Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[CH:3][CH:4]=3)[C:16]=12
Reactant: Nc1ccc(-c2nn([C@H]3CCOC3)c3ncnc(N)c23)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(4-aminophenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1 g, 0.34 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)benzoyl chloride (0.050 mL, 0.34 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. The reaction proceeded until completion as judged by TLC and LC-MS, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD67. ESI-MS m/z [M+H]+ found 469.4, calculated 469.2.
Reaction SMILES: C=O.[F:3][C:4]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=3)=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7].[CH2:36](Cl)Cl.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O>[F:3][C:4]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH2:19][CH2:20][N:21]([CH3:36])[CH2:22][CH:23]=3)=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4=CCNCC4)c3c2)c1F
Reactant: ClCCl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4=CCN(C)CC4)c3c2)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
37% Aqueous formaldehyde (100 μL) was added to a solution of 2,6-difluoro-3-(propylsulfonamido)-N-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (22 mg, 0.046 mmol) in 5:1 CH2Cl2/MeOH (6 mL), followed by a drop of AcOH. After 5 minutes, sodium triacetoxyborohydride (49 mg, 5 equiv) was added, and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was quenched with MeOH, concentrated, and purified by silica gel chromatography (10:90:1 MeOH/CHCl3/NH4OH) to afford 2,6-difluoro-N-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a white solid (14 mg, 62%). 1H NMR (400 MHz, CD3OD) δ 8.90-8.88 (m, 1H), 8.62-8.60 (m, 1H), 7.70-7.63 (m, 1H), 7.17-7.11 (m, 1H), 6.57-6.53 (m, 1H), 3.35-3.31 (m, 2H), 3.14-3.09 (m, 2H), 2.90-2.83 (m, 4H), 2.49 (s, 3H), 1.92-1.82 (m, 2H), 1.08-1.04 (m, 3H); m/z (APCI-pos) M+1=491.0.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[Cl:28].Cl>O1CCCC1.O>[Cl:28][C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[C:20]1[O:19][N:18]=[CH:17][C:16]=1[CH2:3][CH2:2][C:1]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1cnoc1-c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cnoc1-c1cc(Cl)ccc1Cl
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
To a solution of diethyl malonate (2.89 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 655 mg) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(2,5-dichlorophenyl)isoxazole (2.15 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (1.35 g, yield 58%) of 3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propionic acid. melting point: 103–104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([N:25]1[CH2:33][C:32]2([C:34]([O:36][CH3:37])=[O:35])[CH:27]([C:28](I)=[CH:29][CH2:30][C:31]2([CH3:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([N:25]1[CH2:33][C:32]2([C:34]([O:36][CH3:37])=[O:35])[CH:27]([C:28]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:29][CH2:30][C:31]2([CH3:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2(C)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(OC)cc1)=CCC2(C)c1ccccc1
Yield: 51.7 %

Procedure:
A solution of 20.1 g (0.132 mol) of 4-methoxyphenylboronic acid in 580 cm3 of methanol and 1170 cm3 of a 2N aqueous sodium carbonate solution were successively added to a solution of 58.6 g (0.12 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and of 7 g of tetrakis(triphenylphosphine)palladium in 30 cm3 of toluene and then the mixture was brought to reflux for twenty-four hours. After returning to a temperature in the region of 20° C., the reaction mixture was extracted with ethyl acetate, washed with distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (98/02 by volume) mixture. 29 g (52%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4-methoxyphenyl)-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a brown powder, the characteristics of which were as follows:
Reaction SMILES: I[C:2]1[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([CH:20]=1)[C@@H:7]1[O:19][C@H:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8]1.[CH:23]1[C:40]2=[C:41]3[C:30]([C:31]4[C:42]5[C:35](=[CH:36][CH:37]=[CH:38][C:39]2=5)[CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:28]=[CH:27][C:26]3=[C:25]([C:43]#[CH:44])[CH:24]=1.CCN(CC)CC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:23]1[C:40]2=[C:41]3[C:30]([C:31]4[C:42]5[C:35](=[CH:36][CH:37]=[CH:38][C:39]2=5)[CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:28]=[CH:27][C:26]3=[C:25]([C:43]#[C:44][C:2]2[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([CH:20]=2)[C@@H:7]2[O:19][C@H:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8]2)[CH:24]=1
Reactant: C#Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reactant: CC(C)(C)C(=O)OC[C@@H]1CC[C@H](n2cc(I)c(=O)[nH]c2=O)O1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OC[C@@H]1CC[C@H](n2cc(C#Cc3ccc4c5cccc6cccc(c7cccc3c74)c65)c(=O)[nH]c2=O)O1
Temperature: 25 °C
Reaction time: 43 h
Yield: 95.5 %

Procedure:
A solution of 5-iodo-5′-O-pivaloyl-2′,3′-dideoxyuridine (442 mg, 1 mmol) and 3-perylenylacetylene (345 mg, 1.25 mmol) in 10 mL of DMF was degassed three times by alternation between vacuum and argon. Then Pd(PPh3)4 (115 mg, 0.1 mmol), CuI (38 mg, 0.2 mmol) and Et3N (0.278 mL, 2 mmol) were added and the flask was degassed once again, filled with argon, and the mixture was stirred for 43 hours at ambient temperature. The mixture was diluted with 300 mL of EtOAc, washed 3×200 mL of water, dried with Na2SO4, and evaporated. Chromatography on a silica gel column using a 0 to 2% of EtOH/CHCl3 gradient gave rise to a chromatographically homogeneous (Rf 0.28, 5% EtOH/CHCl3) product as orange foam (545 mg, 96%). 1H-NMR (DMSO-d6): 11.85 (s, 1H, NH), 8.44 (d, 1H, J 7.8), 8.39-8.35 (m, 3H), 8.32 (d, 1H, J 8.2) (perylenyl), 8.06 (s, 1H, H-6), 7.83-7.81 (m, 2H), 7.69-7.60 (m, 2H), 7.58-7.53 (m, 2H) (perylenyl), 6.00 (dd, 1H, J1′,2′α 6.9 J1′,2′β 4.6, H-1′), 4.37-4.34 (m, 1H, H-4′), 4.32-4.26 (m, 2H, H-5′), 2.42-2.36 (m, 1H, H-2′), 2.17-2.12 (m, 1H, H-2′), 2.06-2.00 (m, 1H, H-3′), 1.90-1.83 (m, 1H, H-3′), 1.17 (s, 9H, tBu).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH:9]1[CH2:10][CH2:11][O:12][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl([O-])(=O)(=O)=O.[Li+].[N-:21]=[N+:22]=[N-:23].[Na+].O>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:14]1[C@H:9]([N:21]=[N+:22]=[N-:23])[CH2:10][CH2:11][O:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCOCC21
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
3-Oxa-7-aza-bicyclo[4.1.0]heptane-7-carboxylic acid tert-butyl ester (intermediate E) (5.2 g, 26 mmol) was dissolved in 100 mL acetonitrile. Lithium perchlorate (23 g, 207 mmol) and sodium azide (6.8 g, 104 mmol) were added and the reaction mixture was stirred at 80° C. overnight. 200 mL Water was added. The mixture was extracted three times with diethylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0→1:1) yielded the title compound as a colorless oil (3.3 g, 52%), MS: m/e=186 [(M-butene)+].
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:19][C:18]([F:20])([F:21])[C:17]([NH:16][CH2:15][C@@H:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CNC(=O)C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](CNC(=O)C(F)(F)F)CC1
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A solution of 0.53 g of cis-N-(tert-butoxycarbonyl)-4-trifluoroacetylaminomethylcyclohexylamine in methylene chloride was combined with 2 mL of trifluoroacetic acid, and stirred for 2 hours. The reaction solution was basified by addition of a saturated solution of sodium hydrogen carbonate, and then extracted with chloroform. After drying over sodium sulfate, 0.19 g of the desirable compound was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([CH2:20][C:21]1([CH3:32])[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH:23]([N:29]=[C:30]=[O:31])[CH2:22]1)=[C:18]=[O:19]>>[CH2:10]([N:8]([O:9][C:30]([NH:29][CH:23]1[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:21]([CH2:20][NH:17][C:18]([O:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])([CH3:32])[CH2:22]1)=[O:31])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Product: CC1(C)CC(NC(=O)ON(Cc2ccccc2)Cc2ccccc2)CC(C)(CNC(=O)ON(Cc2ccccc2)Cc2ccccc2)C1

Procedure:
The procedure of Example 1 is repeated using 10.66 g (50 mmol) of N,N-dibenzylhydroxylamine and 5.56 g (25 mmole) of 3-isocyanatomethyl-3,5,5-trimethylcyclohexylisocyanate. The residue is recrystallized from a 1:1 heptane:toluene solvent mixture to give 11.0 g (68%) of a white soldi, m.p. 139°-146° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][C:8]([Cl:30])=[C:9]3[C:14]([C:13](=[O:15])[O:12][C:11]([C:16]4[N:17]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=5)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=4)=[N:10]3)=[C:5]2[NH:4][N:3]=1.C(#N)C.O.[CH:35]([NH2:38])([CH3:37])[CH3:36]>[Cl-].[Na+].O>[CH:35]([NH:38][C:13]([C:14]1[C:9]([NH:10][C:11]([C:16]2[N:17]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:12])=[C:8]([Cl:30])[CH:7]=[C:6]2[C:5]=1[NH:4][N:3]=[C:2]2[Br:1])=[O:15])([CH3:37])[CH3:36]
Reactant: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: CC(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)Nc2c(Cl)cc3c(Br)n[nH]c3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
To a suspension of 120 mg (0.24 mmol) of the above 3-bromo-5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 2.4 mL of a mixture acetonitrile:H2O 4:2 (v/v) is added 60 μL (0.71 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:2) affords 56 mg (42%) of a white solid; LC/MS:568/570 (M+H)+, m.p.: 217-218° C.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C(I)=C(C=CC=1)C(O)=O.N1C=CN=N1>>[F:16][C:4]1[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=[CH:2][CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc(F)c1I
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: c1c[nH]nn1
Product: O=C(O)c1cccc(F)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 3-fluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 208 [M+1]+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[CH3:25][O:24][C:22]1[CH:23]=[C:15]2[C:16]([C:17](=[O:19])[N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:13])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:11](=[O:12])[NH:14]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Product: COc1ccc2c(=O)n(S(=O)(=O)c3ccc(C)cc3)c(=O)[nH]c2c1
Yield: 50.8 %

Procedure:
269 mg (1.36 mmol) of p-toluenesulfonylisocyanate and 190 mg (1.20 mmol) of 2-amino-4-methoxybenzoic acid were treated in the same way as in Example 1 to obtain 211 mg of the above-identified compound (yield 53.5%). Properties: colorless crystal, Melting point: 228°-231° C., PMR (δppm, DMSO-d6):2.43 (3H,s), 3.79 (3H,s), 7.07 (1H,d), 7.29 (2H,br), 7.45-7.54 (2H,m), 8.04 (2H,d), 11.37 (1H,s).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][C:2]2=O.Cl.[CH3:11][C:12]1[C:24]2[N:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[CH:17][C:16]=2[C:15]([NH:25][CH2:26][CH2:27][NH2:28])=[N:14][N:13]=1>CO.CO.CS(C)=O>[CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[NH:28][CH2:27][CH2:26][NH:25][C:15]1[C:16]2[CH:17]=[C:18]3[N:23]([C:24]=2[C:12]([CH3:11])=[N:13][N:14]=1)[CH:22]=[CH:21][CH:20]=[CH:19]3
Reactant: Cc1nnc(NCCN)c2cc3ccccn3c12
Reactant: O=C1CCC2CCC1C2
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: Cc1nnc(NCCNC2CCC3CCC2C3)c2cc3ccccn3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure of Example 12, bicyclo[3.2.1]octan-2-one in methanol (3 to 4 mL) was added to a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine hydrochloride in methanol/DMSO (90 mL:30 mL) which had been heated to boiling and then allowed to cool. After stirring at room temperature overnight, the title compound was obtained as the free base after column chromatography (silica gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide) and recrystallized from isopropyl ether. The compound was converted to the dihydrochloride salt by ethanolic HCl, mp 339°-344° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.C[CH2:19][O:20]CC.C([Li])CCC.CN(C)C=O>O>[S:12]1[CH:13]=[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]1=2
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C=Cc2csc3ccccc23)s1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To a chilled (-70° C.), stirred solution of 3-[2-(5-bromo-2-thienyl)-ethenyl]benzo[b]thiophene (16.98 g) and ether (300 ml) was added n-butyllithium (23 ml of a 2.5M solution in hexanes), under nitrogen, over 5 mins. After stirring for 1.5 hrs, the mixture was added via canula to a solution of N,N-dimethylformamide (19.3 g) and ether (500 ml). The mixture was allowed to warm to room temperature, stirred overnight, and then poured into water (500 ml). The aqueous phase was separated, and the organic phase was washed with 10% aqueous hydrochloric acid, water, and 5% aqueous sodium bicarbonate solution. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give 14.9 g of solid. A lot of similarly prepared material (4.1 g) was combined with the solid, and the combined material was purified by high performance liquid chromatography (silica gel, loaded and eluted with 10% hexane in dichloromethane). The appropriate fractions were combined and evaporated. The residue was recrystallized from toluene/hexane to give 9.25 g (51%) of product, mp 105°-107° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[S:3]([O:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH2:17][O:18][S:22]([CH3:21])(=[O:24])=[O:23])[O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(Oc1cccc2oc(CCO)cc12)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cc2c(OS(=O)(=O)C(F)(F)F)cccc2o1

Procedure:
As shown in Scheme 15, 2-(2-Hydroxyethyl)-1-benzofuran-4-yl trifluoromethanesulfonate, prepared as described in Examples 85A-85C herein, is treated with methanesulfonyl chloride and triethylamine in CH2Cl2 at 0° C. to provide 2-{2-[(methylsulfonyl)oxy]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate. 2-{2-[(Methylsulfonyl)oxy]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is treated with (2R)-methylpyrrolidine mono-(L)-tartaric acid salt and Cs2CO3 in MeCN at approximately 35° C. for 1 to 4 days to provide 2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate. 2-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is processed as described in Murata, et al., Journal of Organic Chemistry (2000) 65, 164-168 to provide (2R)-2-methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-yl]ethyl}pyrrolidine. For example, one equivalent of 2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is treated with palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl2dppf), 3 equivalents of triethylamine, and 1.5 equivalents of pinacolborane in 1,4-dioxane at 25° C. for several hours or until the reaction is complete as judged by TLC. (2R)-2-Methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-yl]ethyl}pyrrolidine is treated with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides, a palladium catalyst, such as palladium (II) acetate, a trivalent phosphine such as biphen-2-yl-dicyclohexylphosphine, and aqueous sodium carbonate or potassium phosphate in an organic solvent such as ethanol or tetrahydrofuran at 25° C. to 120° C. to provide compounds of formula (51). Compounds of formula (51) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (51) is partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-n2cnc3ccccc32)nc1-c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
A mixture of 2-chloro-4-phenylthiazole-5-carboxylic acid ethyl ester (134 mg, 0.5 mmol), benzimidazole (Aldrich) (73.8 mg, 0.625 mmol) and LiN(TMS)2 (1N tetrahydrofuran solution, 0.63 ml) in tetrahydrofuran (2 ml) was heated in a micro-wave oven at 120° C. for 30 min. Water (3 ml) was added and the mixture was filtered, washed with water and ethyl acetate, dried in air flow to give 2-(benzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (108 mg, 61%). The aqueous solution was concentrated to remove tetrahydrofuran and then extracted with ethyl acetate to recover an additional amount of the product (100 mg, 75% pure). 1H-NMR (CDCl3) 8.84 (s, 1H); 8.16 (d, 1H); 7.81-7.90 (m, 3H); 7.39-7.58 (m, 5H); 4.37 (q, 2H); 1.27 (t, 3H). MS M/z 350 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[N:14]1([C:10]2[CH2:9][CH2:8][C:7]3[C:12]([CH:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: COc1cccc2c1C=C(N1CCCC1)CC2

Procedure:
To 75 ml of toluene were added 3.52 g (20 mmol) of 8-methoxy-2-tetralone followed by 2.5 g of pyrrolidine. The mixture was heated to reflux for three hours after which the solvent was evaporated in vacuo to give 3-pyrrolidino-5-methoxy-1,2-dihydronaphthalene as a dark oil.