Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[C:28]4[N:30]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:31]=[C:32]([CH2:33][CH3:34])[C:27]4=[CH:26][N:25]=3)[CH2:20][CH2:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(=O)C.[OH-].[OH-].[Pd+2].Cl[Pd]Cl>[NH:14]1[CH2:15][CH:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:29]=[C:28]4[N:30]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:31]=[C:32]([CH2:33][CH3:34])[C:27]4=[CH:26][N:25]=3)[CH2:22][CH2:23]2)[CH2:17]1
Reactant: CCc1nn(-c2ccccc2)c2nc(N3CCN(C4CN(C(c5ccccc5)c5ccccc5)C4)CC3)ncc12
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nn(-c2ccccc2)c2nc(N3CCN(C4CNC4)CC3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 100-mL round-bottom flask was purged, flushed and maintained with a hydrogen atmosphere, then, was added a solution of 6-(4-(1-benzhydrylazetidin-3-yl)piperazin-1-yl)-3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (400 mg, 0.76 mmol, 1.00 equiv) in acetic acid (20 mL) at room temperature. To the resulting mixture was then added Pd(OH)2 (50 mg, 0.4 mmol, 0.5 equiv), in portions at room temperature, followed by PdCl2 (50 mg, 0.28 mmol, 0.37 equiv), in portions at room temperature. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue (250 mg) was purified by Prep-HPLC with the following conditions (Gilson Pre-HPLC): Column, SHISEIDO, CAPCELL PAK C18, 20 mm ID*250 mm, 5 u; mobile phase, methanol/H2O; Detector, UV 254 nm, to yield 6-(4-(azetidin-3-yl)piperazin-1-yl)-3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid.
Reaction SMILES: COC(=O)[C:4]1[C:9](C)=[CH:8][C:7](C2C=CC=C(C(F)(F)F)C=2)=[N:6][C:5]=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.N1C=CC=C(B(O)O)C=1>>[CH3:44][C:28]1[CH:27]=[C:26]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:25]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[N:30][C:29]=1[C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1)=[O:32]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: OB(O)c1cccnc1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cccnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with pyridine-3-yl-boronic acid to give the title compound as colorless oil. MS: 495.3 (MH+).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Cl:11][C:10]1[C:4]2[N:3]=[C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([C:17]([F:31])([F:16])[F:30])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)[NH:6][C:5]=2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Product: FC(F)(F)c1cc(Cl)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (69.3 mg, 0.3 mmol) reacted with 1-(3-trifluoromethylpyridin-2-yl)piperazine (128 mg, 0.5 mmol, Fluorochem) under the conditions of Example 1d to give the title compound as a white solid. M.p. 204° C. MS (ESI, pos. ion) m/z: 450 (M+1).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12](=O)[C:11]=3[C:21](O)=[O:22])=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:26])=O>O1CCCC1>[Cl:26][C:12]1[C:11]2[C:21](=[O:22])[C:6]3[C:5]([C:10]=2[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[CH:4][C:3]1[O:2][CH2:1][O:9][C:8]=1[CH:7]=3
Reactant: O=C(O)c1c(-c2ccc3c(c2)OCO3)c2ccccc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1c2cc3c(cc2-c2c1c(Cl)nc1ccccc21)OCO3
Temperature: 90 °C
Yield: 59.9 %

Procedure:
A mixture of 1,2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline carboxylic acid obtained in reference example 1 (10 g, 32.3 mmol) and phosphorous oxychloride (100 ml, 1.07 mol) was refluxed with heat for 4 hours. The reaction mixture was distilled to dryness and washed with n-hexane several times. To the residue obtained was added 50 g of polyphosphoric acid, and the mixture was heated at 90° C. for 2 hours. The reaction mixture was poured into ice water to filtrate a crystal precipitated. The crystal obtained was dissolved in tetrahydrofuran to filter off undissolved substances,and purified by silica gel column chromatography (eluent: chloroform) to give 6.0 g (yield 59.9%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN1C(=O)CCC1>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(N)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 5.0 g (19.3 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 3.94 g (21.2 mmol) N-Boc-piperazine using 2.94 mL (21.2 mmol) triethylamine in 30 mL NMP. Work up is performed by addition of 500 mL water to the reaction mixture and stirring for 30 min. The solid material is filtered off, washed with water (50 mL three times) yielding 7.25 g (17.7 mmol) of the desired product with sufficient purity.