Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:38][NH:39][CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([CH2:25][N:39]([CH3:40])[CH3:38])=[CH:23][CH:24]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(CN(C)C)cc3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 6) (75 mg) was dissolved in DCM (5 ml). Dimethylamine hydrochloride (18.42 mg) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (160 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, for 5 h. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator overnight to give (S)-2-(6-(4-chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (48.2 mg) as a white solid. LCMS (formate): MH+ 527/529, RT 0.66 min
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1O)=[O:3].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:20][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=3[C:2](=[O:3])[CH:1]=2)=[CH:17][CH:16]=1
Reactant: COc1cccc(O)c1C(C)=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: COc1cccc2oc(-c3ccc(C(F)(F)F)cc3)cc(=O)c12

Procedure:
3 is prepared from 2-hydroxy-6-methoxyacetophenone and 4-trifluoromethylbenzoyl chloride by the procedure of Example 1. The material is purified by flash chromatography (gradient elution using 25% ethyl acetate in hexane, 40% ethyl acetate in hexane, 60% ethyl acetate in hexane; material is loaded on column in methylene chloride), yielding 3 with a melting point of 190°-191° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:15])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: Cc1cc(Br)cc(F)c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(F)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-bromo-2-fluoro-6-methyl benzoic acid (200 g) was dissolved in 1 L of THF and treated portion wise with carbonyldiimidazole (180 g, 1.3 eq). The reaction mixture is stirred at ambient temperature for about 3 hours and then quenched by addition of aqueous ammonium hydroxide (400 ml). The resulting reaction mixture was stirred overnight at ambient temperature and then concentrated under reduced pressure to about 0.5 L volume. The resulting slurry was diluted by adding 1 L of water. The precipitated product was isolated by filtration, washed with water (3×300 ml), dried under vacuum at about 60° C. to obtain 174 g (87% isolated yield) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][CH3:21])[C:13]=1[NH2:25].[C:26](OC)(=[O:30])[C:27]([CH3:29])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:18]([CH:19]([CH2:22][O:23][CH3:24])[CH2:20][CH3:21])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: CCC(COC)Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N
Reactant: COC(=O)C(C)=O
Product: CCC(COC)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-Chloro-4-difluoromethoxy-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.268 g, 0.72 mmol) and methyl pyruvate (130 μL, 1.44 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 122a): 1H NMR (300 MHz, CDCl3) δ □8.54–8.51 (m, 1H), 7.33–7.32 (m,2H), 7.21–7.14 (m, 2H), 6.85–6.37 (t, 1H, J=72.9 Hz), 6.21–6.19, 5.64–5.58 (2m, 1H), 4.40–4.31 (m, 1H), 3.92–3.79 (m, 1H), 3.33 (s, 3H), 2.48 (s, 3H), 2.30–2.20 (m, 1H),2.13–1.96 (m, 1H), 0.90–0.85 (t, 3H, J=7.7 Hz). MS (AP) m/z 424.1 [(M+H)+, 100].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[N+:11]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[O:24][C:25]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[NH:27][N:26]=1)([O-:13])=[O:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:27]1[C:28]([C:30]([F:31])([F:33])[F:32])=[CH:29][C:25]([O:24][C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])=[N:26]1)=[O:10]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cc(C(F)(F)F)[nH]n1
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CNC(=O)n1nc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
Potassium carbonate (0.58 g, 4.2 mmol) and methyl isocyanate (0.20 g, 3.5 mmol) were added to a solution of 3-(2-nitro-4-trifluoromethylphenyloxy)-5-trifluoromethylpyrazole (1.43 g, 4.2 mmol) in ethyl acetate (15 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5→1/1), to give a yellowish solid of N-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)-5-trifluoromethylpyrazole-1-carboxamide (0.70 g, yield: 50.4%). mp: 102-104° C./1H-NMR (CDCl3, TMS, ppm): δ 3.53 (s, 3H), 5.63 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.95 (d, J=8.3 Hz, 1H), 8.39 (s, 1H), 10.05-10.75 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12](C(C)=C)[C:11]3=[O:22])[C:4]=2[CH:3]=1.CO.O.Cl>C(Cl)Cl.C(Cl)Cl.CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:22])[C:4]=2[CH:3]=1
Reactant: C=C(C)n1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2ccccc2n1Cc1csc2ccc(Cl)cc12
Temperature: 80 °C
Yield: 89.6 %

