Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[CH3:29][I:30]>CC(C)=O>[I-:30].[CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:14]2[CH2:19][CH2:18][N+:17]([CH3:29])([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CI
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Solvent: CC(C)=O
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1C[N+](C)(C)CC2)C(C)(C)C
Product: [I-]
Reaction time: 18 h
Yield: 24.6 %

Procedure:
(S)—N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-7-methyl-3-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (Compound 48; 0.09 g, 0.24 mmol) was dissolved in acetone (2 mL) and methyl iodide (0.038 g, 0.26 mmol) was added. The reaction mixture was stirred for 18 hours. The mixture was concentrated, ethyl acetate was added and the resulting solid was filtered, washed with cold ethyl acetate and dried under vacuum to provide the desired product, Compound 311 (0.031 g, 24%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ: 0.93 (s, 9H), 2.59 (d, 3H), 3.30 (s, 6H), 3.86 (t, 2H), 4.32 (d, 1H), 4.57 (t, 2H), 5.06 (dd, 2H), 7.54 (m, 4H), 7.82 (m, 2H), 8.17 (m, 1H); LCMS (+ESI) m/z 398.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14][OH:15].N1C=CC=CC=1>C(C(C)=O)C>[C:1]([O:15][CH2:14][CH2:13][Br:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: OCCBr
Solvent: c1ccncc1
Solvent: CCC(C)=O
Product: O=C(C=Cc1ccccc1)OCCBr
Yield: 86.9 %

Procedure:
35.3 g (0.212 mol) of cinnamic acid chloride and 100 mL of methyl ethyl ketone were placed in a reaction vessel and stirred under a nitrogen atmosphere. 28.2 g (0.225 mol) of 2-bromoethanol and 21 g of pyridine were dissolved in 100 mL of methyl ethyl ketone and added dropwise in the aforementioned reaction vessel. After completion of dropping, the solution was refluxed with stirring for 2 hours and cooled. Pyridine hydrochloride was precipitated, and then separated from the solution by filtration. The filtrate was concentrated and then dissolved in methylene chloride. The solution of methylene chloride was poured into a separating funnel and washed with water. Then the solution was dried with anhydrous sodium sulfate and concentrated. Thus 47 g of 2-bromoethyl cinnamate was obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].C(Cl)(=O)CCCCCCCCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: CCCCCCCCCC(=O)Cl
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 83 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, decanoyl chloride (0.251 g, 1.32 mmol) was reacted with 2-azidoethanamine (0.114 g, 1.32 mmol) and triethylamine (0.267 g, 2.64 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)decanamide (0.262 g, 83%). 1H NMR (300 MHz, CDCl3) δ 6.49 (s, 1H), δ 3.36 (s, 2H), δ 3.35 (s, 2H), δ 2.14 (t, 2H), δ 1.46 (m, 2H), δ 1.21 (m, 12H), δ 0.81 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.1, 50.9, 39.1, 36.8, 32.0, 29.7, 29.6, 29.5, 29.4, 25.9, 22.8, 14.3 ppm; HRMS (ESI) calcd for C12H24N4O (M+) 240.1950, found 240.1947.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[NH2:15][C:16]([NH2:18])=[S:17]>>[BrH:1].[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[N:15]=1
Reactant: NC(N)=S
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(N)n2)c(C)s1
Yield: 97.5 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was allowed to react with thiourea (12 mg) as described in Example 154, step (a), to give 54 mg (70% yield) of methyl 4-(2-amino-(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ2.69 (s, 3H), 3.83 (s, 3H), 7.00 (s, 1H), 8.05 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C10H10O2S3N2, 286.41 (M+H), found 287.1;
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]/[CH2:4][O:5][C:6]1[C:14]2[S:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:16]1[C:26]2[CH2:25][CH2:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[CH:21]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl[CH2:38]/C=C/CCl>>[CH:27]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH:21]([N:31]3[CH2:32][CH2:33][N:34]([CH2:38]/[CH:2]=[CH:3]/[CH2:4][O:5][C:6]4[C:14]5[S:13][C:12]([CH3:15])=[N:11][C:10]=5[CH:9]=[CH:8][CH:7]=4)[CH2:35][CH2:36]3)[C:22]=2[CH:30]=[CH:29][CH:28]=1.[Cl:1]/[CH:2]=[CH:3]/[CH2:4][O:5][C:6]1[C:14]2[S:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: ClC/C=C/CCl
Reactant: c1ccc2c(c1)CCc1ccccc1C2N1CCNCC1
Agent: Cc1nc2cccc(OC/C=C/Cl)c2s1
Product: Cc1nc2cccc(OC/C=C/CN3CCN(C4c5ccccc5CCc5ccccc54)CC3)c2s1

