Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)CCC.O.CCOC(C)=O>C1COCC1.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>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(-c2nccs2)n1
Temperature: 75 °C

Procedure:
A mixture of commercially available methyl 6-bromopicolinate (300 mg; 1.38 mmol), 2-(tributylstannyl)thiazole (623 mg; 1.66 mmol), and PdCl2(PPh3)2 (97 mg; 0.13 mmol) in anh. THF (8 ml) was heated to 75° C., under nitrogen, for 18 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded methyl 6-(thiazol-2-yl)picolinate as a pale yellow solid. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 220.95 g/mol.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:25])[CH:23]=3)[CH:18]=[N:17]2)=[CH:12][CH:11]=1.C1COCC1.O>CCOC(C)=O>[Br:8][C:23]1[C:22]([OH:25])=[CH:21][CH:20]=[C:19]2[C:24]=1[N:16]([C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1)[N:17]=[CH:18]2
Reactant: Oc1ccc2cnn(-c3ccc(F)cc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc2cnn(-c3ccc(F)cc3)c2c1Br
Reaction time: 1 h
Yield: 62.9 %

Procedure:
NBS (16.2 g, 91 mmol) was added in one portion to a solution of 1-(4-fluorophenyl)-1H-indazol-6-ol (96, R1=4-Fluorophenyl) (20.3 g, 89 mmol) and THF (500 mL) under a nitrogen atmosphere at about 0° C. After about 1 h, water (500 mL) and EtOAc (400 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting solid was slurried in DCM (50 mL) then collected by filtration rinsing with DCM (4×25 mL). The solid was dried to afford 7-bromo-1-(4-fluorophenyl)-1H-indazol-6-ol (97, R1=4-Fluorophenyl) (17.2 g, 63% yield) as a faint orange solid. LC/MS, method 3, Rt=2.02 min, MS m/z 307 and 309 (M+H)+. 1H NMR (400 MHz, DMSO) δ 10.52 (d, J=0.9 Hz, 1H), 8.20 (d, J=0.9 Hz, 1H), 7.67 (dd, J=8.6, 0.9 Hz, 1H), 7.54-7.47 (m, 2H), 7.38-7.29 (m, 2H), 6.95 (dd, J=8.6, 0.9 Hz, 1H).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=2)=[O:8])=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O>C(Cl)Cl>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][NH:9][C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2ccc(-c3ccccc3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1cccc(CNC(=O)c2ccc(-c3ccccc3)cc2)c1
Reaction time: 8 h
Yield: 102 %

Procedure:
tert-Butyl 3-{[(1,1′-biphenyl-4-ylcarbonyl)amino]methyl}phenylcarbamate (250 mg, 0.6 mmol) was dissolved in DCM (10 ml). Trifluoroacetic acid (0.2 ml) was added. The mixture was stirred overnight. HPLC showed that more than 50% of the starting material was not reacted. More trifluoroacetic acid (0.3 ml) was added. The mixture was stirred overnight again. Water was added into the mixture. The phases were not clear. DCM was evaporated in vacuum Ethyl acetate was added to the residue. The obtained organic phase was washed with water (×3) and dried with magnesium sulphate. The solvent was then evaporated. Solid product (185 mg) was obtained, yield 99%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][C:11]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:22][CH2:21][C:11]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:28](=[O:30])[CH3:29])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(CN2CCC3(CCNc4ccccc43)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-benzyl-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline] 1ad (4.5 g, 15.4 mmol) in dry CH2Cl2 (35 mL) was added NaHCO3 (6.47 g, 77 mmol) at room temperature. Then acetyl chloride (1.2 g, 15.4 mmol) was added dropwise at ambient temperature. The mixture was stirred for 2 hours at room temperature. After filtration, the filtrate was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give a white solid, which was washed with ether and filtered to afford the pure product 1-(1-benzyl-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1′-yl)ethanone 1ae (not shown). The solid (5.2 g, 15.6 mmol) was dissolved in MeOH (50 mL), then Pd(OH)2/C (0.25 g) was added under Ar. The suspension was hydrogenated under H2 (50 psi) at 50-55° C. overnight. After cooling and filtration, the filtrate was evaporated under reduced pressure to give 1-(2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1′-yl)ethanone 1ae (3.12 g, 83%, two steps). 1H NMR (CDCl3, 300 MHz) δ 7.46-7.49 (m, 2H), 7.21-7.26 (m, 3H), 3.82 (t, J=5.7 Hz, 2H), 3.38 (d, J=12.9 Hz, 2H), 3.08-3.16 (m, 2H), 2.38-2.48 (m, 2H), 2.24 (s, 3H), 1.97 (t, J=6.0 Hz, 2H), 1.77 (d, J=14.7 Hz, 2H). MS (ESI) m/z (M+H+) 245.2.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Total protein assays were done using a Pierce BCA kit (Rockford, Ill.). Tryptophan racemase assays with the mutant enzyme were performed in triplicate using the wild-type enzyme prepared in the same manner as a positive control. The assays contained per mL: 30 mM L-tryptophan, 50 mM potassium phosphate pH8, 10 μM PLP, and approximately 200 μg of racemase protein in a cell free extract. Zero, 20 minute, 1 hour, and overnight samples were collected, treated with 2% formic acid, filtered, and diluted 1:10 for analysis using the chiral amino acid method described in Example 1. At the 20 minute time point, the Y396C mutant produced approximately 264 ppm D-tryptophan, as compared to 761 ppm for the wild-type enzyme. At 1 hour, the mutant produced an average of 444 ppm D-tryptophan, as compared to 1110 ppm for the wild-type enzyme. The overnight samples contained 2300 ppm D-tryptophan, whereas the wild-type enzyme had reached equilibrium by producing approximately 3000 ppm D-tryptophan.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17](N(OC)C)=[O:18])=[N:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1.Cl.[CH2:26]1COCC1>>[C:17]([C:10]1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[CH:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[O:23][CH3:24])[N:9]=1)(=[O:18])[CH3:26]
Reactant: C1CCOC1
Reactant: COc1cc(I)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Agent: Cl
Product: COc1cc(I)ccc1-n1cc(OC)c(=O)c(C(C)=O)n1
Reaction time: 0.33 h