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[N:44]=[C:45]([C:51](=[O:53])[CH3:52])[C:46]([O:48][CH2:49][CH3:50])=[O:47]>O1CCCC1>[CH3:1][C@H:2]1[CH2:7][C@H:6]([O:8]/[N:44]=[C:45](/[C:51](=[O:53])[CH3:52])\[C:46]([O:48][CH2:49][CH3:50])=[O:47])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(=N\O[C@H]1C[C@H](C)CC[C@H]1C(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1R, 2S, 5R-)-(-)-Menthol (7.3 g, 45 mmol) and triphenylphosphine (8.65 g, 33 mmol) in dry tetrahydrofuran under argon were cooled in an ice bath and diethyl azodicarboxylate (5.2 ml, 5.7 g, 33 mmol) in dry tetrahydrofuran (30 ml) was added dropwise over 15 minutes. The ice bath was removed and ethyl 2-hydroxyimino-3-oxobutyrate (4.77 g, 33 mmol) in dry tetrahydrofuran (30 ml) was added dropwise over 20 min. The mixture was stirred at room temperature for 18 h and then warmed at 50° C. for 1.5 h. The mixture was cooled and the tetrahydrofuran was removed by evaporation in vacuo. Toluene was added to the residue and evaporated in vacuo. The residual yellow oil was chromatographed on silica gel, eluting with carbon tetrachloride, followed by hexane, followed by hexane/ethyl acetate mixtures. After evaporation of relevant fractions the title compound was obtained as an oil, νmax (CH2Cl2) 2945, 2920, 2860, 1740, 1685, 1365, 1315, 1235, 1070 and 1005 cm-1 ; δ (250 MHz, CDCl3) 0.87 (3H, d, J 7.3 Hz), 0.90 (3H, d, J 6.8 Hz), 0.92 (3H, d, J 6.3 Hz), 0.95-1.14 (2H, m), 1.14-1.35 (1H, m), 1.32 (3H, t, J 7.2 Hz), 1.49-1.63 (2H, m), 1.63-1.80 (2H, m), 2.13 (1H, m), 2.40 (3H, s), 4.34 (2H, q, J 7.1 Hz), 4.70 (1H, broad s).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:9]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])(=[O:13])=[O:12])=[O:4].O[Li].O>>[C:22]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH3:21])(=[O:13])=[O:12])[CH:8]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NS(=O)(=O)c1ccc(C)cc1C
Agent: [Li]O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(C)(C)C)sc2C(=O)O)c(C)c1
Yield: 70 %

Procedure:
Hydrolysis of the 5-tert-Butyl-3-(2,4-dimethyl-benzenesulfonylamino)-thiophene-2-carboxylic acid methyl ester (55 mg, 0.14 mmol) using LiOH.H2O (22 mg) as previously described provided the 5-tert-Butyl-3-(2,4-dimethyl-benzenesulfonylamino)-thiophene-2-carboxylic acid (36 mg, 70% yield) as a solid. 1H NMR (CD3OD, 400 MHz) 7.85 (d, J=8.6 Hz, 1H), 7.14-7.10 (m, 2H), 7.0 (s, 1H), 2.56 (s, 3H), 2.31 (s, 3H), 1.27 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([CH2:18][CH2:19][CH3:20])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH3:22])[CH:14]=3)[C:9]=2[O:23][CH2:24]OC)=[CH:4][CH:3]=1.Cl.O1CCOCC1.FC1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[C:37]([C:43]([F:46])([F:45])[F:44])[CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([CH2:18][CH2:19][CH3:20])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH3:22])[CH:14]=3)[C:9]=2[O:23][C:24]2[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[C:37]([C:43]([F:44])([F:46])[F:45])[CH:36]=2)=[CH:6][CH:7]=1
Reactant: CCCc1cc2cc(OC)ccc2c(OCOC)c1-c1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)c(C(F)(F)F)c2)c1-c1ccc(F)cc1
Yield: 98.1 %

Procedure:
2-(4-Fluoro-phenyl)-6-methoxy-1-methoxymethoxy-3-propyl-naphthalene (225) (0.6 g, 1.69 mmol), 4 N HCl/Dioxane (12 mL), 4-fluoro-2-trifluoromethyl-benzaldehyde (0.277 mL, 2.03 mmol), Cs2CO3 (1.38 g, 4.23 mmol) and DMSO (12 mL) were reacted as described above to give 0.80 g (98%) of the title compound (226) as oil. 1H NMR (400 MHz, d-CDCl3): δ 0.83 (t, J=7.3 Hz, 3H), 1.47-1.55 (m, 2H), 2.54 (t, J=7.8 Hz, 2H), 3.95 (s, 3H), 6.75 (dd, J=2.3, 8.7 Hz, 1H), 6.94-6.99 (m, 3H), 7.06-7.10 (m, 3H), 7.19 (m, 1H), 7.63-7.66 (m, 2H), 7.89 (d, J=8.8 Hz, 1H), 10.18-10.19 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7]C)=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]2)=[CH:16][CH:15]=1>>[C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:25]([CH2:26][CH:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[CH2:21][C:22]([OH:24])=[O:23])[NH:1][C:2]=2[CH:3]=1)([OH:7])=[O:6].[ClH:13]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(C(=O)O)cc2[nH]1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.4, starting from methyl 3,4-diaminobenzoate and 3-(4-chlorophenyl)glutaric anhydride, 4-(5-carboxy-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid•HCl was obtained as colourless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[N:24][C:25]([Cl:28])=[N:26][CH:27]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.CC(C)([O-])C.[K+]>O1CCCC1>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:21]([C:22]3[CH:27]=[N:26][C:25]([Cl:28])=[N:24][CH:23]=3)[CH2:20][CH2:19]2)[CH2:7][CH2:8]1)=[O:13])([CH3:17])([CH3:18])[CH3:16]
Reactant: CCOC(=O)C1(CCNc2cnc(Cl)nc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1cnc(Cl)nc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 4-[2-(2-chloro-pyrimidin-5-ylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (188 mg, 0.46 mmol) in tetrahydrofuran (4 mL) was added 1 M solution of potassium-tert-butoxide in tetrahydrofuran (0.55 mL, 0.55 mmol). The resulting mixture was stirred for 2 hours at ambient temperature and then added NaHCO3 (aq) (20 mL), extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford a crude solid which was then purified by flash column chromatography (0 to 10% MeOH/CH2Cl2) to provide 125 mg (74% yield) of the title compound as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].Cl.[NH2:10][OH:11]>C(Cl)(Cl)Cl.O>[Br:1][CH2:2][C:3](=[N:10][OH:11])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C(CBr)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: ON=C(CBr)C(F)(F)F
Reaction time: 25 h

Procedure:
To a solution of 2.5 g of 1-bromo-3,3,3-trifluoropropan-2-one in 15 mL of chloroform (passed through a pad of basic alumina) was added a solution of hydroxylamine hydrochloride in 2.5 mL of water and the mixture heated to reflux. After 25 hours, the reaction mixture was cooled and 15 mL of H2O was added. The layers were separated and the aqueous layer was washed with 3×15 mL dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Note: As the product is a volatile liquid, excessive application of the vacuum to remove the co-solvent reduced the yield of the product. it's the product was used without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH:13]1[CH2:22][C:21]2[C:16](=[C:17]([C:25]([C:27]3[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=3)=[O:26])[CH:18]=[C:19]([C:23]#[N:24])[CH:20]=2)[O:15][CH2:14]1)[S:9]([CH3:12])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([Mg]Br)=[CH:36][CH:35]=1.[NH4+].[Cl-]>O1CCCC1>[CH2:1]([N:8]([CH:13]1[CH2:22][C:21]2[C:16](=[C:17]([C:25]([C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)([OH:26])[C:27]3[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=3)[CH:18]=[C:19]([C:23]#[N:24])[CH:20]=2)[O:15][CH2:14]1)[S:9]([CH3:12])(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(=O)c1cc(C#N)cc2c1OCC(N(Cc1ccccc1)S(C)(=O)=O)C2
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1cc(C#N)cc2c1OCC(N(Cc1ccccc1)S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To suspension of Example 7 (25 mg, 0.5 mmol) in tetrahydrofuran (0.5 mL) at 0° C. was added a solution of p-chlorophenyl magnesium bromide (1M in ether, 0.1 mL, 0.1 mmol). After stirring for 2 h at RT, the mixture was treated with NH4Cl solution and extracted with dichloromethane. The combined organic extracts were dried, concentrated and the residue was purified by reverse phase preparative HPLC. The appropriate fraction were mixed, concentrated and converted to HCl salt to afford the title compound (25 mg, 87%). LC/MS: (M+H)+=561, 563 (3:1 ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1c(C)nc(-c2ccc(NC(=O)CCl)cn2)nc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 52 (0.100 g, 0.434 mmol) in THF (5 mL), was added triethylamine (0.065 g, 0.65 mmol) and chloroacetylchloride (0.073 g, 0.65 mmol), and the reaction mixture was stirred at room temperature for a period of 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.C(OC(=O)C)(=O)C.[CH3:65][S:66]([CH3:68])=O>C(OCC)(=O)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][CH2:65][S:66][CH3:68])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: CS(C)=O
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCSC)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of the FR-900506 substance (100 mg) in dimethyl sulfoxide (1.5 ml) was added acetic anhydride (1.5 ml), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to thin layer chromatography on silica gel (developing solvent: diethyl ether) to give 17-allyl-1,14-dihydroxy-23, 25-dimethoxy-13,19 21,27-tetramethyl-12-[2-(4-methylthiomethoxy-3-methoxycyclohexyl-1 -methylvinyl]-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18-diene-2,3,10,16-tetraone (51 mg), 17-allyl-1-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18diene-2,3, 10,16-tetraone (18 mg) and 17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21, 27-tetramethyl-12-[2-(4-methylthiomethoxy-3-methoxycyclohexyl)-1-methylvinyl] -11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (10 mg), respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH2:36]([N:38]([C:46]([CH3:50])([CH3:49])[CH:47]=O)[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:37].N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:50][C:46]([N:38]([CH2:36][CH3:37])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=O
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (236 mg, 0.5 mmol, 1 equiv) and tert-butyl ethyl(2-methyl-1-oxopropan-2-yl)carbamate (2.15 g, 10 mmol, 20 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4 A molecular sieves. The resulting mixture was stirred for 2 h at 110° C. The solids was filtered out, the filtrate was diluted with 200 mL of ethyl acetate, washed with brine, dried over Na2SO4, concentrated and purified by silica gel column (ethyl acetate/MeOH 10/1) to give 60 mg (19%) of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([CH:14]([CH3:17])[CH2:15]O)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:26][CH2:15][CH:14]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=2[F:13])[C:5](=[O:23])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1)[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn(C(C)CO)c2c(F)c(F)c(F)cc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C(C)CCl)c2c(F)c(F)c(F)cc2c1=O

Procedure:
0.988 gm (3.0 mmol) of ethyl 6,7,8-trifluoro-1,4-dihydro-1-(1-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylate was dissolved into 50 ml of chloroform. To this was added 0.714 gm (6.0 mmol) of thionyl chloride and the mixture was reacted with heating under refluxing for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 1.001 gm of colorless, needlelike crystals of ethyl 1-(1-chloroprop-2-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[N:9]1[C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[NH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([O:32]CC[Si](C)(C)C)=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[N:9]1[C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[NH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([OH:32])=[O:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1ccc([C@H]2SC[C@@H](C(=O)OC(C)(C)C)N2C(=O)CNC(=O)Nc2cccc(C(=O)OCC[Si](C)(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CN(C)c1ccc([C@H]2SC[C@@H](C(=O)OC(C)(C)C)N2C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)cc1
Yield: 10.4 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 4.0 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(4-dimethylaminophenyl)-3thiazolidinyl]-2-oxoethyl}ureido}benzoate and 4.2 cm3 of 1M tetrabutylammonium fluoride solution. The crude product is purified by chromatography on silica [eluent: ethyl acetate/methanol (90/10 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in diisopropyl ether, 0.35 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(4-dimethylaminophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoic acid is thus obtained in the form of an amorphous solid. ([α]D20 =+138°±3° (C=0.37%; CHCl3)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 6.7 (bd, 2H, (Me)2N--C6H4 in position 3 and 5); 7.3 and 7.6 (m, 5H, aromatic); 8.0 (bs, 1H, N--C6H4 -- in position 2). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2975, 2930, 2805, 2600, 1715, 1690, 1650, 1610, 1555, 1520, 1485, 1365, 1230, 1150, 815, 760, 685].