Procedure:
The title compound was prepared according to Method GA from trans-7-(3-chloro-allyloxy)-2-methyl-benzothiazole and 1-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)piperazine. mp 151-152° C.; LSIMS m/z 496. The trans-7-(3-chloroallyloxy)-2-methyl-benzothiazole was prepared by Method IV with trans-1,4-dichloro-2-butene as the alkylating agent.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1.C(O)(C(F)(F)F)=O>O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:17]=3)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccon2)s1
Yield: 54 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 5-isoxazol-3-ylthiophene-2-sulfonyl chloride (13.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol) and with a slightly modified purification method using 0.1% TFA in water as buffet. The title compound was obtained in 54% yield (11.1 mg). MS (ESI+) calcd mass for C14H10N6O3S2 374.025580, found 374.025400.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][C:5]1[CH:15]=[C:16]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:17]=[CH:18][C:4]2=1)[CH3:2].C([C@]12CC[C:37](=[O:40])[CH2:36][C@H]1CCCC1C=C(OS(C(F)(F)F)(=O)=O)C=CC2=1)C.C(O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1(C)C=CC=CC=1>[F:25][C:23]([F:26])([F:24])[S:20]([O:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3]3([CH2:1][CH3:2])[CH2:13][CH2:12][C:11]4([O:40][CH2:37][CH2:36][O:14]4)[CH2:10][CH:9]3[CH2:8][CH2:7][CH2:6][C:5]=2[CH:15]=1)(=[O:21])=[O:22]
Reactant: CC[C@@]12CCC(=O)C[C@@H]1CCCc1cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: CC[C@]12CCC(=O)C[C@H]1CCCc1cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC12CCC3(CC1CCCc1cc(OS(=O)(=O)C(F)(F)F)ccc12)OCCO3
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A flask equipped with a Dean-Stark apparatus was charged with trifluoro-methanesulfonic acid (7aR,11aS)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cyclohepten-3-yl ester; compound with trifluoro-methanesulfonic acid (7 aS,11aR)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cyclohepten-3-yl ester (19, R2=Ethyl) (2.2 g, 5.63 mmol), ethane-1,2-diol (1.571 mL, 28.2 mmol), pTSA (0.107 g, 0.563 mmol) and toluene (44 mL). The mixture was heated to reflux for about 21 h. The mixture was cooled to rt, EtOAc (20 mL), sat. aq. NaHCO3 (10 mL) were added and the layers were separated. The organic layer was washed with brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-40% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to yield rac-(4aR,11bS)-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-yl trifluoromethanesulfonate (20, R2=Ethyl) (2.2 g, 90%); LC/MS, method 3, Rt=3.05 min, MS m/z 435 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.42-7.35 (m, 1H), 7.26-7.22 (m, 2H), 3.91-3.69 (m, 4H), 3.04-2.77 (m, 2H), 2.43-2.37 (m, 1H), 2.22-2.13 (m, 1H), 2.11-1.94 (m, 2H), 1.71-1.62 (m, 2H), 1.61-1.54 (m, 2H), 1.52-1.35 (m, 3H), 1.32-1.17 (m, 2H), 0.59 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([C:9]#[C:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].C(=O)([O-])[O-].[H][H]>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH3:19][Si:2]([CH3:1])([CH2:9][CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:3][CH2:4][C:5]([F:6])([F:7])[F:8]
Reactant: [H][H]
Reactant: C[Si](C)(C#CCOC1CCCCO1)CCC(F)(F)F
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[Si](C)(CCCOC1CCCCO1)CCC(F)(F)F
Temperature: 25 °C

Procedure:
A suspension of compound 3 (5.00 g, 20.00 mmol) palladium hydroxide on charcoal (0.68 g, 0.21 mmol) in ethyl acetate and ethanol (100 ml, 9:1) and sodiumhydrohen carbonate (0.165 g, 1.96 mmol) were stirred at room temperature and a pressure of 100 pounds inch-2 under hydrogen for 24. The reaction mixture was filtered and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.58] to yield a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[CH:16]([C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:12][CH:11]=[N:10][N:9]2[C:13]=1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=[O:17]
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Reactant: N#Cc1ccc(Br)cc1
Product: N#Cc1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 5e (162 mg, 0.698 mmol) was coupled with 4-bromobenzonitrile (190 mg, 1.04 mmol) using the procedures described in Example 20, Step A to afford compound 76a. Mass spectrum (LCMS, ESI pos.) Calcd. For C18H15N5O2: 334.1 (M+H). found 334.1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:16]([OH:18])=O)[CH:10]=[CH:9][CH:8]=[CH:7]1.N1(C2C=CSC=2C(O)=O)C=CC=C1>>[S:12]1[C:11]2[N:6]3[C:10](=[CH:9][CH:8]=[CH:7]3)[CH2:16][C:15]=2[CH:14]=[CH:13]1.[S:12]1[C:11]2[N:6]3[C:7](=[CH:8][CH:9]=[CH:10]3)[C:16](=[O:18])[C:15]=2[CH:14]=[CH:13]1
Reactant: O=C(O)c1ccsc1-n1cccc1
Agent: O=C(O)c1sccc1-n1cccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1c2ccsc2-n2cccc21
Product: c1cc2n(c1)-c1sccc1C2

