-isopropylamino)pyrimidine (the present compound (107)).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[CH3:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:3][CH:4]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cnc(N)c2ccccc12
Product: CCOC(=O)C(=CNc1ncc(OC)c2ccccc12)C(=O)OCC
Reaction time: 0.1 h

Procedure:
A mixture of 1-amino-4-methoxyisoquinoline (297 mg., 1.7 mmoles) and diethyl ethoxymethylenemalonate (370 mg., 1.7 mmoles) was plunged into an oil bath at 110° and kept there for 6 minutes. The mixture melted and then solidified. The crude product, m.p. 150°-153°, was used without purification.