Procedure:
To a solution of 1-(4-iodo-2-methoxyphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (8.90 g) in THF (150 mL) was added dropwise 1M methylmagnesium bromide THF solution (30 mL) at −78° C., and the mixture was stirred for 20 min. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate, and recrystallized from methanol/water to give the title compound (5.12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[C:12]([CH2:17][OH:18])=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[C:12]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(c1ccc(Cl)cc1)c1cccnc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution cooled (0° C.) solution of {3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-yl}-methanol (206 mg, 0.768 mmol) and Et3N (165 μL, 1.15 mmol) in CH2Cl2 (4 mL) was added MsCl (67 μL, 0.845 mmol). The mixture was warmed to ambient temperature and stirred for 1 h. Water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford methanesulfonic acid 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl ester (269 mg, 99%) as a yellow solid. 1H NMR (CDCl3) δ 1.70 (s, 6H), 3.01 (s, 3H), 4.78 (s, 2H), 7.05 (d, 2H, J=6.0 Hz), 7.29 (d 2H, J=6.0 Hz), 7.37 (dd, 1H, J=6.0, 3.0 Hz), 7.96 (dd, 1H, J=7.5, 3.0 Hz), 8.59 (dd, 1H, J=6.0, 3.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][C:3]=1[CH:4]=O.C(O[BH-](O[C:37](=O)[CH3:38])OC(=O)C)(=O)C.[Na+].[CH3:41][OH:42]>ClCCCl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][C:3]=1[CH2:4][NH:13][CH2:14][CH2:15][N:16]1[CH2:37][CH2:38][O:42][CH2:41][CH2:17]1
Reactant: CN1C(c2ccc(F)c(C=O)c2)c2ccc3cccnc3c2NS1(=O)=O
Reactant: CO
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1C(c2ccc(F)c(CNCCN3CCOCC3)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 34 %

Procedure:
In a similar fashion, using route 37 general procedure 90, 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzaldehyde 422 (15.9 μl, 0.13 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) in DCE (2 ml) gave the title compound (22 mg, 34%) after trituration from MeOH.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:15][C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=3)[CH2:30][CH2:29]2)[CH:23]=1)=[O:20]
Reactant: CCCOc1ccc(C=O)c2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CCCOc1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc12

Procedure:
Prepared by Procedure F and Scheme R using 4-propoxy-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 445.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:27][C:25]#[N:26])=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCCOc1ccc(C=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Product: Cc1oc(-c2ccccc2)nc1CCCOc1ccc(C=CC#N)cc1

Procedure:
According to the method described for Reference Example 35, 4-[3-(5-methyl-2-phenyl-4-oxazolyl)propoxy]benzaldehyde was allowed to react with diethyl cyanomethylphosphonate to give 4-[3-(5-methyl-2-phenyl-4-oxazolyl)propoxy]cinnamonitrile. Recrystallization from ethyl acetate--isopropyl ether--hexane gave colorless prisms, m.p.97°-98° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[C:18]([NH:23]C(OCC3C=CC=CC=3)=O)[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([NH2:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(=Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Yield: 94.7 %

Procedure:
A mixture of 5-(2-benzyloxycarbonylamino-2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester (524 mg, 1.16 mmol) and 10% palladium on carbon (60 mg) in methanol (20 mL) was shaken for 4.5 h under 50 psi hydrogen gas using a Parr hydrogenator. The reaction mixture was evacuated and purged with nitrogen. Then, the reaction mixture was filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (351 mg, 95%). 1H-NMR (CDCl3, 500 MHz) δ 8.12–8.10 (m, 2H), 7.55 (br s, 1H), 7.37 (dd, J=8.9, 1.5 Hz, 1H), 3.77–3.75 (m, 1H), 3.70 (s, 3H), 3.19 (dd, J=13.7, 5.5 Hz, 1H), 2.99 (dd, J=13.7, 8.0 Hz, 1H), 1.72 (s, 9H). Mass spec.: 320 (MH)+.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N+:23]1([O-])[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.[Cl:31]([O-:35])(=[O:34])(=[O:33])=[O:32].[Na+]>CO.O>[Cl:31]([O-:35])(=[O:34])(=[O:33])=[O:32].[CH3:21][N:14]([CH2:13][CH2:12][CH2:11][O:10][N+:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)c2ccccc2)cc1
Reactant: Cc1cccc[n+]1[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: Cc1cccc[n+]1OCCCN(C)c1ccccc1

Procedure:
3-(N-Methylanilino)propyl p-toluenesulfonate (21.2 g, 0.0665 mole) and 2-picoline-N-oxide (7.3 g, 0.0665 mole) were heated together on a steam bath for 1/2 hour. The mixture was allowed to cool, then dissolved in methanol (50 ml). A solution of sodium perchlorate (9.3 g, 0.076 mole) in water (12 ml) was added and the mixture chilled. The solid which separated was collected and washed with a little 90% methanol, then with ether. The yield was 14.3 g (60%), m.p. 111°-113° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([CH3:12])[CH:6]=1.C([BH3-])#N.[Na+]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:6][C:7]=1[CH3:12]
Reactant: CON=Cc1ccc(F)c(C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(C)c1

Procedure:
Reduction of 4-fluoro-3-methyl-benzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 1-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8: 2) (94% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.27 (3H, broad s, CH3), 3.50 (3H, s, OCH3), 3.97 (2H, broad s, NCH2), 5.67 (1H, broad, NH), 6.95 (1H, m, aromatic), 7.11-7.17 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 162° C. Anal. calcd for C9H12FNO—HCl: C, 52.56; H, 6.37; N, 6.81. Found: C, 52.80; H, 6.33; N, 6.70.
Reaction SMILES: Cl.Cl.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3SC(CN5CCNCC5)=CC=3)=CC=CC=4)C)N=C(C3C=C(O)C=C(F)C=3)C=12.O[CH:47]([C:49]1[O:50][C:51](=[O:72])[C:52]2[C:57]([C:58]=1[C:59]1[S:60][C:61]([CH2:64][N:65]3[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]3)=[CH:62][CH:63]=1)=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH3:48].[F:73][C:74]1[CH:75]=[C:76]([C:82]2[C:90]3[C:85](=[N:86][CH:87]=[N:88][C:89]=3[NH2:91])[NH:84][N:83]=2)[CH:77]=[C:78]([O:80][CH3:81])[CH:79]=1>>[NH2:91][C:89]1[N:88]=[CH:87][N:86]=[C:85]2[N:84]([CH:47]([C:49]3[O:50][C:51](=[O:72])[C:52]4[C:57]([C:58]=3[C:59]3[S:60][C:61]([CH2:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[CH:62][CH:63]=3)=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH3:48])[N:83]=[C:82]([C:76]3[CH:77]=[C:78]([O:80][CH3:81])[CH:79]=[C:74]([F:73])[CH:75]=3)[C:90]=12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCN(C)CC2)s1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCNCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: Cl
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCN(C)CC4)s3)c3ncnc(N)c23)c1
Yield: 62.8 %

Procedure:
The title compound was made in a similar way as that of the compound of example 134, step a, from 3-(1-hydroxyethyl)-4-(5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)-1H-isochromen-1-one (Intermediate B39, 411 mg, 1.069 mmol), and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate G1, 305 mg, 1.176 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)-1H-isochromen-1-one (420 mg, 0.671 mmol, 62.8% yield) as a brown solid.
Reaction SMILES: [C:1](#N)[CH3:2].[CH2:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:5].[OH-:13].[Na+]>CO.O>[O:13]([CH2:1][CH2:2][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:4][CH3:5])=[CH:7][CH:8]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC#N
Reactant: CCc1ccc(O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1ccc(OCCOc2ccccc2)cc1
Yield: 98 %

Procedure:
Subsequently, 50 ml of acetonitrile, 0.092 mol of β-phenoxyethyl-p-tosylate, and 0.1 mol of p-ethylphenol were placed in a flask equipped with a stirrer. A 48 wt% aqueous solution of caustic soda (0.12 mol equivalent) was added dropwise at an inner temperature of not more than 75° C. while stirring. The mixture was stirred while refluxing for 2 hours. The reaction mixture was allowed to cool. On pouring the reaction mixture at about 40° C. into a methanol-water mixture, crystals precipitated. These crystals were separated by filtration, and then dried to yield 1-phenoxy-2-p-ethylphenoxyethane (m.p., 107°-108° C.). The yield was 98%.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:24]=[C:23]([O:25][CH:26]3[CH2:44][CH:43]4[N:28]([C:29](=[O:58])[N:30]([CH2:49][C:50]5[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=5)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH:38]5[C:40]([C:46](O)=[O:47])([NH:41][C:42]4=[O:45])[CH2:39]5)[CH2:27]3)[C:22]3[C:17](=[C:18]([CH3:61])[C:19]([O:59][CH3:60])=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:24]=[C:23]([O:25][CH:26]3[CH2:44][CH:43]4[N:28]([C:29](=[O:58])[N:30]([CH2:49][C:50]5[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=5)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH:38]5[C:40]([C:46]([NH:7][S:4]([CH:1]6[CH2:3][CH2:2]6)(=[O:6])=[O:5])=[O:47])([NH:41][C:42]4=[O:45])[CH2:39]5)[CH2:27]3)[C:22]3[C:17](=[C:18]([CH3:61])[C:19]([O:59][CH3:60])=[CH:20][CH:21]=3)[N:16]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4nc(-c5ccc(F)cc5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Reactant: NS(=O)(=O)C1CC1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4nc(-c5ccc(F)cc5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Yield: 33 %

Procedure:
Cyclopropanesulfonamide (99 mg, 0.8 mmol) was coupled to the acid 102 (200 mg. 0.27 mmol) as described in example 21. Purification by HPLC gave the title compound (75 mg, 33%).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH3:3].[Cl-].[Cl-].[Cl-].[Al+3].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:2]([O:4][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)=[O:15])[CH3:3]
Reactant: Clc1ccccc1
Reactant: CCOC(=O)CCCCCCCC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCCCCC(=O)c1ccc(Cl)cc1

Procedure:
Using the method described by Papa et al. [J. Amer.Chem.Soc. 69 (1947), 3018], 12.3 g of azelaic acid ethyl ester chloride in 20 ml of chlorobenzene are mixed cold with 9.5 g of aluminium trichloride and the mixture is then heated at 150° overnight. After adding dilute hydrochloric acid to the complex, the organic phase is washed and concentrated; the residue is extracted with diethyl ether. After column chromatography, and concentration of the solution, 8.3 g of 9-(4-chlorophenyl)-9-oxo-nonanoic acid ethyl ester are obtained as a viscous oil.
Reaction SMILES: O=P(Cl)(Cl)Cl.FC(F)(F)[C:8]([O-])=[O:9].C[NH2+]CC1C=CC(C2N=CC3N4C(NC(=O)CC=3)CCC=24)=CC=1.[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:45]=[C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([O:54][CH3:55])=[O:53])[N:47]3[CH:56]=2)=[CH:40][CH:39]=1)#[N:37]>CN(C=O)C>[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:45]=[C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([O:54][CH3:55])=[O:53])[N:47]3[C:56]=2[CH:8]=[O:9])=[CH:40][CH:39]=1)#[N:37]
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)cn12
Agent: C[NH2+]Cc1ccc(C2=C3CCC4NC(=O)CC=C(C=N2)N34)cc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(C=O)n12
Yield: 58 %

Procedure:
POCl3 (5.0 eq.) was added to a solution of Example 1, A2 in DMF (0.1 M) at RT. The reaction mixture was heated to reflux for 1 h. After cooling down, the reaction mixture was quenched by the addition of ice water, then, the aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column on silica using a gradient of EtOAc/Petroleum ether from 40:60 to 70:30 to yield (58%) the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 300K) δ 9.80 (1H, s), 8.22-8.15 (3H, m), 8.04 (2H, d, J=8.4 Hz), 7.87 (1H, dd, J=8.8, 7.0 Hz), 7.70 (1H, d, J=7.0 Hz), 3.92 (3H, s). MS (ES+) C17H11N3O3 requires: 305, found: 306 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C1(C)C=CC=CC=1.[OH-].[Na+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O>[CH2:1]([NH:4][C:15](=[O:16])[O:17][CH2:18][CH3:19])[C:2]#[CH:3]
Reactant: CCOC(=O)Cl
Reactant: C#CCN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCNC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
115 g (2. 1 mol) of propargylamine is introduced into 1 1 of toluene, 91 g of sodium hydroxide dissolved in 400 ml of water are added, and 239 g (2.2 mol) of ethyl chloroformate are added dropwise at 10° C. The mixture is stirred for three hours at room temperature, the organic phase is separated off, the aqueous phase is extracted using toluene, the organic solutions are dried over magnesium sulphate and concentrated, and the concentrate is distilled.