Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([OH:9])[CH2:4][CH:3]1[Si:5](C)(C)[CH3:6].[CH3:10][C:11]1(O)[CH2:13][CH:12]1[Si](C)(C)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>ClCCl.C(N(CC)CC)C>[CH3:1][C:2]1([O:9][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:4][CH:3]1[SiH2:5][CH2:6][C:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC[Si](C)(C)C1CC1(C)O
Reactant: CC1(O)CC1[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C[SiH2]C1CC1(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
1.6 g (0.010 mole) of a trans isomer, a cis isomer or a trans/cis isomer mixture of 1-methyl-1-hydroxy-2-(trimethylsilyl)cyclopropane, prepared in Section (1), was dissolved in 15 ml of dichloromethane and 23 g of triethylamine was added thereto. The reaction solution was cooled to 0° C., 1.3 g (0.011 mole) of methanesulfonyl chloride was gradually added thereto and the mixture was vigorously stirred for 1 hour. 5 mL of a saturated aqueous NaHCO3 solution was added to the reaction mixture to complete the reaction. An organic layer was separated from the reaction solution, dried over anhydrous magnesium sulfate (MgSO4), and concentrated by distillation of the solvent at a low temperature of 30° C. or less. Although the concentrate may be used directly without any further purification, it was purified over silica gel again to obtain 1.74 g (7.3 mmole, yield: 74%) of 1-methyl-1-(methanesulfonyloxy)-2-(trimethylethylsilyl)cyclopropane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: Nc1cc(F)ccc1S
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2ccc(F)cc2N)c1
Yield: 88.2 %

Procedure:
Following General Procedure A, the title compound (750 mg, 88%) was prepared from 2-amino-4-fluorobenzenethiol (417 mg, 2.92 mmol) and methyl 3-(bromomethyl)benzoate (666 mg, 2.92 mmol), K2CO3 (1.21 g, 8.75 mmol) in DMF (10 ml).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:17])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:18]([O:20]C(Cl)=O)C.Cl>N1C=CC=CC=1>[CH3:17][N:3]1[C:2]2[NH:1][C:18](=[O:20])[C:16]3[C:11]([C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: CCOC(=O)Cl
Reactant: Cn1c(N)c(-c2ccccc2)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c2ccccc2c2c3ccccc3c(=O)[nH]c21
Temperature: 75 °C
Yield: 46.3 %

Procedure:
To a solution of 2.59 g (0.01 mole) of 2-amino-1-methyl-3-phenylindole in 15 ml of pyridine, 2.84 g (0.026 mole) of ethylchlorocarbonate is added. The reaction mixture is heated to 75° C. for about 2 hours, allowed to cool and 2.84 g more of ethylchlorocarbonate is added. The reaction mixture, heated for a further 3 hours, is then poured into about 200 ml of aqueous 10% HCl solution, the product is extracted with ethyl ether and the organic layer washed with water. The resulting etheral solution, dried over sodium sulfate, is concentrated to a volume of about 30 ml, 20 ml of hexane is added and the solution is once again concentrated to 35 ml. The product, 2.3 g of 1-methyl-3-phenylindole-2-carbamic acid ethyl ester, is thus crystallized; (m.p. 159°-161° C.; yield 80%). A quantity of 1.4 g of the so obtained carbamate is heated to 270° C. for 15 minutes and the residue crystallized from dimethylformamide, yielding 1.15 g of 7-methylindolo[2,3-c]isoquinolin-5(6H)-one. M.p. 350° C. (with decomposition). Yield 95%.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:11][C@H:12]([C:14]([C:16]1([NH2:35])[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH3:33])[C:17]1=[O:34])=[O:15])[CH3:13]>>[CH:6]1([CH:2]([OH:1])[C:3]([NH:11][C@H:12]([C:14]([C:16]2([NH2:35])[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[N:18]([CH3:33])[C:17]2=[O:34])=[O:15])[CH3:13])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C(O)C(O)C1CCCC1
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using (±)-α-hydroxy-cyclopentylacetic acid (Example P) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound was prepared as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][OH:21])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][O:21][C:25](=[O:26])[NH:24][CH2:22][CH3:23])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(Oc3ccccc3CO)cn12
Reactant: CCN=C=O
Product: CCNC(=O)OCc1ccccc1Oc1ccc2nnc(C(C)C)n2c1
Temperature: 60 °C
Yield: 48 %

