Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[C:12]3[N:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:22]=[C:12]3[N:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccn2nc(-c3ccc(OC)cc3)cc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3nc(C(=O)O)ccn3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (485 mg; 1.63 mmol) in THF (10 mL) and water (3 mL) was added lithium hydroxide hydrate (206 mg; 4.9 mmol) and the mixture was stirred at room temperature for 3 hours. Concentrated hydrochloric acid was then slowly added (ca. 0.5 mL) until pH reached 1 and the mixture was concentrated under reduced pressure. The resulting solid was dissolved in methylene chloride, filtered, concentrated and dried under high vacuum. The crude product was used directly in the next step. LCMS m/z 270.1 (M+H)+, ret. time=2.20 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[O:28])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18]
Reactant: Fc1cc2c(N3CCNCC3)ccnc2cc1Cl
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)c(F)cc23)CC1

Procedure:
7-Chloro-6-fluoro-4-(piperazin-1-yl)quinoline (0.36 g, 1.35 mmol) and 4-fluorophenyl isocyanate (171 μL, 1.5 mmol) in THF (10 mL) are reacted according to method C yielding the product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10]O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([CH3:12])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22].[NH2:10][N:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[N:5][C:4]1=[NH2+:9]
Reactant: Cc1cc(C)nc(N)n1
Reactant: NO
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)n(N)c(=[NH2+])n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4,6-Dimethyl-pyrimidin-2-ylamine (25 g, 200 mmol) in 400 mL of CH2Cl2 was added dropwise a solution of hydroxylamine-2,4,6-Trimethyl-benzenesulfonate (105 g, 488 mmol) in 300 mL of CH2Cl2 at 0° C., and the mixture was stirred at 0° C. for 1 hour and filtered. The solid collected was washed with CH2Cl2 (100 mL) to give 1-Amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 2,4,6-Trimethyl-benzenesulfonate (40 g, yield: 62%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)[CH:9]=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1.[CH3:43]C1N=COC=1C1C=C(C=CC=1)N>>[CH3:43][C:4]1[N:3]=[CH:2][O:1][C:5]=1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]5[S:38][CH:39]=[CH:40][CH:41]=5)[CH:31]=[CH:32][CH:33]=4)=[N:21][N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=34)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: Cc1ncoc1-c1cccc(N)c1
Product: Cc1ncoc1-c1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Temperature: 25 °C

Procedure:
The title compound was synthesized from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (see Example 2, step B) and 3-(4-methyl-1,3-oxazol-5-yl)aniline following the protocol described in Example 2, step E. The reaction formed a suspension on cooling to rt. The suspension was filtered and provided the title compound in 81% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:10])=[O:9].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].C(N(CC)CC)C>CN(C=O)C>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([N:11]2[C:22](=[O:23])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH:13]=[N:14][C:15]=1[O:20][CH3:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(NS(=O)(=O)c2ccccc2N)cnc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N2C(=O)Nc3ccccc3S2(=O)=O)cnc1OC
Yield: 49 %