Procedure:
1-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (0.53 g, 1.56 mmol) was treated with MeOH (5 mL) followed by water (5 mL). To this heterogeneous reaction mixture was added 37% hydrochloric acid (4 mL). This heterogeneous reaction mixture was heated to 80° C. for 30 min. A white solid was precipitated out. TLC indicated that reaction was complete (starting material Rf 0.8, product Rf 0.4, CH2Cl2:MeOH 95:5). The reaction mixture was diluted with CH2Cl2 (at this point a white precipitate was completely soluble in CH2Cl2) and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.44 g (89%) of the desired product as a white solid. This product was used for the next reaction without further purification. LCMS (ESMS): m/z 315.79 (M+H+).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[S:24][C:23]([S:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[N:22][N:21]=1.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[S:24][C:23]([S:25][CH2:26][C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:28])=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: O=C(CSc1nnc(S)s1)N1CCOCC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(SCC(=O)N4CCOCC4)s3)CS[C@H]12

Procedure:
While utilizing 0.680 g of 7-ACA, 0.900 g of 5-mercapto-2-morpholinocarbonylmethylthio-1,3,4-thiadiazole, 4.0 ml of acetonitrile and 2.70 g of DCPA, the procedure was carried out in accordance with Example 5, and there was obtained 1.02 g (83.3% of yield) of red brown powder of 7-amino-3-[(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]2[N:12]([CH2:13][C:14]([CH3:27])([CH3:26])[CH:15]2[O:24][CH3:25])[C:11]=1[C:28](=O)[C:29]([O:31]CC)=[O:30].O.NN.[OH-].[K+].Cl>C(O)COCCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]2[N:12]([CH2:13][C:14]([CH3:26])([CH3:27])[CH:15]2[O:24][CH3:25])[C:11]=1[CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)C(=O)c1c(-c2cc3ccccc3o2)c(-c2ccccc2)c2n1CC(C)(C)C2OC
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: COC1c2c(-c3ccccc3)c(-c3cc4ccccc4o3)c(CC(=O)O)n2CC1(C)C
Reaction time: 4 h

Procedure:
Ethyl 6-(2-benzofuranyl)-2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetate (example 21b, 0.92 g, 2 mmol) in diethylene glycol (20 ml) is heated at 60° C. for 30 min. with hydrazine hydrate 80% (1.56 ml, 40 mmol), then treated with KOH techn. 85% (2.1 g, 32 mmol) and the mixture is kept at 130° C. for 4 h (until the end of the evolution of gas and fading of the coloration). The mixture, which is poured onto ice, is brought to pH 3 using HCl 10%, and the fine precipitate is filtered off with suction and dried over P2O5.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:17][C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCCC1CCCCC1=O
Product: CCOC(=O)CCCCCC1=C(OC(C)=O)CCCC1

Procedure:
Treatment of 2-(5-carbethoxypentyl)cyclohexan-1-one (Example 15) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: CN1CCC(=O)CC1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CN1CCC(N2CCN(c3ccc(N/C=C4\C(=O)NC(=O)c5ccc(I)cc54)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), 1-methyl-piperidin-4-one (0.318 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 45 mg (78%) of the title compound as a yellow solid. MS (ESI) m/z 572.2 (M+H)+1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[Br:23]
Reactant: Nc1cc(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1c(Br)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 1 h

Procedure:
A mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.64 g) and N-bromosuccinimide (1.78 g) in carbon tetrachloride (30 ml) was stirred and heated under reflux for 1 hour. Further N-bromosuccinimide (0.89 g) was added, and reflux was continued for a further 1 hour. The mixture was cooled, filtered, and the filtrate was evaporated in vacuo to give an orange solid. Recrystallization from petroleum ether gave 5-amino-4-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole in the form of white crystals (2.6 g) m.p. 119-120° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13](N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].[CH:21](=[O:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>O.Cl>[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([C:25]2[O:26][C:22]([CH:21]=[O:27])=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccco1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(-c2ccc(OCc3ccccc3)cc2)o1
Reaction time: 0.75 h

Procedure:
A mixture of 236 g (1.0 mole) of p-benzyloxyaniline hydrochloride in 1.5 l of water and 230 ml of conc. HCl was warmed on a steam bath for 11/2 hours. No solution was effected. The mixture was then cooled down to 0°-5° and a solution of 76 g (1.1 mole) of sodium nitrite in 500 ml of water was added in about 1 hour while keeping the temperature at 4°-7°. The mixture was allowed to stir further for an additional 45 minutes while the temperature gradually rose to 10°. Furfural (192 g, 2 moles) and 55 g of cupric chloride dihydrate in a minimum amount of water was added and the mixture was allowed to stir at ambient temperature overnight. Solid started to separate after 2 days of stirring. The solid was collected, washed well with water. The filtrate and the water washings were combined and allowed to stir for an additional 4 days while more solid separated. The dark gummy solids were combined, triturated with ether, filtered and air dried. Repeated recrystallizations from hot cyclohexane gave 48.5 g (17.5%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:21]([O:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37](Cl)=[N:38][CH:39]=2)[CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[Si:21]([O:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:38][CH:39]=2)[CH2:30]1)([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(Cl)nc2)C1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)C1
Temperature: 120 °C
Yield: 0 %