Procedure:
A suspension of [2-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-phenyl]-methanol (28 mg, 0.1 mmol) and ethyl isocyanate (14 μL, 0.2 mmol) was heated at 60° C. for 18 hours. The reaction was then cooled and concentrated in vacuo to an oil. The crude was purified by flash chromatography (eluting with 2% methanol/ethyl acetate), followed by suspension in 7:3 hexane:ethyl acetate. The solid was filtered to give the title compound as a white solid (17 mg, 48%) LCMS (m/z) 355.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](OCC)=[O:11].[Na].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CCOCC.C(O)C>[CH2:15]([C:9]1([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:10]1=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Reactant: Nc1ccccn1
Reactant: Fc1ccc(CBr)cc1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: O=C1N=C2C=CC=CN2C1(Cc1ccccc1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1 %

Procedure:
630 mg (6.7 mmol) of 2-aminopyridine and 1.72 g (6.7 mmol) of ethyl 2-bromo-3-phenylpropionate were refluxed under heating in 50 ml of ether for 12 hours. The reaction mixture was allowed to cool to room temperature and ether was removed by decantation. The residue was added with and dissolved in 30 ml of absolute ethanol, which was added to a solution of 150 mg (6.5 mmol) of sodium in 10 ml of absolute ethanol and stirred at room temperature for one hour. Then, 0.8 ml (6.5 mmol) of 4-fluorobenzylbromide was added and stirred for overnight. The reaction mixture was added to ice water and extracted with methylene chloride. Then, the solvent was removed under reduced pressure and the residue was purified with silica gel column chromatography, thus obtaining 22 mg (yield: 1%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([NH2:11])=[O:10].C(=O)([O-])O.[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:18][CH2:19][C:20]([N:6]1[CH2:5][C:4](=[O:7])[N:3]([CH2:8][C:9]([NH2:11])=[O:10])[C:2]1([CH3:12])[CH3:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An ice cold solution of 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (1 g) in 20 ml of saturated solution of sodium hydrogen carbonate was added with an additional 2 g of sodium hydrogen carbonate and treated dropwise with chloroacetyl chloride (3 ml). After 30 minutes of stirring the precipitate was collected and crystallized from methanol, to give 3-(2-chloroacetyl)-2,2-dimethyl-5-oxo-1-imidazolidineacetamide (0.53 g) as a white powder m.p. 214°-216° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:16]([CH3:23])[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].[Br-:24].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S(=O)(=O)(O)O>CO.C1COCC1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>[Br:24][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([N:16]([CH3:23])[C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[CH:7]=[C:8]([S:10]([F:14])([F:15])([F:13])([F:12])[F:11])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1cc(N(C)C(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)C(F)(F)F)c1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 164.6 %

