Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14]C)[CH:10]([C:16]1([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17]1)[NH:9][CH2:8][CH2:7]2.C=O.[C:34]([BH3-])#N.[Na+]>CO>[ClH:1].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[CH:10]([C:16]1([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)[CH2:17][CH2:18][CH2:19]1)[N:9]([CH3:34])[CH2:8][CH2:7]2
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1OC)C(C1(c3ccc(-c4ccccc4)cc3)CCC1)NCC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCc2cc(O)c(O)cc2C1C1(c2ccc(-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
A mixture of 6,7-dimethoxy-1-[1-(4-biphenylyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.5 g, prepared as described in Example RC20), methanol (50 ml), 37% aqueous formaldehyde solution (5 ml) and sodium cyanoborohydride (2.08 g) was stirred at ambient temperature for 24 hours. The solvents were removed in vacuo and the residue was partitioned between aqueous sodium hydroxide solution and ether. The ether extracts were dried over magnesium sulphate, the solution was filtered and the solvent removed in vacuo. The residue was dissolved in glacial acetic acid (30 ml). 48% Aqueous hydrobromic acid (30 ml) was added, and the mixture was heated under reflux under nitrogen for 6 hours. The solvents were removed in vacuo and the residue was recrystallised from methanol to give a solid which was partitioned between concentrated aqueous ammonia solution and ether. The ether extracts were washed with brine, dried and filtered. Dry hydrogen chloride was bubbled through the filtrate to yield 6,7-dihydroxy-2-methyl-1-[1-(4-biphenylyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.1 g), m.p. 131°-135° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13](Cl)(=[O:15])=[O:14])[C:5]=2[O:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].C(N(CC)CC)C.O>O1CCCC1>[OH:24][CH2:23][CH2:25][NH:26][S:13]([C:12]1[C:5]2[O:4][C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=[CH:10][CH:11]=1)(=[O:15])=[O:14]
Reactant: NCCO
Reactant: Cc1c(-c2ccccc2)oc2c(S(=O)(=O)Cl)cccc2c1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)oc2c(S(=O)(=O)NCCO)cccc2c1=O

Procedure:
A solution of 5 g of Intermediate VIII in 37 ml of tetrahydrofuran was added dropwise at 0° C. to a mixture of 2.5 ml of ethanolamine and 2.5 ml of triethylamine in 25 ml of tetrahydrofuran. After stirring at 20°-25° C., the reaction mixture was poured into 400 ml of water. A precipitate formed, and was collected by suction filtration, washed with water and air dried, yielding 4.6 g of 8-(2-hydroxyethylsulfamyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, melting at 186°-187° C. after crystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2Br)[CH3:10])[C:5]([C:22]#[N:23])=[C:4]([CH3:24])[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:35][CH:34]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH2:35][CH:34]=2)[CH3:10])[C:5]([C:22]#[N:23])=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2Br)c1C#N
Reactant: CC(C)(C)OC(=O)NC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2=CCC(NC(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 100 °C
Yield: 86.8 %

