Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:4]=2[O:3]1.[CH3:18][N:19](C)C=O.CC(C)=O.C(Cl)(=O)OCC.[CH2:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34]>O>[CH2:33]([N:35]1[CH2:38][CH2:39][CH2:37][CH:36]1[CH2:18][NH:19][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=1)=[O:13])[CH3:34]
Reactant: CCN(CC)CC
Reactant: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)O)c2O1
Reactant: CN(C)C=O
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 15 °C
Reaction time: 8 h

Procedure:
To a solution of 6 g of (-)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid [[α]D =-17.04° (dimethylformamide, c=1)] in a mixed solvent of 55 ml of dimethylformamide and 55 ml of acetone is added 5.9 g of triethylamine and the whole is stirred. The solution is cooled to 15° C., and 2.7 g of ethyl chlorocarbonate is added dropwise for 10 minutes. After stirring at room temperature for 40-45 minutes, 7.5 g of (-)-2-aminomethyl-1-ethylpryrrolidine is added and the reactant is stirred at room temperature for 20 minutes and allowed to stand overnight. Excess triethylamine and acetone are distilled off under diminished pressure and the residue obtained is poured with stirring into 500-600 ml of water. Precipitated crystals are collected by suction filtration, washed with water and dried. The filtrate, aqueous layer is extracted with ethyl acetate three times and the extract layer is washed with water and dried. Ethyl acetate is distilled off under reduced pressure to afford crude crystals. Both the crude crystals are combined and recrystallized from ethyl acetate to give crystals of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 155°-156° C., [α]D =-64.671° (dimethylformamide, c=1), which is an optically active compound.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:5](S(C)(=O)=O)=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].[CH3:34][NH2:35].CCCCCC>CN(C1C=CN=CC=1)C.C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:5]([NH:35][CH3:34])=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: COC(=O)c1ccc(C)c(-n2c(S(C)(=O)=O)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNc1nc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)OC)ccc1C
Temperature: 25 °C

Procedure:
Methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-(methylsulfonyl)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 1) (0.35 g, 0.64 mmol), DMAP (0.01 g, 0.06 mmol), and methylamine (0.97 mL of a 2M solution in THF, 1.93 mmol) were combined and stirred at ambient temperature. Reaction complete after 4 h. Washed with 5% citric acid, extracted in DCM, dried over Na2SO4, filtered, concentrated, and dried in vacuo to give a brown film. Dissolved in a small amount of DCM, added hexane, and cooled. Filtered precipitate and washed with a solution of cold 50% DCM/hexane. Dried resulting white solid in vacuo (0.22 g, 69%). 1H NMR (CD3OD/400 MHz) δ8.04 (m, 1H), 7.77 (s, 1H), 7.58 (q, 1H, J=8.8 Hz), 7.53 (d, 1H, J=8.4 Hz), 6.99 (m, 2H), 5.52 (s, 2H), 3.87 (s, 3H), 2.84 (s, 3H), 2.10 (s, 3H). ESHRMS m/z 494.0523 (M+H calculated for C21H19 BrF2N3O4 requires 494.0522).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[N+](=[CH2:12])=[N-].N(CNC(N)=O)=O.[OH-].[K+]>C(O)(=O)C.C(OCC)C>[CH3:12][O:7][C:3]([C:2]([F:9])([F:8])[F:1])=[CH:4][C:5]#[N:6]
Reactant: C=[N+]=[N-]
Reactant: N#CCC(=O)C(F)(F)F
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=CC#N)C(F)(F)F
Yield: 35.1 %

Procedure:
Diethylether (300 ml) was added to trifluoroacetoacetonitrile (13.7 g, 0.100 mole) and to this was added an ethereal solution of diazomethane, which was prepared from N-nitrosomethylurea (25.77 g, 0.250 mole), a 50% solution of potassium hydroxide (112.22 g, 1.00 mole) and diethylether (180 ml), with ice cooling. The solution was allowed to stand over night while cooling with ice. Next day, until the pH being 3-4 (by an universal test paper) acetic acid in limited amounts was added to the reaction mixture to decompose an excess of diazomethane and the solution was concentrated to about 200 ml at atmospheric pressure by using a distillation apparatus equipped with a fractionating column. The concentrate was washed with a 8% solution of sodium bicarbonate and water and dried with anhydrous sodium sulfate. Diethyl ether was distilled off by using a distillation apparatus equipped with a fractionating column at atmospheric pressure and the residue was distilled under reduced pressure to give the title compound (5.31 g, 35.1%) as a colorless liquid, b.p. 58.0° C./68 mmHg-64.0° C./70.0 mmHg. The structure of the product was confirmed by IR and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([CH3:12])C(O)=O)=O)=[CH:4][CH:3]=1.[OH-:15].[K+].O.NN.[CH2:20]([OH:29])COCCOCCO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH2:8][CH3:12])[C:20]([OH:29])=[O:15])=[CH:13][CH:14]=1
Reactant: CC(C(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: [OH-]
Reactant: OCCOCCOCCO
Agent: NN
Agent: [K+]
Solvent: O
Product: CCC(C(=O)O)c1ccc(Cl)cc1
Temperature: 142 °C
Reaction time: 0.5 h