Procedure:
A 10 mL reaction vessel was charged with compound 245 (75.0 mg, 276 mmol), (R)-5-(3-(t-butyldimethylsilyloxy)pyrrolidin-1-yl)-2-chloropyridine (86.5 mg, 276 mmol), tris(dibenzylideneacetone)dipalladium (0) (19.0 mg, 20.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (24.0 mg, 41.5 mmol), sodium t-butoxide (53.1 mg, 553 mmol), and dioxane (1.5 mL). The reaction was heated with microwave energy (300 W) for 2 hours at 120° C. in the resulting solution was added to ethyl acetate (40 mL) and washed with water (30 mL) followed by brine (30 mL). The organic phase was dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution 35% ethyl acetate in hexanes) afforded compound 278 as a yellow solid (59 mg, 39%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[C:28]2=[N:29][CH:30]=[C:31]([OH:33])[CH:32]=[C:27]2[CH:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:31]4[CH:32]=[C:27]5[CH:26]=[CH:25][NH:24][C:28]5=[N:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cnc5[nH]ccc5c4)ncnc32)CC1
Temperature: 160 °C
Yield: 32.1 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 1H-pyrrolo[2,3-B]pyridin-5-ol (Matrix Scientific, Columbia, S.C., USA; 26 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (21 mg, 33%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.80-2.15 (m, 4H), 3.02 (br s, 2H), 4.08 (d, 2H, J=12.4 Hz), 4.85-5.10 (m, 1H), 6.45-6.52 (m, 1H), 7.58 (d, 1H, J=2.9 Hz), 7.94 (d, 1H, J=2.5 Hz), 8.20 (d, 1H, J=2.5 Hz), 8.22 (s, 1H), 8.50 (s, 1H), 11.85 (br s, 1H). Mass spectrum (ES) MH+=436. HRMS Calcd. for C22H26N7O3 (MH+): 436.2092. Found: 436.2090.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[O:11][C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(CC)CC)C.CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.Cl[C:49]([O:51][CH2:52][CH3:53])=[O:50]>C1COCC1>[CH2:52]([O:51][C:49](=[O:50])[O:14][C:13]1[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[O:11][C:10](=[O:22])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:53]
Reactant: CON1CCC2(CC1)OC(=O)C(c1cc(C)ccc1C)=C2O
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)OC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-oxa-8-aza-spiro[4.5]dec-3-en-2-one (120 mg, 0.40 mmol), triethylamine (0.08 ml, 60 mg, 0.60 mmol) and 4-dimethylaminopyridine DMAP (2 mg, 0.02 mmol) in 4 ml THF at 0° C. was added a solution of ethyl chloroformate (0.05 ml, 52 mg, 0.50 mmol) dissolved in 1 ml THF dropwise. The suspension was kept at 0° C. for 30 minutes under argon and left stirring at room temperature overnight. Then the solvent was removed under vacuum. Ethyl acetate was added to the residue and the precipitation was filtered off. The filtrate was concentrated under vacuum to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate/cyclohexane 1:9). Yield: 111 mg of carbonic acid 3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-oxa-8-aza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound P1.1) as a light yellow gum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30]Cl>>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Product: CN(C)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
When 3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran is reacted with 3-dimethylaminopropyl chloride by the procedure described in Example 1, 3-[4-(3-dimethylaminopropoxy)phenylsulfonyl]-2-phenylbenzofuran is obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][CH:35]=O.C([BH3-])#N.[Na+]>CO>[C:28]1([C:21]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([CH2:34][CH2:35][N:10]3[CH2:9][CH2:8][C:7]4[C:12](=[CH:13][C:4]([C:3]([F:2])([F:14])[F:15])=[CH:5][CH:6]=4)[CH2:11]3)[C:17]2=[O:16])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=CCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1N(CCN2CCc3ccc(C(F)(F)F)cc3C2)CCC1(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.153 g, 0.644 mmol), the product from Example 67B (0.120 g, 0.430 mmol) and sodium cyanoborohydride (0.040 g, 0.644 mmol) were stirred together in methanol (0.5 mL) at room temperature. After stirring overnight, the reaction was concentrated, dissolved in minimal dichloromethane and was loaded directly onto a SF15-12 column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.42 (m, 1H), 7.29-7.34 (m, 4H), 7.18-7.26 (m, 2H), 7.12-7.18 (m, 6H), 3.66 (s, 2H), 3.63 (t, J=6.2 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.69-2.84 (m, 8H); MS (ESI+) m/z 465 (M+H)+.