Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na][Na].[Cl:3][C:4]1[CH:5]=[C:6]([N:11]2[C:15](=[O:16])[NH:14][NH:13][C:12]2=[O:17])[CH:7]=[C:8]([Cl:10])[CH:9]=1.Br[CH2:19][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br>CN(C=O)C>[Si:24]([O:23][CH:20]1[CH2:21][N:13]2[C:12](=[O:17])[N:11]([C:6]3[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=3)[C:15](=[O:16])[N:14]2[CH2:19]1)([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25]
Reactant: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OC(CBr)CBr
Agent: [Na][Na]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1Cn2c(=O)n(-c3cc(Cl)cc(Cl)c3)c(=O)n2C1

Procedure:
A mixture of the disodium salt of 4-(3,5-dichlorophenyl)-[1,2,4]triazolidine-3,5-dione (7.65 g, 26.4 mmol) (Preparation 4) and 1,3-dibromo-2-(tert-butyldimethylsilyloxy)propane [11.7 g, 35.2 mmol; prepared according to Axenrod, et al. J. Org. Chem., Vol. 60 (1995), at pp. 1959-64] in DMF (160 ml) was heated under reflux for 2 h 45 min. The solvent was then removed under vacuum, and the resulting solid was chromatographed over silica gel (CH2Cl2) to yield the above compound as a white solid (2 g, mp=129° C.). 1H NMR (CDCl3): 7.51 (2H, m), 7.35 (1H, m), 4.52 (1H, br s), 3.95 (2H, d, J=11.6 Hz), 3.49 (2H, dd, J1=11.6 Hz, J2 =2 Hz), 0.81 (9H, s), 0.09 (6H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]C)=[O:11])=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[C:6]=2[CH:18]=1.O[Li].O>O1CCOCC1.O>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:21])=[O:22])=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[C:6]=2[CH:18]=1
Reactant: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a suspension of methyl 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate (2.90 g, 6.92 mmol) in 1,4-dioxane/H2O (30 mL/5 mL) was added LiOH.H2O (870 mg, 20.75 mmol). The mixture was stirred at room temperature overnight. Then it was concentrated in vacuo, diluted with water, acidized with HCl (aq. 2 M) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated give the product of 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (2.50 g, yield: 89%). It was used for the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 9.16 (br s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 3.17 (s., 6H), 2.82 (d, J=4.4 Hz, 3H). (M+H)+: 405/407.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([C:18](=[O:21])[CH2:19]Cl)[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(OCC)(=O)C>C(#N)C.[I-].[Na+]>[C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([C:18](=[O:21])[CH2:19][N:30]4[CH:34]=[CH:33][N:32]=[CH:31]4)[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Cn1ccnc1)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 42.5 %

Procedure:
To a solution of 1-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-chloro-ethanone (0.216 g., 0.614 mmol) in 2 mL acetonitrile was added potassium carbonate (0.101 g., 0.737 mmol), imidazole (0.209 g., 3.07 mmol) and sodium iodide (2 mg, cat.), and the resulting suspension was refluxed for 2 hours. The reaction mixture was added to 100 mL ethyl acetate, and the inorganic components extracted three times with 50 mL water. The aqueous fraction was extracted twice with 50 mL ethyl acetate, and the combined organic fractions were dried over sodium sulfate and concentrated in vacuo. The crude solid was recrystallized from 3 mL dichloromethane to give 100 mg (42%) of 1-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-imidazol-1-yl-ethanone as a white solid. MS: 385 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:4](=[O:6])[C@@H:3]5[CH2:7][CH2:8][CH2:9][N:2]5[CH3:1])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.3 %

Procedure:
A mixture of 1-methyl-L-proline (170 mg, 1.3 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol), 1-hydroxybenzotriazole (175 mg, 1.3 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (490 mg, 1.3 mmol), N,N-diisopropylethylamine (330 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr, and then at 40° C. for 4 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (15 mg, 5%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.Cl.[CH3:14]O>>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: CO
Agent: Cl
Product: COC(=O)c1c(F)cc(Br)cc1F