Procedure:
A microwave vial was charged with (S)-2-amino-4-((1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile (0.07 g, 0.181 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (0.076 g, 0.236 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.015 g, 0.018 mmol) and sodium bicarbonate (0.030 g, 0.362 mmol) in dioxane (2 mL) and water (0.500 mL). The reaction mixture was heated to 100° C. for 40 minutes in a microwave reactor. Following reaction, the solvent was removed under a nitrogen stream and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate and purified on a silica gel column (20-80% ethyl acetate/heptanes gradient) to give the title compound as a tan solid (79 mg, 87%). ESI-MS m/z [M+H]+ calc'd for C27H34N8O2, 503. found 503.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:36])[C:22]([OH:35])([C:27]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=1)[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.Cl([O-])=[O:38].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:36])[C:22]([OH:35])([C:27]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=1)[C:23]([F:25])([F:26])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:38])=[O:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=1
Reactant: CC(c1ccc(Oc2ccc(C=O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Product: CC(c1ccc(Oc2ccc(C(=O)O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 214, step 2, 4-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-propyl]-phenoxy}-2-trifluoromethyl-benzaldehyde was oxidized with sodium chlorite to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=548.1 [M−H+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])=[C:6]([NH:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH:5]=1)(=[O:3])[CH3:2].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C([O:46][C@@H:47]1[C@@H:50]([C@H:51]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[CH3:52])[C:49](=O)[NH:48]1)(=O)C.S([O-])(O)(=O)=O.[K+]>ClCCl.[Cl-].[Na+].O.[I-].[Zn+2].[I-].CCOCC.C(N(CC)CC)C>[CH2:28]([O:27][C:25]([NH:24][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][C@@H:49]2[C@@H:50]([C@H:51]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:55])[CH3:56])[CH3:52])[C:47](=[O:46])[NH:48]2)[CH:9]=[CH:8][C:7]=1[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:26])[CH:29]=[CH2:30]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCOC(=O)Nc1cc(C(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To 4-nitrobenzyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate (10.0 g) and triethylamine (8.2 mL) in dichloromethane (100 mL) was dropped at 0° C. trifluoromethanesulfonic acid trimethylsilyl ester (11.9 g). After detecting the production of silylenol ether by TLC, (2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinyl acetate (6.98 g) and zinc iodide (4.65 g) were added thereto at 0° C. After stirring for 1 hour, further (2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinyl acetate (3.0 g) was added thereto and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added a 5% aqueous potassium hydrogensulfate solution (380 mL) and saturated brine (100 mL), and the mixture was extracted with ethyl acetate (200 mL, 2×100 mL). The organic layers were combined, dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified with column chromatography (SiO2 500 g, hexane/ethyl acetate 1:1˜1:3) to give the object compound (11.4 g, 70%) as a pale amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([S:26][CH3:27])[C:17]([NH:18][C:19](=O)OC(C)(C)C)=[C:13]2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].I[CH2:31][CH2:32]C.Cl.C(OCC)(=O)C.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([S:26][CH3:27])[C:17]([NH:18][CH2:19][CH2:31][CH3:32])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CSc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1NC(=O)OC(C)(C)C
Reactant: CCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCNc1c(SC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (150 mg) in N,N-dimethylformamide (3 mL), sodium hydride (60%, 21 mg) was added while cooling on ice, and then 1-iodopropane (0.041 mL) was added and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was dissolved in ethyl acetate (1 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (60 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([CH2:15][NH:16]C(=O)C)[C:6]=1[OH:20])(=[O:4])[CH2:2][CH3:3].[ClH:21]>CO>[ClH:21].[C:1]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([CH2:15][NH2:16])[C:6]=1[OH:20])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1c(O)c(CNC(C)=O)cc2c1CCCC2
Agent: Cl
Solvent: CO
Product: CCC(=O)c1c(O)c(CN)cc2c1CCCC2

Procedure:
To 400 mg of the compound obtained in Example 4 (a) above were added 2 ml of methanol and 1 ml of concentrated hydrochloric acid followed by refluxing for 15 hours. The mixture was concentrated, and the residue was washed with diethyl ether and dissolved in methanol. Activated carbon was added to the solution which was then filtered. Diethyl ether was added to the filtrate and the precipitated crystals were filtered to obtain 160 mg of the title compound having the following physical properties.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[OH-].[NH4+:13]>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[N:3][C:2]([NH2:13])=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(C(F)(F)F)nn1
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 3-chloro-6-trifluoromethyl-pyridazine (1.6 g, 8.8 mmol) (prepared by a procedure similar to that described in Tetrahedron, 1999, 55 (52), 15067-15070) and ammonium hydroxide (30 ml) in THF (10 ml) was heated at 100° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 1 h. After this period, the reaction mixture was evaporated and the residue extracted with dichloromethane. The combined extracts were dried (MgSO4), filtered and the solvents evaporated in vacuo to give D6 (1.3 g, 93%). C5H4F3N3 requires 163; Found 164 (MH+)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.C[Si]([N:33]=[C:34]=[O:35])(C)C>>[CH2:15]([C:13]1[N:12]([CH2:20][CH2:21][O:22][C:23]([F:24])([F:26])[F:25])[C:11]2[CH:27]=[CH:28][C:8]([S:5]([CH:3]3[CH2:2][N:1]([C:34]([NH2:33])=[O:35])[CH2:4]3)(=[O:7])=[O:6])=[CH:9][C:10]=2[N:14]=1)[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CNC3)ccc2n1CCOC(F)(F)F
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CN(C(N)=O)C3)ccc2n1CCOC(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using 5-(azetidin-3-ylsulfonyl)-2-neopentyl-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazole (STEP C of Example 7) and trimethylsilyl isocyanate instead of methanesulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[NH2:15][C:16]1[CH:17]=[N:18][C:19](Br)=[CH:20][CH:21]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:19]1[N:18]=[CH:17][C:16]([NH2:15])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Br)nc1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccc(N)cn1
Yield: 49 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 3-amino-6-bromopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 68 mg, 49%) which was obtained as a light brown foam. MS: m/e=276.3 [M+H]+.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)(O)[O-].[Na+].[CH2:9]([NH:11][C:12]([C@@H:14]1[CH2:18][C@H:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:16][NH:15]1)=[O:13])[CH3:10].[Cl-].[Na+]>CN(C)C=O>[CH2:9]([NH:11][C:12]([C@@H:14]1[CH2:18][C@H:17]([S:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH2:16][N:15]1[CH2:1][CH3:2])=[O:13])[CH3:10]
Reactant: CCI
Reactant: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
301 μl of ethyl iodide and 314 mg of sodium bicarbonate were added, whilst ice-cooling, to a solution of 1.00 g of (2S, 4S)-2-ethylcarbamoyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 8 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was 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, after which the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel (eluted with ethyl acetate) to afford 982 mg of the title compound as colorless crystals, melting at 60°-61° C.
Reaction SMILES: C[O:2][P:3](=[O:36])([O:34]C)[O:4][C@@H:5]([CH3:33])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[N:11]=[C:10]2[NH:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:9]=12.C[Si](Br)(C)C>C(Cl)Cl>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[C:9]2[C:10](=[N:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])=[N:13][C:8]=2[NH:7][CH2:6][C@@H:5]([O:4][P:3](=[O:2])([OH:34])[OH:36])[CH3:33])[NH:23][N:24]=1
Reactant: COP(=O)(OC)O[C@@H](C)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: C[C@@H](CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12)OP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To (S)-phosphoric acid 2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-1-methyl-ethyl ester dimethyl ester (3.1 g, 5.74 mmol) in 35 mL methylene chloride was added trimethylsilyl bromide (2.97 mL, excess) The reaction mixture was stirred for four hours at room temperature, and then solvent was removed under reduced pressure. Methanol (80 mL) was added, and the reaction mixture was stirred at room temperature. Solvent was again removed under reduced pressure, and the residue was added to 2N NaOH (100 mL) and EtOAc (mL). The mixture was stirred for 15 minutes, then the organic layer was separated, washed with saturated brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 2.243 g of (S)-phosphoric acid mono-{2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-1-methyl-ethyl}ester, MS (M+H)=512. This solid was converted to 2.182 g of the corresponding disodium salt by treatment with 15 Ml of 0.5M NaOCH3 in MeOH; MP>300° C., MS (M+H)=512.
Reaction SMILES: [C:1]([C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([NH:13]C(=O)C)=[CH:5][CH:4]=1)#[N:2].[ClH:17]>CCO>[ClH:17].[NH2:13][C:6]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(=O)Nc1ccc(C#N)c2c1CCCC2
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(N)c2c1CCCC2
Temperature: 25 °C