Procedure:
The title compound (257 mg, 0.77 mmol) was prepared from 2-amino-N-(5,6-dimethoxypyridin-3-yl)benzenesulfonamide (486 mg, 1.57 mmol), 1,1′-carbonyldiimidazole (1.02 g, 6.29 mmol) and triethylamine (0.44 mL, 3.14 mmol) in DMF (3 mL) using the methods of (IntA14), step 3.
Reaction SMILES: C(OCOC([C:9]1[C:14]([F:15])=[C:13]([CH3:16])[CH:12]=[CH:11][C:10]=1[B:17]1[O:21][C:20]([CH3:23])([CH3:22])C(C)(C)[O:18]1)(C)C)C.Cl>C1COCC1>[F:15][C:14]1[C:9]2[C:20]([CH3:22])([CH3:23])[O:21][B:17]([OH:18])[C:10]=2[CH:11]=[CH:12][C:13]=1[CH3:16]
Reactant: CCOCOC(C)(C)c1c(B2OC(C)(C)C(C)(C)O2)ccc(C)c1F
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(c1F)C(C)(C)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of the crude compound 2-(2-(2-(ethoxymethoxy)propan-2-yl)-3-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.17 g, 14.7 mmol) in THF (147 mL) was added 6 N HCl (147 mL). The reaction mixture was stirred at room temperature overnight, and the resulting mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried over with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE-EA (10:1) to give 4-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (1.52 g, 53.8% yield over 2 steps) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.339 (d, J=7.5 Hz, 1H), 7.200 (t, J=6.5 Hz, 1H), 5.652 (s, 1H), 2.330 (s, 3H), 1.642 (s, 6H) ppm.
Reaction SMILES: [Li+].[BH4-].[CH3:3][OH:4].C(OC(=O)C(C)(C)C[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]([C:33](OCC)=[O:34])([CH3:32])[CH3:31])[CH:24]=2)[S:22][CH2:21][CH2:20][CH2:19][S:18]1)C.[NH4+].[Cl-]>C(Cl)Cl>[OH:34][CH2:33][C:30]([CH3:31])([CH3:32])[CH2:29][C:25]1[CH:24]=[C:23]([C:17]2([C:12]3[CH:11]=[C:16]([CH2:11][C:12]([CH3:17])([CH3:13])[CH2:3][OH:4])[CH:15]=[CH:14][CH:13]=3)[S:18][CH2:19][CH2:20][CH2:21][S:22]2)[CH:28]=[CH:27][CH:26]=1
Reactant: CO
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C2(c3ccccc3CC(C)(C)C(=O)OCC)SCCCS2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Product: CC(C)(CO)Cc1cccc(C2(c3cccc(CC(C)(C)CO)c3)SCCCS2)c1
Temperature: 25 °C
Yield: 170.4 %

Procedure:
To a suspension of LiBH4 (0.78 g, 35.8 mmol) in CH2Cl2 (55 mL) was added methanol (1.04 g, 32.5 mmol) at room temperature. After the addition of 229 (6.5 g, 12.3 mmol), the reaction mixture was heated to reflux for 6 h. After cooling to room temperature, saturated aqueous NH4Cl solution (20 mL) and CH2Cl2 (15 mL) were added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford 230 (4.66 g, 85%) as an oil. 1H NMR (CDCl3): δ 7.42 (s br., 2H), 7.17 (m, 4H), 6.97 (m, 2H), 3.63 (s, 4H), 3.16 (s, 4H), 2.69 (m, 2H), 2.47 (m, 4H), 1.88 (m, 2H), 0.75 (s, 12H). 13C NMR (CDCl3): δ 142.39, 139.18, 131.69, 129.88, 128.05, 127.01, 71.12, 44.89, 43.74, 36.70, 29.63, 24.22.
Reaction SMILES: [OH:1]/[CH:2]=[C:3](/[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)\[C:4](OC)=O.[NH2:18][C:19]([NH2:21])=[S:20]>CO>[N:9]1([CH2:8][C:3]2[C:2](=[O:1])[NH:18][C:19](=[S:20])[NH:21][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: COC(=O)/C(=C\O)Cn1ccc2ccccc21
Reactant: NC(N)=S
Solvent: CO
Product: O=c1[nH]c(=S)[nH]cc1Cn1ccc2ccccc21
Temperature: 50 °C
Yield: 70.5 %