Procedure:
The triheterocyclic substrates thieno[2,3-b]pyrrolizine and thieno [2,3-b]pyrrolizin-4-one; thieno[3,2-b]pyrrolizine and thieno[3,2-b]pyrrolizin-4-one are prepared exactly according to Rault et al., Heterocycles, 20 (1983) 477. The process involves the cyclization in boiling phosphoryl chloride of amide derivatives of 2-(1-pyrrolyl)-3-thienylcarboxylic acid and 3-(1-pyrrolyl)-2-thienylcarboxylic acid to yield thieno[2,3-b]pyrrolizin-4-one and thieno[3,2-b]pyrrolizin-4-one respectively. These ketones in accordance with Method I can be derivatized to the corresponding spiro-hydantoins: spiro-(thieno [3,2-b]pyrrolizin-4,4'-imidazolidine)-2',5'-dione and spiro-(thieno [3,2-b]pyrrolizin-4,4'-imidazolidine)-2',5'-dione. Both thieono [2,3-b]pyrrolizin-4-one and thieno[3,2-b]-pyrrolizin-4-one can be reduced with 1.75 equivalents of lithium aluminum hydride in the presence of 3.5 equivalents aluminum chloride to yield the corresponding 4H-thieno-pyrrolizines quantitatively. The resulting thieno[2,3-b]pyrrolizine and thieno[3,2-b]pyrrolizine can be derivatived according to Methods II, III and IV into the corresponding spiro-thiazolidinediones, spiro-oxazolidinediones and spirosuccinimides, such as spiro-(thieno[3,2-b]pyrrolizin-4,5'-thiazolidine)-2',4'-dione, spiro-(thieno[2,3-b]pyrrolizin-4,5'-oxazolidine)-2',4'-dione and spiro-(thieno[3,2-b]pyrrolizin-4,3'-succinimide).
Reaction SMILES: Cl.N1C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@H:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)[C:23]3[C:18](=[CH:19][C:20]([O:39]C)=[CH:21][CH:22]=3)[O:17][CH2:16]2)=[CH:11][CH:10]=1>CO.O.C(=O)([O-])O.[Na+]>[OH:39][C:20]1[CH:19]=[C:18]2[C:23]([C@@H:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:27][CH:26]=3)[C@H:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[CH2:16][O:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 135 °C

Procedure:
A mixture of anhydrous pyridine hydrochloride (0.289 g, 2.50 mmol) and (±)-trans-3-(4-fluorophenyl)-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane (0.11 g, 0.25 mmol) was heated to 135° C. for 18 h. The resulting dark brown solid was dissolved in a mixture of methanol (10 ml), water (50 ml) and sodium hydrogen carbonate solution (5 ml), and the product extracted into 9:1 dichloromethane /methanol (3×50 ml). The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to an orange gum. The product was purified by column chromatography on silica gel 60, with 5% methanol in dichloromethane eluent, giving the purified product as a colourless wax.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15]O)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.CS([Cl:27])(=O)=O.C(Cl)Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:27][CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2c(c1)Nc1nccnc1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a solution of 7 g of 10H-pyrazino[2,3-b][1,4]benzothiazine-8-methanol and 6.1 ml of pyridine in N,N-dimethylformamide (50 ml) was added dropwise 5.9 ml of methanesulfonyl chloride at 0° C. After stirring at room temperature for 1 hour, the reaction mixture was poured into a pre-cooled aqueous solution of methylene chloride/sodium hydrogencarbonate, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were diluted with a small amount of ethyl acetate, taken up by filtration and washed with diethyl ether. Thus 4.7 g of the title compound was obtained as a yellow powder.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:8]([C:14]2[C:19]([CH:20]=O)=[CH:18][N:17]=[C:16]([S:22][CH3:23])[N:15]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1.O>CCCCCC.C1C=CC=CC=1>[CH:3]1([N:8]2[C:14]3[N:15]=[C:16]([S:22][CH3:23])[N:17]=[CH:18][C:19]=3[CH:20]=[C:9]2[C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)CN(c1nc(SC)ncc1C=O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1cc2cnc(SC)nc2n1C1CCCC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
Sodium hydride (3.85 g, 167 mmol) (freshly washed with hexane) was added to a solution of compound 226 (12.95 g, 41.9 mmol) in benzene (150 mL). The reaction was stirred at 70° C. After 1 h, the reaction contents were poured into water (300 mL) and extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 50% ethyl acetate in hexanes) afforded compound 227 (4.24 g, 34.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=C)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:19].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:11])=[C:9]2[C:12](=[C:16]=[O:19])[CH:13]=[CH:14][CH:15]=[C:8]2[O:7]1)=[O:5])[CH3:2]
Reactant: C=Cc1cccc2oc(C(=O)OCC)c(C)c12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: CCOC(=O)C1Oc2cccc(=C=O)c2=C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
To a solution of 0.250 g (1.087 mmol) of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester (Example 87, Step 1) in 7.5 mL of dioxane and 2.5 mL of water was added 0.272 mL of 2.5 weight % osmium tetroxide in t-butanol (0.022 mmol) and the reaction was stirred for 10 minutes at room temperature, turning yellow-brown in color. Sodium periodate (0.488 g, 2.282 mmol) was then added in several portions over 30 minutes and a white precipitate formed. The reaction was stirred at room temperature for 2 h and then diluted with water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.225 g of 4-carbonyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30]Cl)[C:25]=1[CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CO.C(OCC)(=O)C>[CH2:14]([O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:25]=1[CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCOc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 108.6 %