Procedure:
A suspension of 2C (0.40 g, 1.87 mmol) in a mixed solvent of EtOH (2 mL) and conc. HCl (2 mL) was refluxed for 2 h. The resulting solution was allowed to cool to rt and concentrated under reduced pressure. The obtained solid was evaporated with toluene (2×) to yield compound 2D (0.25 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][C:10]=1[CH3:17])([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:22]([C:21]2[C:20]([CH3:19])=[N:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:11][C:10]=1[CH3:17])[CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1C
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[2-methyl-4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
Reaction SMILES: C(OC(=O)[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[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:40]([CH3:41])=[CH:39][N:38]=[C:37]([CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[C:40]([CH3:41])=[CH:39][N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)c(C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)c(C)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M123) (0.29 g, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (220 mg, 94%).
Reaction SMILES: [C:1](=[S:4])([O-:3])[CH3:2].[K+].Br[CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][Br:16])[C:8]([O:10][CH3:11])=[O:9]>CS(C)=O>[C:1]([S:4][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][Br:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: COC(=O)C(Br)CCCCBr
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCCCBr)SC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat potassium ethanethioate (571 mg, 5 mmol) was added to a solution of methyl 2,6-dibromohexanoate (1440 mg, 5 mmol) in DMSO (5 mL) and the mixture was stirred at rt overnight. The reaction was quenched with water and extracted with ether, washed with water, brine and dried (MgSO4). The crude isolate was purified by silica gel FCC (DCM) to afford methyl 2-(acetylthio)-6-bromohexanoate as a clear oil.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([C:28]2[NH:29][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:30][CH:31]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(CN)cc1
Product: CCOC(=O)c1nc(-c2ccc(C(C)(C)C)cc2)[nH]c1-c1ccc([N+](=O)[O-])cc1
Yield: 31.8 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-nitrophenyl)-3-oxopropionate (47.8 g) and 4-tert-butylbenzylamine (35.4 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give ethyl 2-(4-tert-butylphenyl)-5-(4-nitrophenyl)imidazole-4-carboxylate (22.5 g), melting point 190-191° C.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=O>>[C:2]1([C:1]2[O:8][CH:11]=[C:12]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1ccccc1
Product: CCOC(=O)c1ccc(-c2coc(-c3ccccc3)n2)cc1
Yield: 29 %

Procedure:
In the same manner as in Example 1, benzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-(2-phenyl-4-oxazolyl)benzoate. The product was recrystallized from ethanol. Yield: 29%. Pale yellow prisms. Melting Point: 110 to 112° C.