Procedure:
To a solution of methyl (2Z)-3-hydroxy-2-(1H-indol-1-ylmethyl)-2-propenoate (1.138 g, 4.92 mmol) in MeOH (20 mL) was added thiourea (1.0 g, 13.14 mmol) in one portion. The mixture was heated at 50° C. overnight. Purification via reverse phase flash chromatography then afforded the title compound (0.93 g, 3.47 mmol, 70.5% yield). LCMS: rt=2.28 min, [M+H+]=258
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([C:22]3[N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][C:23]=3[CH:37]=[O:38])[CH2:12][C:13]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][O:19][C:15]=4[CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(=O)(=O)([OH:41])N.Cl([O-])=O.[Na+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([C:22]3[N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:24][C:23]=3[C:37]([OH:41])=[O:38])[CH2:12][C:13]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][O:19][C:15]=4[CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCn1c(-c2ccccc2)nc(C=O)c1N(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: CCCCn1c(-c2ccccc2)nc(C(=O)O)c1N(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde 213 (263 mg, 0.5 mmol) in actone (10 mL) and water (5 mL) is added sulfamic acid (107 mg, 1.1 mmol) at room temperature and the mixture is stirred for 30 min. Sodium chlorite (63 mg, 0.7 mmol) is added and the mixture is stirred for additional 30 men at room temperature. Evaporation of most actone and the residure is extracted with chloroform. The organic phase is washed with water, brine and dried over sodium sulfate. The solvent is removed aid the product is dried in vacuo. Yield: 281 mg; LC-MS (MH+): 542.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCc1ccccn1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCCc1ccccn1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(2-aminoethyl)pyridine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (CF3CO2D) δ 8.84 (1H, d, J=6 Hz), 8.79 (1H, s), 8.71 (1H, t, J=8 Hz), 8.55 (1H s), 8.20 (1H, d, J=8 Hz), 8.11 (1H, t, J=7 Hz), 7.35 (2H, dd, J=8.6, 5.3 Hz), 7.20 (2H, t, J=8.6 Hz), 4.48 (2H, s), 4.26 (2H, t, J=7 Hz), 3.75 (2H, t, J=7 Hz); ES+ MS: 4419 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 244.1, 80 mg, 0.167 mmol), pyrimidin-5-ylboronic acid (41.5 mg, 0.335 mmol), Pd(PPh3)2Cl2 (11.76 mg, 0.017 mmol) and Na2CO3 (71.0 mg, 0.670 mmol) were added to a MW vial and treated with a mixture of DME (710 μL), water (203 μL) and EtOH (101 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 10 min, diluted with MeOH (1 mL) and DCM (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 69.8 mg, 0.1 mmol). The solvent was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/(MeOH-1% NH4OH), from 2% to 12% (MeOH-1% NH4OH). Product was further purified by preparative SFC (Column DEAP, from 25% to 30% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.90 min, m/z=476.9 [M+H]+, m/z=521.0 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.75 (d, J=10.39 Hz, 2H) 3.27 (dd, J=10.33, 3.61 Hz, 2H) 3.88 (br. s, 2H) 5.09 (d, J=3.18 Hz, 2H) 6.97 (d, J=8.93 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.20 Hz, 1H) 8.86 (s, 2H) 9.17 (s, 1H) 10.11 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:27][C:28]1[C:33]([C:2]2[CH:3]=[C:4]([C:8]3([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)c1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Product: CC(C)c1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)ccn1
Yield: 42 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-isopropylpyridin-4-yl)-1H-isoindol-3-amine (Example 113) as described in Example 67 Scheme #10, D in 42% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.29 (d, J=5.30 Hz, 1 H), 8.19-8.11 (m, 1 H), 7.97-7.90 (m, 1 H), 7.82-7.70 (m, 2 H), 7.49-7.27 (m, 7 H), 7.18-7.11 (m, 1 H), 7.05 (dd, J=5.31, 1.77 Hz, 1 H), 6.84 (br s, 2 H), 2.93-2.77 (m, 1 H), 1.08 (d, J=6.82 Hz, 6 H); MS (ESI) m/z 423 [M+1]+.
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:13]3=[N:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)S2)=CC=1)C1C=CC=CC=1>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CCC(=O)C4CCCCC4)cnc32)cc1
Agent: O=C([O-])O
Agent: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ccc(C4CCCCC4)n23)cc1
Reaction time: 6 h
Yield: 42.4 %