Procedure:
To a liquid prepared by dissolving with stirring 5.7 g (0.038 mol, 0.9 eq.) of 2-mercaptobenzimidazole and 9.7 g (0.0504 mol, 1.2 eq.) of a 28% sodium methoxide solution in 120 mL of methanol, a liquid containing 12.0 g of 4-nonyloxy-2-chloromethyl-3-methylpyridine dissolved in 60 mL of methanol was added at 29° C. Subsequently, the mixture was heated to reflux for 0.5 hours and cooled, and then methanol was solid dried under reduced pressure. A brown oily residue resulting therefrom was dissolved in 240 mL of ethyl acetate, and then the organic layer was washed with 120 mL of water. 36 g of silica gel was added with stirring to the organic layer, subsequently the silica gel was removed by filtration, and then the filtrate was concentrated to dryness under reduced pressure, to obtain 16.4 g of pale green brown crystals. The pale green brown crystals were recrystallized from ethyl acetate (10 vol.), to obtain 5.5 g of pale brown crystals (HPLC: 98.8 Area %, yield 32.9%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]=2[CH:5]=[C:4]([F:23])[CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].[C:30](=O)(O)[O-].[Na+].CI>C1COCC1.O>[Br:1][C:2]1[C:10]2[O:9][C:8]([S:11]([CH3:30])(=[O:13])=[O:12])=[C:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]=2[CH:5]=[C:4]([F:23])[CH:3]=1
Reactant: O=S(=O)(Cl)c1oc2c(Br)cc(F)cc2c1Cc1cccc(F)c1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CS(=O)(=O)c1oc2c(Br)cc(F)cc2c1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
7-Bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-2-sulfonyl chloride (0.63 gm, 1.5 mmol) was dissolved in THF (5 ml) and added dropwise to a mixture of sodium sulfite (0.504 gm, 4 mmol) and sodium bicarbonate (0.336 gm, 4 mmol) in water (12 ml). The mixture was refluxed for three hours, cooled to room temperature, and methyl iodide (0.75 ml, 12 mmol) was added. The mixture was heated to 50° C. for two hours then cooled to room temperature and stirred for 16 hours. The mixture was diluted with water and extracted twice with dichloromethane. The solution was dried over magnesium sulfate and purified by preparative thin layer chromatography (1/4, ethyl acetate/hexanes) to give 7-bromo-5-fluoro-3-(3-fluoro-benzyl)-2-methanesulfonyl-benzofuran (0.35 gm, 58% yield), (M+H)+ 402.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([C@H:27]3[CH2:32][CH2:31][C@H:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[N:18]=2)=[CH:13][C:12]=1[O:40][CH3:41]>C(O)C>[NH2:26][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:19]([C@H:27]3[CH2:32][CH2:31][C@H:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)[N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([N:10]=[CH:1][C:2]4[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=4[OH:4])=[C:12]([O:40][CH3:41])[CH:13]=3)[C:25]=12
Reactant: O=Cc1ccccc1O
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: CCO
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Salicylaldehyde (0.034 g, 0.000282 mol) and trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.117 g, 0.000268 mol) were combined in absolute ethanol and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)imino]methylphenol which was used without further purification. Trimethylsulfoxonium iodide (0.145 g, 0.00068 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and a 60% dispersion of sodium hydride in parafine (0.027 g, 00068 mol) was added at once. After 10 min., the solution of trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl) imino]methylphenol in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (50 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)-3-methoxyphenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.096 g, 0.000142 mol) as a white solid.