Procedure:
N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide (1.03 g) was dissolved in a mixture of methanol (20 ml) and THF (20 ml). Phenyltrimethylammonium tribromide (1.05 g) was added while stirring. After stirring at RT for 5 h, the mixture was left to stand overnight, then further phenyltrimethylammonium tribromide (100 mg) was added and the mixture was heated to 60° C. for 2 h. After cooling, the reaction mixture was added to 2N sulfuric acid and stirred for 10 min. Then the aqueous phase was extracted three times with EA. The combined organic phases were dried over magnesium sulfate and, after filtering off the desiccant, dried under reduced pressure. 1.2 g of the title compound were obtained, which had sufficient purity for the next reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([O:27]C)[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([OH:27])[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(F)cc3)nn2n1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(O)ccc23)cc1
Temperature: 200 °C
Yield: 38.4 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine (321 mg) and pyridine hydrochloride (1.4 g) was heated to and at 200° C. in a sealed vessel (Reactivial™) for 3 hours. The cooled reaction was poured into water (20 ml), and extracted with ethyl acetate (3×30 ml). The combined organic extracts dried (MgSO4), filtered and evaporated in vacuo to give a solid which was triturated with diethyl ether to give the title compound as a beige solid (119 mg). Tlc, SiO2, Rf 0.07 (1:2 cyclohexane/ethyl acetate), detection UV. MH+ 384.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1)[C:22]([CH3:24])([CH3:23])[CH:21]2[OH:25])=[O:20])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cncc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cncc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
To a mixture of 4-[(5-bromo-pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (33.8 g, 100 mmol) and Ytterbium(III) triflate hydrate (6.2 g, 10 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (9.2 mL, 100 mmol) and water (1.8 mL, 100 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(5-bromo-pyridin-3-yl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (42.2 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H21BrN2O3 (M+H)+: 406.29, observed: 405.0 & 406.9.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[CH:4]=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[CH3:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]CC(O)=O.[C:32](#N)C>[N+]([O-])([O-])=O.[Ag+].O.CC(OC)(C)C>[CH2:10]([C:5]1[C:6](=[O:9])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3](=[O:11])[C:4]=1[CH3:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Reactant: CC#N
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCC=CCC=CCCCCCCCC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a 250 ml round bottom flask was added 2,3,5-trimethyl-[1,4]benzoquinone (1.50 g, 9.98 mmole), linolenic acid (2.94 g, 10.4 mmole), and silver nitrate (1.83 g, 10.8 mmole) in a 1:1 mixture of water and acetonitrile (100 ml). The solution was heated to 70° C. under argon and an aqueous solution of K2S2O8 (2.55 g, 11.5 mmole in 50 ml water) was added dropwise to the homogenous solution over 2.5 hours using a syringe pump. The reaction mixture was allowed to stir an additional 30 minutes at 70° C., then cooled to room temperature. To the mixture was added MTBE (200 ml) and water (100 ml). The organic layer was separated and washed with saturated NaHCO3 (100 ml), then brine (2×200 ml). The MTBE solution was dried over sodium sulfate then concentrated to a yellow oil. The crude product, which contained residual unreacted starting quinone by TLC, was further purified by silica gel chromatography (120 g, 0-30% EtOAc:heptane) to give pure 2-heptadeca-8,11-dienyl-3,5,6-trimethyl-[1,4]benzoquinone (210; 0.474 g, 12.3%) as a yellow oil. 1H NMR (400 MHz; d6-DMSO; ppm): 5.36-5.26 (m, 4H), 2.73 (t, J=5.6 Hz, 2H), 2.42-2.38 (m, 2H), 2.02-1.93 (m, 4H). 1.95 (s, 3H), 1.93 (s, 6H). 1.34-1.22 (m, 16H), 0.84 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)\[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl.[NH2:59][CH:60]1[C:85](=[O:86])[N:62]2[C:63]([C:69]([O:71][CH:72]([C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)=[O:70])=[C:64]([CH2:67][Cl:68])[CH2:65][S:66][C@H:61]12>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:18][CH:19]=1)\[C:12]([NH:59][CH:60]1[C:85](=[O:86])[N:62]2[C:63]([C:69]([O:71][CH:72]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)=[O:70])=[C:64]([CH2:67][Cl:68])[CH2:65][S:66][C@H:61]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To an ice-cooled solution of (Z)-2-t-butoxycarbonylmethoxyimino-2-(tritylaminothiazol-4-yl)acetic acid (IVg') (2.71 g, 5 mmoles) in CH2Cl2 (20 ml) was added PCl5 (1.24 g, 6 mmoles), and the solution was stirred for 20 minutes at room temperature. The acid chloride solution was added under ice-cooling to a solution of the silylated 7-ACA ester, which was prepared by adding bis(trimethylsilyl)acetamide (BSA, 3.7 ml, 15 mmoles) to a stirred suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (V) (2.25 g, 5 mmoles) in CH2Cl2 (20 ml). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 ml) and washed with an aqueous NaHCO3 solution and water. After drying over Na2SO4, the solution was evaporated and the residue was purified by silica gel chromatography (Wako gel C-200, 60 g). The desired fractions, eluted by CHCl3, were combined and concentrated to give 3.16 g (67%) of the title compound VIg'.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:53])[C:31]4[C:36]([C:37]=3[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]5OC(C)(C)C(C)(C)[O:45]5)[CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:12]=3)[C:3]=12.Cl.C(Cl)Cl.O>CC#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:53])[C:31]4[C:36]([C:37]=3[C:38]3[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=3)[CH:44]=[O:45])=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:12]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(C=O)c1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Reaction time: 8 h
Yield: 0.1 %