Procedure:
A mixture of 4-bromo-2,6-difluorobenzoic acid (6.7 g, 28.3 mmol), MeOH (200 ml) and concentrated HCl (2.0 ml) was heated at reflux for 12 h. The reaction mixture was brought to ambient temperature and the volatiles were evaporated. EtOAc was added and the organic phase was extracted with a aquous solution of Na2CO3 (10%). The combined alkaline phases was acidified at 0° C. with aqueous HCl (10%) to pH 1 and extracted with EtOAc. The combined organic phases was dried (Na2SO4), filtered and concentrated in vacuo to afford pure title compound (3.1 g). MS m/z (rel. intensity, 70 eV) 252 (M+, 22), 250 (M+, 23), 221 (99), 219 (bp), 112 (44).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13][C:12](Cl)=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:42]=[CH:41][C:29]([C:30]([NH:32][C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:40])=[O:31])=[CH:28][CH:27]=1.C(P(C(C)(C)C)C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C(O[Pd]OC(=O)C)(=O)C.C1(C)C=CC=CC=1>[CH3:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:40])[C:33]=1[NH:32][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[CH2:16][CH2:17][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][C:10]=3[N:11]=2)=[CH:42][CH:41]=1
Reactant: Clc1nc2c(c(-c3ccccc3)n1)CCN(Cc1ccccc1)C2
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(N)cc1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc3c(c(-c4ccccc4)n2)CCN(Cc2ccccc2)C3)cc1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
To a round bottomed flask containing 7-benzyl-2-chloro-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (73 mg, 0.22 mmol) was added commercially available 4-amino-N-(2,6-dimethylphenyl)benzamide (56 mg, 0.23 mmol), diacetoxypalladium (II), (12 mg, 0.05 mmol) di-tert-butyl(phenyl)phosphine (39 mg, 0.13 mmol), cesium carbonate (125 mg, 0.38 mmol), and toluene (5 mL). The reaction mixture was heated to 100° C. for 14 h, then cooled to rt and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The material was purified by flash column chromatography to afford N-(2,6-dimethylphenyl)-4-{[4-phenyl-7-(phenylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]amino}benzamide (60 mg, 50%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 9.53 (s, 1H), 7.93 (m, 4H), 7.61 (m, 2H), 7.50 (m, 3H), 7.29 (m, 5H), 7.11 (m, 3H), 3.64 (m, 2H), 3.56 (m, 2H), 2.90 (m, 2H), 2.81 (m, 2H), 2.17 (s, 6H). MS (EI) for C35H33N5O: 540.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[I:26]C1C=CC(C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)=CC=1>>[I:26][C:23]1[CH:24]=[CH:25][C:20]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[CH:21][CH:22]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: CSc1ncnc2sc(-c3c(-c4ccc(I)cc4)ncn3C)cc12
Product: Cn1cnc(-c2ccc(I)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(4-iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 62) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Solid (200 mg, 100%);
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:8]([CH2:9][CH2:10][CH:11]=[CH:12][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:13]
Reactant: C=CCCC(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)CCC=Cc1cccnc1

Procedure:
A solution of 3-bromopyridine (7.9 g), methyl 4-pentenoate (7.15 g), palladium acetate (0.11 g) and tri-o-tolylphosphine (0.6 g) in 50 ml of triethylamine is refluxed for 24 hours under argon and the solvent evaporated. The residue is taken up in methylene chloride (50 ml) and washed with water (2×40 ml). The organic phase is dried and evaporated to yield 3-(4-methoxycarbonylbut-1-enyl)pyridine as a colorless liquid; NMR (CDCl3) 3.72 (s, 3H), 6.40 (s, 1H); IR (film) 1725 cm-1.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:14]([Cl:15])=[CH:13][C:12]3[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH2:18][O:19][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].O.[S:25](=[O:29])(=O)([OH:27])[OH:26]>>[CH2:1]([O:2][C:1]([C:4]1[O:5][C:6]2[C:14]([Cl:15])=[CH:13][C:12]3[C:16]4[CH:23]=[CH:22][C:21]([S:25]([OH:27])(=[O:29])=[O:26])=[CH:20][C:17]=4[CH2:18][O:19][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)=[O:3])[CH2:4][CH2:9][CH3:8]
Reactant: O=C(O)c1cc(=O)c2c3c(cc(Cl)c2o1)-c1ccccc1CO3
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCCCOC(=O)c1cc(=O)c2c3c(cc(Cl)c2o1)-c1ccc(S(=O)(=O)O)cc1CO3
Temperature: 0 °C

Procedure:
A solution of 7.0 gm (0.022 mol) of 2-chloro-6H-dibenzo-[b,d]-pyranyl-(3)-fumaric acid ether in concentrated sulfuric acid (see Example 9) was stirred for 2 hours at room temperature. The dark reaction mixture was then poured into ice water, and the resulting precipitate, consisting mainly of 2-carboxy-4-oxo-12-chloro-4H,6H-[2]-benzopyrano-[3,4-f][1]-benzopyran, was filtered off. The aqueous phase was extracted with n-butanol, and the obtained solution was evaporated to dryness. After addition of ether, 2.5 gm (23.8% of theory) of the compound named in the heading, m.p. 95°-97° C, were obtained (contained 3 mols of water of crystallization).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: Fc1cccnc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccnc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 21 h
Yield: 82.4 %