Procedure:
4-Chlorobenzoyl propionic acid [Formula VII: R1 =R2 =R4 =H; R3 =Cl] (49.94 g, 234.9 mM) was dissolved under nitrogen in 320 mL of triethylene glycol. To the stirred room temperature solution was added potassium hydroxide (44.5 g, 794 mM) followed by 98% hydrazine hydrate (29.0 g, 580.0 mM). The mixture was heated to reflux temperature (142° C.) for 2 hours. Water and hydrazine hydrate were distilled off at atmospheric pressure; the pot temperature rose to 195°-200° C. After 0.5 hours at 195°-200° C., the mixture was cooled to ambient temperature and diluted with 320 mL of water. The aqueous solution was poured into hydrochloric acid (200 mL, 6N) and further diluted with 200 mL of ice water. Upon standing a solid formed which was filtered off, washed with water and vacuum dried (25° C., 15 Pa) to render 43.61 g (93%) of white solid.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33].CN(C=O)C>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.COCCOC>[NH2:26][C:27]1[CH:28]=[C:29]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: Cc1ccc(B(O)O)cc1N
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cc1ccc(-c2c(F)ccc3c2/C(=C/c2[nH]cnc2C)C(=O)N3)cc1N

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3-amino-4-methylphenylboronic acid (51.2 mg, 0.339 mmol) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 4 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-4-(3-Amino-4-methyl-phenyl)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 19 mg, 40%).
Reaction SMILES: S(Cl)(Cl)=[O:2].C(=O)(O[CH2:10][O:11][C:12](=[O:15])[CH2:13][CH3:14])SCC.[CH2:17]([Cl:19])Cl>>[C:12]([O:11][CH2:10][C:17]([Cl:19])=[O:2])(=[O:15])[CH2:13][CH3:14]
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Reactant: CCSC(=O)OCOC(=O)CC
Product: CCC(=O)OCC(=O)Cl
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Thionyl chloride (101 μL, 1.25 mmol) was added drop-wise to a solution of 53 (160 mg, 0.832 mmol) in CH2Cl2 (0.5 mL) at 0° C. then the solution was stirred for a further 1.5 hr. The solvent was removed under reduced pressure resulting in the volatile chloroformate 54 (138 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J=7.4, 3H), 2.45 (q, J=7.4, 2H), 5.83 (s, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]#N)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[OH2:29]>C(OCC)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]([C:7]3[CH:8]=[N:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:29])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: O
Reactant: Brc1cnc2ccccc2c1
Reactant: N#CC1(c2ccc(Cl)cc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1cnc2ccccc2c1)C1(c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of n-butyl lithium (1.6 M in hexanes, 1.5 ml) was added to 3-bromoquinoline (CAS Reg. No. 5332-24-1) (500 mg) in diethyl ether (16 ml) at −78° C. The mixture was stirred at −78° C. for 1 h. A solution of 1-(4-chlorophenyl)-1-cyclopropanecarbonitrile (CAS Reg. No. 64399-27-5) (427 mg) in 3 ml diethyl ether was added at −78° C. to the red mixture and then stirred for 15 min at −78° C. The mixture was allowed to warm to room temperature, then poured into water (40 ml) and extracted with diethyl ether. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 0:100-20:80, then ethyl acetate/DCM 0:100-10:90) to give the title compound as a light yellow oil (100 mg). MS (m/e)=308.3 [M+H+].
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[CH2:14][CH2:15]1
Reactant: CNC
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Agent: Cl
Product: CN(C)CC1CCN(c2ccc(CN3CCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 16 and dimethylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[CH2:15]/[C:16](/[C:19]3[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=3)=[N:17]\[OH:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1.C(OCC)(=O)C>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH2:15]/[C:16](=[N:17]\[OH:18])/[C:19]2[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[C:28]([CH3:34])[CH:29]=1