Procedure:
To a solution of 1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-one (0.050 g, 0.12 mmol) in THF (2 mL) was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.071 g, 0.13 mmol, TCI). After about 6 h at ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and NaHCO3 (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of 40-90% EtOAc in heptanes to provide 8-cyclohexyl-3-tosyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine as a tan solid (0.020 g, 42%). LC/MS (Table 2, Method a) Rt=3.39 min; MS m/z: 394 (M+H)+.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[C:16]([C:20]1[CH:21]=[C:22]([CH2:27][CH:28]([NH2:34])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[OH:26])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[C:16]([C:20]1[CH:21]=[C:22]([CH2:27][CH:28]([NH:34][C:6](=[O:8])[CH:2]([NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]([CH3:4])[CH3:5])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[OH:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)c1cc(CC(N)c2nccs2)ccc1O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a solution of Boc-Val-OH (890 mg, 4.09 mmol), 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamine (1.03 g, 3.73 mmol) and CMPI (653 mg, 1.05 mmol) in THF (10 ml), TEA (1 ml) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (1.88 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:32])[C@@H:24]([NH2:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:33])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:51][C:52]([CH3:54])=[O:53])[C:5]([C@@:7]1([CH3:50])[C@H:12]([C@@H:13]2[O:34][C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])[C@:11]2([O:45][C:46]([CH3:48])=[O:47])[CH2:43][O:44][C@@H:10]2[CH2:9][C@@H:8]1[OH:49])=[O:6].C([O-])(O)=O.[Na+].[C:60](Cl)(=[O:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.CCCCC>CCOC(C)=O.C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:32])[C@@H:24]([NH:31][C:60]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)=[O:67])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:33])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:51][C:52]([CH3:54])=[O:53])[C:5]([C@@:7]1([CH3:50])[C@H:12]([C@@H:13]2[O:34][C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])[C@:11]2([O:45][C:46]([CH3:48])=[O:47])[CH2:43][O:44][C@@H:10]2[CH2:9][C@@H:8]1[OH:49])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](N)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
In a 10 ml round-bottom flask, 0.031 g (0.041 mmol, 1.0 eq) of N-debenzoyl-paclitaxel were dissolved in 1.25 ml of AcOEt. The clear yellow solution was added with 1.25 ml of a NaHCO3 aqueous saturated solution. 7.1 ml (0.064 mmol, 1.5 eq) of benzoyl chloride were dropped into the resulting diphasic mixture, under strong magnetic stirring. The progress of the reaction was checked by TLC (SiO2, CHCl3/CH3OH 9:1). After disappearance of the starting product, a single spot having Rf=0.50 was observed. The reaction mixture was diluted with AcOEt. The organic phase was separated from the aqueous one, which was extracted with AcOEt (three extractions). The combined organic phases were dried over MgSO4, filtered and concentrated. The crude (0.037 g) was dissolved in a 1:1 mixture of CH2Cl2/ethyl ether, then n-pentane (0.030 g, 0.035 mmol, 86%) was added to precipitate paclitaxel, having the spectroscopic characteristics reported in literature.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:9][C:8]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Br)cc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(3-cyclopentyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: CC(OC(N1CCN(C(NC2(C(OCC3C=CC=CC=3)=O)CCCCC2)=O)CC1)=O)(C)C.[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:46][C:47]2([C:53]([O:55]CC3C=CC=CC=3)=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>>[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:46][C:47]2([C:53]([OH:55])=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Agent: CC(C)(C)OC(=O)N1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)CC1
Product: CC(=O)Nc1ccc(S(=O)(=O)NC2(C(=O)O)CCCCC2)cc1
Yield: 95.7 %

Procedure:
The same procedure as in Reference Example 8 was repeated except that the phenylmethyl 1-[N-[4-(2-methyl-2-propyloxycarbonyl)piperazine-1-carbonyl]amino]cyclohexanecarboxylate was replaced by 11.5 g of said phenylmethyl 1-[N-(4-acetylaminobenzenesulfonyl)amino]cyclohexanecarboxylate, whereby 8.7 g of the captioned 1-[N-(4-acetylaminobenzenesulfonyl)amino]cyclohexanecarboxylic acid was obtained in a yield of 97%.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[N:4]1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[N:4]=1)#[N:9]
Reactant: N#Cc1ccn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 58.8 %

Procedure:
1.00 g of 1-(chloromethyl)-3-cyano-1H-pyrazole and 1.15 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 1.96 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.11 g of [(3-cyano-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (9), hereinafter) shown by below formula.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>C(O)CCC>[F:10][C:7]1[CH:6]=[C:3]2[C:4]([NH2:5])=[N:13][NH:12][C:2]2=[N:9][CH:8]=1
Reactant: NN
Reactant: N#Cc1cc(F)cnc1Cl
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2ncc(F)cc12
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol), and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2×) and Et2O (2×) and dried in vacuo overnight to give compound 5 (44 g, 88%) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, 1H); 8.35 (dd, 1H); 12.02 (s, 1H).