Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1[C:60]2[N:59]=[C:58]([NH2:61])[NH:57][C:56]=2[CH:55]=[C:54]([S:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[C:60]2[NH:59][C:58]([NH:61][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:57][C:56]=2[CH:55]=[C:54]([S:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CCOC(=O)c1cc(SCC)cc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(SCC)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 83 %

Procedure:
0.4 g (2.0 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.26 g (1.0 mmol) of 2-amino-6-ethylsulfanyl-1H-benzoimidazole-4-carboxylic acid ethyl ester as described in general procedure A to produce 0.35 g (0.83 mmol, 83%) of 6-ethylsulfanyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 421 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:21]([O:20][C:18]([N:10]([CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: C=C(CBr)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To ethyl 2-(bromomethyl)acrylate (104.4 g) in an acetonitrile (900 ml) solution, di-tert-butyl imino dicarboxylate (122.4 g) and potassium carbonate was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated in vacuo. To the residue, ethyl acetate (1.4 liter) and water (700 ml) were added, and the layers were separated. The organic layer was washed with water (350 ml), dried over sodium sulfate, then concentrated to obtain ethyl 2-{[di(tert-butoxycarbonyl)amino]methyl}acrylate (compound S62a) as a crude product (182.7 g).
Reaction SMILES: [P:1]([O-:37])([O-:36])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:11]2)=[N:6]1)=[O:2].O>CC(O)=O.CC(C)=O>[P:1]([OH:37])([OH:36])([O:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:11]2)=[N:6]1)=[O:2]
Reactant: Cc1cc(-c2ncccc2-c2ccc3nn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)cc3c2)ccc1F
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Cc1cc(-c2ncccc2-c2ccc3nn(COP(=O)(O)O)cc3c2)ccc1F
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Di-tert-butyl[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methyl phosphate (N2, 100 mg, 0.21 mmol) was dissolved in AcOH:H2O (0.5 mL, 4:1) and the clear homogenous solution heated at 60° C. After 1 h, analysis of the reaction mixture LC/MS indicated the 97% consumption of di-tert-butyl[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methyl phosphate leading to the desired product of [5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methyl dihydrogen phosphate (AUC 85%). At this stage heating was discontinued and the reaction mixture was polish filtered by suction. Concentration of the filtrate by rotary evaporator under vacuum (water bath temp 26-28° C.) resulted in a thick viscous liquid which was diluted with acetone (7 mL). The white heterogenous suspension was stirred for 30 min and filtered. The filter cake was washed with acetone (25 mL) and suction dried for a period of 1 h. The collected filter cake was further processed by drying under high vacuum over P2O5 for 24 h to provide [5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methyl dihydrogen phosphate (63 mg, 71%). 1H NMR (DMSO-d6): δ 8.64 (dd, 1H, J=0.5 and 4.7 Hz), 8.51 (s, 1H), 7.86 (d, 1H, J=7.6 Hz), 7.70 (s, 1H), 7.50-7.41 (app m, 3H), 7.00-6.88 (m, 3H), 6.05 (d, 2H, 3JPH=10 Hz), 2.13 (s, 3H). 19F NMR (DMSO-d6): δ −118.60. 31P NMR (DMSO-d6): δ −2.63. LCMS: 97%, MS (m/e) 414 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(OCC)(O[CH2:23][CH3:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([NH:4][C:5]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:23][CH3:24])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2nc3ccccc3nc12
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1c2ccccc2Nc2c(NC(C)=O)cccc21

Procedure:
Scheme 8 provides a synthetic route to a 1-acetamido-N-ethyl phenazine derivative (35). A 3-amino-catechol hydrochloride (30) is reacted with silver oxide and anhydrous sodium sulfate in ethyl acetate to give 3-amino-1,2-quinone (31), which is further reacted in situ with ortho phenylenediamine (32) to give 1-amino phenazine (33). The amino phenazine (33) is acetylated with acetic anhydride in acetic acid to give 1-acetamido phenazine (34). The resulting 1-acetamido phenazine is reacted with diethyl sulfate in the presence of potassium carbonate to give N-ethyl-1-acetamido-phenazine (35)
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH2:33][CH3:34])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH2:33][CH3:34])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: CCOc1ccc(B(O)O)c(Cl)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: CCOc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c(Cl)c1
Yield: 2.4 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-4-ethoxyphenylboronic acid (available from Combi-Blocks Inc.; 100 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-ethoxy-biphenyl-2-carboxylic acid (3 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.48 (s, 2H), 8.33 (d, J=1.9 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 8.09 (dd, J=8.4, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 6.90-7.02 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.36 (t, J=6.9 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:4].[NH2:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22].[I-].[Na+].[O-2].[Mg+2]>CN(C)C=O>[C:21]([C:20]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:19]=1[NH:18][CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:4])(=[O:22])[NH2:23]
Reactant: NC(=O)c1ccc(Cl)cc1N
Reactant: COc1ccc(CCNC(=O)CCl)cc1OC
Agent: [I-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)CNc2cc(Cl)ccc2C(N)=O)cc1OC
Reaction time: 4.5 h
Yield: 68.2 %