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(N)cc2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(NC(=O)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of (E)-5-(3-(4′-aminobiphenyl-4-yl)-3-(4-fluoro-2-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one (0.05 g, 110 μmol, example 259) in N,N-dimethylformamide was added at room temperature succinic anhydride (12.1 mg, 121 μmol) and the resulting solution was stirred at room temperature for 26 hours. The reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate and the organic layers were washed twice with water and once with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown foam (0.043 g, 70%). MS (ESI+): m/z=556.2 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13](I)=[CH:12][N:11]=[CH:10][N:9]=1)(C)(C)C.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:7][C:8]3[N:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH:26]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ncncc1I
Reactant: C#Cc1ccc(C(=O)OC)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc3cncnc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a solution of (5-iodo-pyrimidin-4-yl)carbamic acid tert-butyl ester (1.46 g, 4.55 mmol) (reference example 44a) in DMF (15 mL) is added 4-ethynyl-benzoic acid methyl ester (0.721 g, 4.5 mmol)(reference example 46), copper iodide 99.999% (21 mg, 0.112 mmol), bis(triphenylphosphine)palladium(II)chloride (158 mg, 0.225 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 mL, 10 mmol). The resulting solution is heated to 100° C. and stirred for 1 hour then cooled to 20° C. The solution is diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 50% ethyl acetate, 5% methanol in hexanes) to give 601 mg of title compound as a yellow crystalline solid. 1H NMR (DMSO) δ 3.89 (s, 3H), 7.24 (s, 1H), 8.06 (d, J=8 Hz, 2H), 8.14 (d, J=8 Hz, 2H), 8.81 (bs, 1H), 9.05 (bs, 1H), 12.79 (bs, 1H). MS (ion spray) m/z 254 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:3][CH2:1][CH3:2])[O:19][CH2:20][CH3:21])[CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 79.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(naphthalen-1-ylmethyl)propan-2-amine (Compound IX-2) 686 mg (2.4 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 1.15 g (2.51 mmol) and purified on Buch silica gel column chromatography (n-hexane:ethyl acetate=7:3) to obtain the title compound 1.384 g (79%).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[N:12]1([CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(OCCCN2CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCCN2CCCCC2)cc1
Reaction time: 18 h

Procedure:
A mixture of 1-[3-(4-nitro-phenoxy)-propyl]-piperidine (15.5 g, 58.6 mmol) and 10% Pd/C (12.5 g) in 150 mL of EtOH was placed under a balloon of H2. The mixture was stirred for 18 h. The catalyst was removed by suction filtration and the organics concentrated to give 4-(3-piperidin-1-yl-propoxy)-phenylamine as a yellowish oil.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O)[C:2]#[CH:3].[ClH:12].O1CCOCC1>O1CCOCC1>[Cl:12][CH2:3][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:4][CH:1]=1
Reactant: Cl
Reactant: C#CCS(=O)c1ccccc1
Solvent: C1COCCO1
Product: ClCc1csc2ccccc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
In 50 mL of 1,4-dioxane, was dissolved 5.02 g (30.6 mmol) of the compound obtained in Example 12. The resulting solution was heated at 100° C. After 5 hours and 30 minutes, the solution was cooled to keep the internal temperature of the reaction system at 10° C. To the cooled solution, was subsequently added 8.42 mL (33.7 mmol) of a 4 M hydrogen chloride-dioxane solution. The obtained mixture was allowed to stand at room temperature. After 15 minutes, the reaction liquid was concentrated and dissolved in 50 mL of ethyl acetate. The resulting solution was washed with 40 mL of water. The organic layer was dried with magnesium sulfate. After concentrating, the concentrate was redissolved in 50 mL of ethyl acetate in order to remove the dioxane. The obtained solution was washed with 40 mL of water three times. The organic layer was dried over magnesium sulfate and vacuum concentrated to provide 5.18 g of 3-(chloromethyl)-benzo[b]thiophene. The yield was 93%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH2:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:16]>>[ClH:1].[CH2:15]([N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Reactant: CCCCCCCNCC
Product: CCCCCCCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Product: Cl