Procedure:
2-Chloro-3-fluoropyridine (0.4380 g, 3.33 mmol), 4-chlorophenylboronic acid (0.6248 g, 3.996 mmol), palladium tetrakistriphenylphosphine (0.1924 g, 0.1665 mmol), sodium carbonate (0.4235 g, 3.996 mmol), toluene (10 mL), and water (1 mL) were placed in a teflon lined vial. The vial was sealed and stirred at 125° C. for 21 hour. The mixture was cooled to ambient temperature and the whole mixture was purified on silica gel (EtOAc-hexanes gradient) to provide 569.4 mg of the title compound as white solid (82%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][O:14][C@H:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CO[C@H]1CCCN(C(=O)OC(C)(C)C)C1)C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CO[C@H]1CCCNC1)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A mixture of (S)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyloxy]-piperidine-1-carboxylic acid tert-butyl ester (50 mg; 0.09 mmol; 1 eq.) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 30 minutes then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in to afford the title compound (40 mg, 98%) as an off-white solid. 1H NMR (CDCl3) δ 7.39-7.26 (m, 4H), 5.03-4.88 (m, 2H), 4.63-4.47 (m, 4H), 3.63-3.30 (m, 1H), 2.94-2.71 (m, 5H), 2.62-2.53 (m, 3H), 1.83-0.72 (m, 7H). HPLC (max plot) 100%, Rt 2.63 min. UPLC/MS: (MS+) 440.2 ([M+H]+).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].FC(F)(F)C(O)=O.[F:17][C:18]1[C:19]([O:27][C:28]2[N:33]=[CH:32][N:31]=[C:30]3[N:34]([CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[N:35]=[CH:36][C:29]=23)=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[C:21]#[N:22].C(OC(N1CCC(N2C3=NC=NC(OC4C(C#N)=CC=C(F)C=4F)=C3C=N2)CC1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC1C=CC(OC2N=CN=C3N(C4CCNCC4)N=CC=23)=C(F)C=1)C.C(N(C(C)C)CC)(C)C>ClCCl.O>[CH:5]1([O:4][C:2]([N:40]2[CH2:39][CH2:38][CH:37]([N:34]3[C:30]4=[N:31][CH:32]=[N:33][C:28]([O:27][C:19]5[C:20]([C:21]#[N:22])=[CH:23][CH:24]=[C:25]([F:26])[C:18]=5[F:17])=[C:29]4[CH:36]=[N:35]3)[CH2:42][CH2:41]2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: N#Cc1ccc(F)c(F)c1Oc1ncnc2c1cnn2C1CCNCC1
Reactant: O=C(Cl)OC1CCCC1
Agent: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4c(C#N)ccc(F)c4F)ncnc32)CC1
Agent: CCOc1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(F)c(F)c1Oc1ncnc2c1cnn2C1CCN(C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Cyclopentyl chloroformate (3B Scientific Corporation, Libertyville, Ill., USA; 46 mg, 0.31 mmol) was added to a mixture of 3,4-difluoro-2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate salt (which was prepared from 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester [Example 49] following the procedure described for the preparation of Intermediate 29; 145 mg, 0.31 mmol), diisopropylethylamine (120 mg, 0.93 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (130 mg, 90%) as a white solid. Mass spectrum MH+=469.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([C:9]([Cl:24])=[O:10])[CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CSC2(C(=O)O)CCN(OC)CC2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CSC2(C(=O)Cl)CCN(OC)CC2)cc1
Temperature: 100 °C

Procedure:
700 mg 1-Methoxy-4-(4-methoxy-benzylsulfanyl)-piperidine-4-carboxylic acid (from Step 5) was dissolved in 10 ml toluene, 1 drop N,N-dimethylformamide was added, followed by 400 mg thionyl chloride. The mixture was heated to 100° C. for 1 hour, at which time the evolution of gas has ceased. The solvent was evaporated, to yield crude 1-methoxy-4-(4-methoxy-benzylsulfanyl)-piperidine-4-carbonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[O:11][C:10](=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:20].CN1CCOCC1>CN(C)C=O>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][NH:17][C:12]([CH2:13][N:8]([CH2:9][C:10]([OH:11])=[O:15])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)OC(=O)C1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)NCC(=O)c1ccc(Br)cc1
Yield: 80.2 %

Procedure:
2,6-Dioxo-morpholine-4-carboxylic acid tert-butyl ester (2.5 g, 11.6 mmol) was added to a solution of 2-amino-1-(4-bromo-phenyl)-ethanone hydrochloride (3.05 g, 12.2 mmol) and 4-methylmorpholine (1.92 mL, 17.4 mmol) in dimethylformamide (15 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and washed with water (50 mL), aqueous hydrogen chloride (0.5 N, 2×50 mL), and saturated sodium bicarbonate (2×50 mL). The basic extracts were neutralized and extracted with ethyl acetate (2×75 mL). The combined organic phases from the second extraction were dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to provide ({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetic acid (4 g, 9.3 mmol, 80%). C17H21BrN2O6 calculated 428.0 observed [M+1]+ 431.1; rt=2.36 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].C1COCC1.CO>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:9])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OCC)cc2)CC1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C(=O)NC2(C(=O)O)CC2)cc1
Temperature: 20 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
Charge an 800 L reactor with ethyl 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylate (12.19 kg), THF (45.5 kg) and MeOH (20.2 kg). Add a solution of LiOH monohydrate (2.49 kg) in water (25.6 kg) to the reactor maintaining the temperature of less than 23° C. during the transfer. Stir the resulting solution at 20±3° C. for overnight (19 h). Remove THF and MeOH by vacuum distillation and then add water (67 kg) to reactor. Adjust the pH of the reaction to pH about 2.0 with 5N HCl (about 12 L) at 17±2° C. Stir the resulting product slurry at 17±2° C. for 50 minutes. Collect the solids by filtration and wash with water (3×40 Kg). Dry the wet cake at 47° C. under vacuum to afford 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylic acid (10.74 kg, 98% yield, >99% purity by HPLC, 0.03% KF) as a white powder solid. LC-MS (M+1=250).
Reaction SMILES: [CH2:1]([C:3]([NH:24][CH3:25])([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH3:2].C=O.[C:28]([BH3-])#N.[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CO>[CH2:1]([C:3]([N:24]([CH3:28])[CH3:25])([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[CH3:2]
Reactant: CCC(CCCc1cc(OC)c(OC)c(OC)c1)(NC)c1cccs1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CO
Product: CCC(CCCc1cc(OC)c(OC)c(OC)c1)(c1cccs1)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
1.7 g of 1-ethyl-4-(3,4,5-trimethoxyphenyl)-1-(2-thienyl)-N-methylbutylamine are dissolved in 15 ml of acetonitrile. 1.5 ml of 35% formalin and 0.59 g of sodium cyanoborohydride are added to the solution, and the mixture is adjusted to pH 6.5 with methanol containing hydrogen chloride and stirred at room temperature for 8 hours. After the reaction, the mixture is acidified with 10% hydrochloric acid and stirred for 30 minutes. The mixture is alkalized with an aqueous 20% potassium carbonate solution and concentrated under reduced pressure. The residue is extracted with ethyl acetate, and the extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:ethanol=30:1) to give 1.4 g of 1-ethyl-4-(3,4,5-trimethoxyphenyl)-1-(2-thienyl)-N,N-dimethylbutylamine as colorless crystals. yield; 79.3% M.p. 62°-63 ° C. (recrystallized from ether-n-hexane)
Reaction SMILES: ClC1C=C(C(OCC)=O)C(C)=C2C=1SCCC2=O.C([O:21][C:22]([C:24]1[C:25]([CH3:36])=[C:26]2[C:31](=[C:32]([CH3:34])[CH:33]=1)[S:30][CH:29]=[CH:28][C:27]2=[O:35])=[O:23])C>>[C:22]([C:24]1[C:25]([CH3:36])=[C:26]2[C:31](=[C:32]([CH3:34])[CH:33]=1)[S:30][CH:29]=[CH:28][C:27]2=[O:35])([OH:23])=[O:21]
Reactant: CCOC(=O)c1cc(C)c2sccc(=O)c2c1C
Agent: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Product: Cc1cc(C(=O)O)c(C)c2c(=O)ccsc12
Reaction time: 18 h
Yield: 96 %

Procedure:
The captioned end product was obtained in the same manner as in Preparation Example 3-3 except that the 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one as a starting material in Preparation Example 3-3 was replaced with 6-ethoxycarbonyl-5,8-dimethylthiochrom-2-en-4-one and that the reflux time was changed to 18 hours. The yield was 96%.