Procedure:
To a mixture of 7.73 g of 2-chloro-N-(3,4-dimetoxyphenethyl)acetamide, 5.12 g of 2-amino-4-chlorobenzamide, 13.5 g of sodium iodide and 3.63 g of magnesium oxide was added 30 ml of dimethylformamide and the resulting mixture was stirred at 90° to 100° C. for 4.5 hours. The reaction solution was concentrated under reduced pressure and the residue was extracted with 500 ml of chloroform. The chloroform extract was washed successively with 10% hydrochloric acid, water, a 5% aqueous sodium carbonate solution, a 5% aqueous sodium sulfite solution and water, dried and then concentrated to dryness under reduced pressure. The residue was recrystallized from methanol to obtain 8.01 g of 2-(2-carbamoyl-5-chlorophenylamino)-N-(3,4-dimethoxyphenethyl)acetamide having a melting point of 167.5°-168.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C:10]([O:12][CH3:25])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 96.7 %

Procedure:
To a solution of 15.6 g (49 mmol) (2S)-3-(4-hydroxyphenyl)-2-[(phenylmethoxy)carbonylamino]propanoic acid in 120 mL methanol was added 9.4 g (49 mmol) of p-toluenesulfonic acid monohydrate. The solution was heated to 70 ° C. for 2 h. After solution was cooled to room temperature, the methanol was removed under reduced pressure. The solid obtained was redissolved in 120 mL methylene chloride. The organic solution was then washed with dilute NaHCO3 solution twice and brine. The organic layer was dried with anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The crude mixture was chromatographed on a silica gel column using 40% ethyl acetate in hexanes as the eluent to yield 15.6 g (96%) of white solid as product: 1H NMR (300 MHz, CDCl3) δ7.38-7.30 (m, 5H), 6.93 (d, J=8.41 Hz, 2H), 6.81 (d, J=8.41 Hz, 2H), 5.39 (br s, 1H), 5.24 (d, J=9.29 Hz, 1H), 5.11 (d, J=12.32 Hz, 1H), 5.06 (d, J=12.29 Hz, 1H), 4.61 (m, 1H), 3.71 (s, 3H), 3.06 (dd, J=5.88, 14.06 Hz, 1H), 2.98 (dd, J=5.88, 14.06 Hz, 1H)
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][C:6]=2[C:5](=[O:21])[N:4]([CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:3]1=[O:32].[OH:33]O>CO>[OH:33][C:10]1[CH:9]=[N:8][C:7]2[N:2]([CH3:1])[C:3](=[O:32])[N:4]([CH2:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:5](=[O:21])[C:6]=2[CH:11]=1
Reactant: OO
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Solvent: CO
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of 1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.8 g, 6.3 mmol) in MeOH (100 mL) at 0° C. was added H2O2 (30% in water, 1.4 mL, 10.6 mmol) dropwise over 5 min. The reaction was allowed to warm slowly to RT, stirred for 16 h, quenched with aq. 1M Na2SO3 solution (100 mL), stirred for 15 min then extracted with EA (3×75 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a residue of 6-hydroxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.1 g, 100% yield) as a solid. LCMS: [MH+-THP] 252 and TR=1.740 min. Used without further purification.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1ccccc1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([S:27]([NH:30][CH2:31][CH2:32][OH:33])(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([S:27]([NH:30][CH2:31][CH2:32][OH:33])(=[O:29])=[O:28])[CH:22]=2)[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(NCCO)c1cncc(Br)c1
Product: N#Cc1ccc(OCC(=O)O)c(C#Cc2cncc(S(=O)(=O)NCCO)c2)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 5-bromo-N-(2-hydroxyethyl)pyridine-3-sulfonamide (Intermediate 31), the title compound was obtained as a yellow solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][CH:13]([SH:17])[CH:14]([SH:16])[CH3:15].[CH3:18][C:19](=[CH:21][CH2:22][CH2:23][C:24](=[CH:26][CH:27]=O)[CH3:25])[CH3:20]>C1CCCCC1>[CH3:25][C:24]([CH2:23][CH2:22][CH:21]=[C:19]([CH3:20])[CH3:18])=[CH:26][CH:27]1[S:17][CH:13]([CH3:12])[CH:14]([CH3:15])[S:16]1
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CC(S)C(C)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)=CCCC(C)=CC1SC(C)C(C)S1
Reaction time: 0.5 h