Procedure:
In a manner similar to Preparation 41 react 1-(3-chloropropoxy)-4-nitrobenzene with N-ethylheptanamine to obtain the title compound.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].O[CH2:9][CH:10]1[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>>[CH:5]1[CH2:10][CH2:9][CH:3]([CH2:2][C:1]([OH:7])=[O:6])[CH:4]=1.[CH:2]12[CH2:3][CH:10]([CH:9]=[CH:1]1)[CH2:11][CH:12]2[C:13]([OH:15])=[O:14]
Reactant: C=CCCC(=O)O
Reactant: O=C1CCC(CO)O1
Product: O=C(O)C1CC2C=CC1C2
Product: O=C(O)CC1C=CCC1

Procedure:
For example, 4-pentenoic acid or an ester thereof yields γ-hydroxymethyl-γ-butyrolactone (5-hydroxymethyldihydrofuran-2-one) in a high yield. Cyclopentene-3-acetic acid yields 2,3-dihydroxycyclopentaneacetic acid γ-lactone, and 5-norbornene-2-carboxylic acid yields 5,6-dihydroxybicyclo[2.2.1]octane-2-carboxylic acid γ-lactone (5-hydroxy-2,6-norbornanecarbolactone=5-hydroxy-3-oxatricyclo[4.2. 1.04,8]nonan-2-one) in high yields.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[N:5]=1.[CH3:19]I>O1CCCC1>[CH3:19][S:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[N:5]=1
Reactant: O=[N+]([O-])c1ccccc1Cc1n[nH]c(S)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cc2ccccc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.61 g of sodium hydride in 50 ml of tetrahydrofuran, 5 g of 5-mercapto-3-(o-nitrobenzyl)-1,2,4-triazole is added in portions with stirring at room temperature over a period of 30 minutes. The mixture is stirred for 2 hours, 1.51 ml of methyl iodide is added at once, the mixture is stirred overnight at room temperature and evaporated to dryness in vacuo. The residue is treated with water and methylene chloride, the aqueous layer is extracted once more with methylene chloride, the combined organic extracts are dried over magnesium sulfate, evaporated to a small volume and diluted with ether to give 5-methylmercapto-3-(o-nitrobenzyl)-1,2,4-triazole, m.p. 120°-132°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16]O)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][N:48]4[C:44](=[O:54])[C:45]5[C:46](=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:47]4=[O:49])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 6. 68 mg, 0.213 mmol), triphenyl phosphine (168 mg, 0.64 mmol) and phthalimide (63 mg, 0.43 mmol) are dissolved in dry THF (3 mL). The stirred solution is cooled to 0° C. and diethyl azodicarboxylate (105 mg of 85% grade, 0.51 mmol) is added dropwise. The solution is stirred at 0° C. for 2 h during which time a white solid deposits and then stirred for 16 h at room temperature. The solution is then diluted with ether (20 mL) and the deposited solid filtered off. The solid is washed with ether and dried to give the first batch of product (20 mg). The ether solution is then washed with water and then extracted with dilute hydrochloric acid. A portion of the product deposits and is filtered off, washed twice with ether and dried to give the product as the hydrochloride salt (16 mg). The acidic phase is washed with ether and then made alkaline with sodium bicarbonate solution. Extraction with ethyl acetate (50 mL×3) followed by drying (MgSO4) and concentration gives the product as an off-white solid (32 mg). 1H NMR (d6-DMSO) δ 4.83 (s, 2H), 6.91 (dd, J=1.8, 7.2 Hz, 1H), 7.22 (t, J=8.9 Hz, 2H), 7.26 (d, J=5.9 Hz, 2H), 7.49 (dd, J=5.6, 8.6 Hz, 2H), 7.71 (s, 1H), 7.81–7.89 (m, 4H), 8.54 (d, J=4.7 Hz, 2H), 8.72 (d, J=7.1 Hz, 1H); APESI-MS m/z 449 (M+1)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[NH2:32]>>[F:28][C:29]1[CH:30]=[C:31]([NH:32][C:2]2[N:7]=[C:6]3[N:8]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[N:9]=[CH:10][C:5]3=[C:4]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=3)[N:3]=2)[CH:33]=[CH:34][C:35]=1[N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(F)c3)nc3c2cnn3C2CCCCO2)c1

Procedure:
N-(3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide can then be reacted with 3-fluoro-4-morpholinoaniline under palladium catalyzed aminolysis conditions to yield N-(3-(6-((3-fluoro-4-morpholinophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide, which can be deprotected under mild acidic conditions to provide N-(3-(6-((3-fluoro-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide.