Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>CN(C)C=O>[CH:32]1([CH2:35][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH2:34][CH2:33]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC2CC2)C1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 51, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (53%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1(C(OC)=O)[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14].[C-]#N>CS(C)=O.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14]
Reactant: COC(=O)C1(CCC2OCCO2)CCCCC1=O
Agent: [C-]#N
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCCCC1CCC1OCCO1

Procedure:
The product of Example 102 was reacted with sod ,m cyanide (0.69 g, 14.1 mmoles) in 25 mL of DMSO at 160° C. for 12 hrs. The reaction mixture was then diluted to 700 mL with water and extracted with ethyl acetate/hexane (1:1). The solvent removed from the extracts to provide the title compound as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CN=C1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:5]2=[O:15]
Reactant: Nc1cccnc1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(c1cccnc1)C2=O
Temperature: 190 °C
Yield: 62.2 %

Procedure:
5-Amino-6-nitroisoindoline-1,3-dione (3.00 g, 14.48 mmol), 3-aminopyridine (5.45 g, 57.92 mmol) and imidazole (3.94 g, 57.92 mmol) were suspended in diphenyl ether (50 mL). The mixture was stirred and heated to 190° C. for 3 days under argon. Then, the solid was filtered, washed with hexanes and purified by column chromatography (silica-gel, CH2Cl2/Acetone=7/3 v/v) to give a yellow solid product, 2.56 g, 62.2% yield. MS: 282.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.65 (d, 1H, J=2.0 Hz), 8.62 (dd, 1H, J1=5.0 Hz, J2=1.0 Hz), 8.46 (S, 2H), 8.42 (s, 1H), 7.89 (m, 1H), 7.60-7.58 (m, 1H), 7.55 (s, 1H).
Reaction SMILES: Cl.[OH:2][C@H:3]([C:15]1[CH:24]=[CH:23][C:18]2[C:19](=[O:22])[O:20][CH2:21][C:17]=2[C:16]=1[CH3:25])[CH2:4][NH:5][C:6]1([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH2:9][CH2:8][CH2:7]1.[CH3:26][C:27]1[C:35]2[CH2:34][O:33][C:32](=[O:36])[C:31]=2[CH:30]=[CH:29][C:28]=1[C@@H:37]1[CH2:39][O:38]1>>[OH:38][C@H:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:32](=[O:36])[O:33][CH2:34][C:35]=2[C:27]=1[CH3:26])[CH2:39][N:12]1[CH2:13][CH2:14][CH:10]([C:6]2([NH:5][CH2:4][C@H:3]([OH:2])[C:15]3[CH:24]=[CH:23][C:18]4[C:19](=[O:22])[O:20][CH2:21][C:17]=4[C:16]=3[CH3:25])[CH2:9][CH2:8][CH2:7]2)[CH2:11]1
Reactant: Cc1c([C@@H](O)CNC2(C3CCNC3)CCC2)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNC2(C3CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)C3)CCC2)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[3-(1-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}cyclobutyl)pyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(1R)-1-hydroxy-2-{[1-(pyrrolidin-3-yl)cyclobutyl]amino}ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 5] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[C:34]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:34]4[C:35]([CH3:40])=[CH:36][C:37]([CH3:39])=[CH:38][C:33]=4[CH3:32])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)cc(C)cc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4,6-trimethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=603.7)=60%.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5].[Br:18]Br>C(O)(=O)C>[Br:18][C:10]1[C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[O:7][C:6]=1[C:4]([N:3]([O:2][CH3:1])[CH3:17])=[O:5]
Reactant: COc1ccc2oc(C(=O)N(C)OC)cc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc2oc(C(=O)N(C)OC)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution (100 mL) of N,5-dimethoxy-N-methyl-1-benzofuran-2-carboxamide (9.24 g) synthesized above in acetic acid was added dropwise bromine (2.21 mL), and the mixture was stirred overnight at room temperature. The resulting precipitate was collected by filtration and washed with diisopropyl ether to give the title object compound (9.48 g, 77%) as an orange solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C1COCC1.[Cl-].[Na+].O>[CH:25]([S:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1)(=[O:29])=[O:28])([CH3:26])[CH3:24]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CC(C)S(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cn(S(=O)(=O)C(C)C)c2ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of methyl 1H-indole-3-carboxylate (0.234 g, 1.336 mmol) in THF (6.68 ml) was added sodium bis(trimethylsilyl)amide (2.67 ml, 2.67 mmol) at RT. After 30 min, propane-2-sulfonyl chloride (0.3 ml, 2.67 mmol) was added and the mixture was stirred for 2 h. The reaction mixture was then poured into brine and extracted twice with EtOAc. The combined extracts were filtered through MgSO4 and concentrated to give the title compound as a brown solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH2:23]O)[CH:20]=[C:19]([CH2:25][CH2:26][CH3:27])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:23][C:21]1[CH:20]=[C:19]([CH2:25][CH2:26][CH3:27])[C:3]([O:4][CH:5]([C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[C:2]([Cl:1])[CH:22]=1
Reactant: CCCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(CBr)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0°-5° C.), magnetically stirred solution of 0.445 g (1.13 mmol) of the product of step D and 0.446 g (1.70 mmol) of triphenylphosphine dissolved in 5 mL of dichloromethane was added 0.564 g (1.70 mmol) of carbon tetrabromide in several portions. After the addition was complete, the reaction was allowed to warm to room temperature and was stirred an additional 30 minutes. The methylene chloride was then removed in vacuo, and the residue was applied to a silica gel flash chromatography column and eluted with 10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound which was used directly in the next step without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=O)[N:8]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccc(Br)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 14.5 %

Procedure:
To a solution of 3-(7-bromo-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide (1.13 g) in methanol (19 ml) and methylene chloride (45 ml) under an atmosphere of argon was added NaBH4 (114 mg) portionwise and the reaction stirred at room temperature for 17 hours. Concentrated hydrochloric acid (0.2 ml) was added and the reaction stirred for a further 1 hour. The reaction mixture was concentrated and the residue resuspended in methylene chloride, washed 2N HCl, dried (magnesium sulfate) and concentrated to give 3-(7-bromo-1-oxoisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a brown solid (157 mg); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 2.10 (s, 3H), 2.85 (m, 1H), 6.80 (d, 1H), 7.42 (d, 1H), 7.51 (d, 1H), 7.78 (d, 1H), 7.79 (s, 1H), 7.89 (d, 1H), 7.97 (d, 1H), 8.35 (s, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].[O:10]1[CH2:33][CH:11]1[CH2:12][O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:16]([CH3:32])([CH3:31])[CH2:15]1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:33][CH:11]([OH:10])[CH2:12][O:13][CH:14]2[CH2:15][C:16]([CH3:31])([CH3:32])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:18]([CH3:20])([CH3:21])[CH2:19]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(O)cc1
Reactant: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Product: C=Cc1ccc(OCC(O)COC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)cc1

Procedure:
4-Vinylphenol is reacted with 4-(2,3-epoxypropoxy)-1-octyloxy-2,2,6,6-tetramethylpiperidine (=epoxide A3)analogously to Example B6) to form the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[H-].[Na+].I[CH2:20][CH3:21]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:20][CH3:21])=[CH:10][CH:9]=2)[CH:15]=1
Reactant: CCI
Reactant: Oc1ccc(Cc2cc(Br)ccc2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc(Br)ccc2F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
To a solution of 4-(5-bromo-2-fluoro-benzyl)-phenol (6.0 g, 21.0 mmol) in anhydrous N,N-dimethylformamide (20 mL) cooled at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.02 g, 25.6 mmol). After stirring at 0° C. for 45 minutes, iodoethane (2.08 mL, 25.6 mmol) was added dropwise and the resulting mixture was allowed to warm up to room temperature. After 18 hours, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 10% ethyl acetate in heptane to afford 4.6 g (58% yield) of the desired product as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[Na+]>CN(C)C=O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
To a solution of (2S, 4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5 g) and triethylamine (1.87 ml) in N,N-dimethylformamide (50 ml) was dropwise added ethyl bromoacetate (1.49 ml) at ambient temperature with stirring. The mixture was stirred at 40° C. for 30 minutes and then allowed to stand at ambient temperature for 6 hours. The reaction mixture was poured into saturated aqueous sodium chloride (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was subjected to a column chromatography on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S, 4R)-4-t-butyldimethylsilyloxy-2-[(ethoxycarbonylmethyl)aminomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.52 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O:25]1[CH2:30][CH2:29][O:28][C:27]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:26]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:25]1[CH2:30][CH2:29][O:28][C:27]2[CH:31]=[C:32]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:33]=[CH:34][C:26]1=2
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCO4)n2n1
Temperature: 110 °C
Yield: 74 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 2,3-dihydrobenzo[b][1,4]dioxin-6-ylboronic acid (41 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 9.5 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (55-65% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (57.2 mg, 74%). Melting point (99.5-99.6° C.). 1H NMR (DMSO-d6) δ: 11.14 (s, 1H), 8.02 (d, J=8.6 Hz, 2H), 7.95 (s, 1H), 7.75 (d, J=2.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.57 (dd, J=8.5, 2.1 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.36 (s, 1H), 4.31-4.40 (m, 4H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 445.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:56][CH2:57][CH:58]([OH:64])[CH2:59][NH:60][CH:61]1[CH2:63][CH2:62]1>CN(C=O)C>[CH:61]1([NH:60][CH2:59][CH:58]([OH:64])[CH2:57][NH:56][C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:63][CH2:62]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: NCC(O)CNC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCC(O)CNC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (208 mg, 0.4 mmol), HOBt (54 mg, 1 eq.) and EDAC (153 mg, 2 eq.) in DMF (1.5 mL) was stirred at rt for 30 mins. To the mixture was added 1-amino-3-cyclopropylamino-propan-2-ol (104 mg, 2 eq.) in DMF (1.5 mL). After stirring at rt for overnight, the reaction was concentrated and purified on a silica gel column to give 115 mg (45%) of the titled compound.
Reaction SMILES: [NH3:1].Cl[CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1>C(Cl)Cl>[NH2:1][CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1
Reactant: N
Reactant: O=C1Nc2ccccc2SC1Cl
Solvent: ClCCl
Product: NC1Sc2ccccc2NC1=O
Yield: 41 %

Procedure:
Anhydrous ammonia gas was bubbled for one hour through a suspension of 500 mg (2.5 mmol) of 2-chloro-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (prepared by the method of Worley, et al; J. Org. Chem., 40, 1731-1734 (1975)) in 5 mL of methylene chloride. The mixture was filtered through Celite and the filtrate evaporated under vacuum. The residue was triturated with 20 mL of chloroform, filtered and the filtrate evaporated under vacuum. Purification by flash chromatography on silica, eluting with ethyl acetate, afforded 185 mg (1.0 mmol, 41%) of the product. 1H NMR (200 MHz, CDCl3): 2.00 (br s,2H), 4.68 (br s,1H), 6.9-7.4 (m,4H), 9.05 (br s,1H). FAB-MS: calculated for C8H8N2OS 180; found 181 (M+h,54%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[Br:16]N1C(=O)CCC1=O.Cl>CN(C=O)C>[Br:16][C:4]1[C:3]2[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
A solution of 1.0 g (4.9 mmol) of methyl 4,7-dimethylindole-2-carboxylate in 22 ml of DMF was cooled to 0° C. A solution of 1.03 g (9.8 mmol) of N-bromosuccinimide in 52 ml of DMF was added dropwise at 0° C. over a period of 1 hour and the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into 400 ml of ice water, acidified with a 1N HCl aqueous solution and extracted with 100 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to provide 510 mg of yellow crystals. Yield: 36%
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][N:10]([CH3:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:12])=[O:8])([O:3]C)=O.C(OCC)C.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][N:10]([CH3:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:12])=[O:8])=[O:3]
Reactant: CNC
Reactant: COC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1ccccc1
Solvent: CCOCC
Product: CN(C)C(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1ccccc1

Procedure:
1-(2-Carbomethoxybenzoyl)-2-methyl-4-phenyl-3-thiosemicarbazide (5 g, 0.148 mole) was suspended in aqueous dimethylamine. The pH of the suspension was adjusted to about 3. A tacky precipitate was formed which became solid after addition of diethyl ether. This solid--title product--had a melting point of 140°-143°, yield 3.7 g.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23]O)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:22][CH2:23][N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7]
Reactant: CN1CCNCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCO)CN2c1ccccc1
Product: CN1CCN(CCN2CN(c3ccccc3)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)CC1

Procedure:
The title compound, MS: m/e=598.1 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-methylpiperazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[CH:17]=[CH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[CH3:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
A mixture of 5-nitro-2-pyridinecarbaldehyde (2.85 g prepared according the procedure described in J. Med. Chem. 1992, 35, 3675) and (carbethoxymethylene)triphenylphosphorane (6.0 g) in dry toluene (120 ml) under nitrogen was stirred and heated at reflux for 6 hours. After standing at room temperature overnight the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica gel eluting with dichloromethane to give the title compound (0.8 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH:10]=[CH2:11])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:10]([CH2:11][OH:20])[CH2:9][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: OCC1Cc2cc(Cl)ccc2O1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-2-(prop-2-en-1-yl)phenol (17 g, crude, nominally 101 mmol) in chloroform (100 ml) was added mCPBA (17.4 g, 101 mmol, 1 eq) with stirring for 1 h at 50° C. in an oil bath. Then the reaction mixture was concentrated under vacuum and re-dissolved in MeOH (100 ml). Potassium carbonate (27.6 g, 200 mmol, 2 eq) was added and the mixture was stirred for 5 hours at 50° C. The solids were filtered off and the filtrate was concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow oil (6.15 g); 1H NMR (300 MHz, CDCl3): δ 7.00-7.18 (m, 2H), 6.80 (d, J=8.7 Hz, 1H), 4.88-4.97 (m, 1H), 3.85-3.90 (m, 1H), 3.70-3.79 (m, 1H), 3.19-3.27 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.98-3.05 (dd, J=7.5 Hz, 15.9 Hz, 1H), 2.10 (broad s, 1H).