Procedure:
3-(1-(4-amino-3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1H-isochromen-1-one (intermediate F5, 654 mg, 0,919 mmol) was dissolved in MeCN, then 2M HCl was added and the mixture was stirred overnight. DCM (25 ml) and water (25 ml) were added then phases were separated and the aqueous phase was washed again with 10 ml of DCM. The collected organic phases were concentrated to give the title compound (490 mg, 0.801 mmol, 87% yield) as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[N:3]=1.S1C(C2C=C(N)C=C3C=2N[N:23]=C3)=CC2C=CC=CC1=2.CCN(CC)CC>COCCOC>[CH3:11][S:8]([C:4]1[N:3]=[C:2]([NH2:23])[CH:7]=[CH:6][N:5]=1)(=[O:10])=[O:9]
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a mixture of 4-chloro-2-methanesulfonyl-pyrimidine (2.54 g, 13.2 mmol) in DME (20 mL) was added a mixture of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 1.95 g, 7.35 mmol) and Et3N (1.43 mL, 10.3 mmol) in DME (160 mL). The reaction mixture was stirred at room temperature for about 16 hours then filtered, then filtrate was adsorbed onto alumina. The mixture was purified by flash column chromatography over alumina using CH2Cl2/MeOH (99:1) as an eluent to yield the initial crop of product. A second crop was obtained by triturating the alumina in CH2Cl2/MeOH (8:2) and combined with the first to afford 7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-(2-methanesulfonyl-pyrimidin-4-yl)-amine (1.09 g, 36% yield): LC/MS (method e) Rt 1.8 min; m/z (ESI−): (M−H)+ 419.9.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[O:26]C(=O)O[C:23]2=O)=[CH:18][CH:17]=1.C[O-].[Na+].CO>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:26])[C:23]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: O=C1OC(=O)C(c2ccc(F)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1nc(C(O)c2ccc(F)cc2)nc2cc(C(F)(F)F)ccc12
Temperature: 50 °C

Procedure:
To 2-amino-4-(trifluoromethyl)benzamide (840 mg, 4.16 mmol), in THF (15 mL) was added 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione from Example 16 (1225 mg, 6.24 mmol) and the mixture was heated at 50° C. for 4 h. The solvent was evaporated and the crude 2-(2-(4-fluorophenyl)-2-hydroxyacetamido)-4-(trifluoromethyl)benzamide was dissolved in MeOH (10 mL), added 0.5 M sodium methoxide in MeOH (2.5 mL, 1.25 mmol) and the reaction mixture was heated at 50° C. for 1 h. The solvent was evaporated and then 1N hydrochloric acid was added. The mixture was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo to afford crude 2-((4-fluorophenyl)(hydroxy)methyl)-7-(trifluoromethyl)quinazolin-4-ol, which was used in next reaction without purification. LC-MS (ESI) m/z 339 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].[C:17](OCC)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:10]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:7]=1)(=[O:12])[CH3:11]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(CO)ccn1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(COC(C)=O)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
(2-Aminopyridin-4-yl)methanol (5.0 g, 40 mmol) was suspended in pyridine (20 mL), acetic anhydride (11 mL, 120 mmol) was added thereto under ice-cooling, and the mixture was stirred for 5 hours at room temperature. Ethyl acetate (150 mL) was added to the reaction mixture, and then the mixture was washed with water (150 mL), saturated aqueous sodium hydrogen carbonate solution (150 mL) and brine (150 mL) successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was filtered off with hexane, then dried under reduced pressure at 40° C. to give 6.7 g of the title reference compound as a colorless solid. (Yield 79%)