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle and hot plate with magnetic stirring apparatus, is placed 0.5 grams para-toluenesulfonic acid, 5.0 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. Over a period of 30 minutes with stirring is added to the reaction mass 7.6 grams (0.05 moles) of citral having the structure: ##STR23## After the citral is added, the reaction mass is heated to reflux and refluxed (with removal of water of reaction) over a period of 9 hours. At the end of the 9 hour period, the reaction mass is cooled and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated sodium chloride solution and then dried over anhydrous sodium sulfate, filtered and distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29](O)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]([NH:13][C@@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C@H:9]([CH2:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:30])[CH2:10]2)=[O:15])=[N:17]1)([CH3:27])[CH3:26]
Reactant: C1COCCN1
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)N3CCOCC3)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 1 of Example 13) and morpholine.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].OO.C(O)(=[O:32])C>C(Cl)Cl>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[NH:18][N:19]=[N:20][N:21]=3)=[CH:15][CH:16]=2)=[O:32])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCCc1c(CSCc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Agent: OO
Solvent: ClCCl
Product: CCCc1c(CS(=O)Cc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 3.8 g. of 5-[4-(4-acetyl-3-hydroxy-2-propylbenzylthiomethyl)phenyl]-tetrazole in 1.5 ml. of 30% hydrogen peroxide, 100 ml. of acetic acid, and 50 ml. of methylene chloride was stirred for 24 hours at room temperature. The solution was evaporated in vacuo and the residue was dissolved in hot isopropyl alcohol. Water was added and the resulting precipitate was recovered by filtration. Recrystallization from isopropyl alcohol gave 0.8 g. of the title sulfoxide, m.p. 112°-116° C. NMR, IR.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:17]1[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1-c1cnn(C)c1
Temperature: 150 °C
Yield: 69.6 %

Procedure:
Step K (1): [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1:1 complex with dichloromethane, 7.0 g, 8.62 mmol) was added to a degassed mixture of 1-bromo-2-methoxy-4-nitrobenzene (20 g, 86.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (23.3 g, 112 mmol), and potassium carbonate (23.6 g, 122 mmol) in DMF (200 mL). The mixture was heated at 150° C. for 18 h. The crude reaction mixture was cooled to rt and filtered through diatomaceous earth (Celite®). The reaction mixture was diluted with EtOAc (200 mL) and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (EtOAc/hexane) to afford 4-(2-methoxy-4-nitrophenyl)-1-methyl-1H-pyrazole (14 g, 70% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([OH:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](=[O:25])[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)CC(O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3,3-dimethyl-butan-1-ol (3.1 g, 8.7 mmol) in dichloromethane (150 mL) was added Dess-Martin periodinane (9.3 g, 22 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h and then quenched with a saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with dichloromethane (50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3,3-dimethyl-butan-1-one (2.5 g, 83%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C19H20N2O3S [M+H]+ 357.45, observed 357.3.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[F:38].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[O:21][C:20]([CH3:22])=[N:19][CH:18]=5)=[C:13]([O:23][CH3:24])[CH:12]=4)=[N:9][N:10]=[C:3]23)=[CH:33][C:32]=1[F:38]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2ccc(Cl)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (200 mg), 4-chloro-3-fluorophenol (73.8 mg), potassium carbonate (199 mg) and DMF (2 mL) was stirred at 100° C. for 30 min, and allowed to cool to room temperature. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (127 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])=[CH:21][CH:20]=1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl>C1COCC1>[F:33][C:34]([F:36])([F:35])[CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)[OH:28]
Reactant: O=Cc1ccccc1-c1ccncc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-c1ccncc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
Tetrabutylammonium fluoride (0.027 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-pyridin-4-yl-benzaldehyde (500 mg, 2.73 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (485 μl, 3.28 mmol) in 5 ml of THF at 0° C. The formed mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 5 ml of 1N HCl and stirred at room temperature overnight. The solvent was evaporated to dryness, 9 ml of 1M sodium carbonate aqueous solution was added, the aqueous phase was extracted with chloroform (3×10 ml), and the combined organic layer was washed with water, dried over MgSO4. The organic solvent was evaporated to give 300 mg of 2,2,2-trifluoro-1-(2-pyridin-4-yl-phenyl)ethanol, yield: 43%.