Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)=[N:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH2:27]([Mg])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(OC)(C)C.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: [Mg]Cc1ccccc1
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of (R)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (1.09 g, 2.68 mmol) in anhydrous TBME (45 mL) at −78° C. under argon was added BF3Et2O (0.57 mL, 5.38 mmol). After 5 min, benzylmagnesium grignard (5.38 mL, 5.38 mmol, 1.0M in ether) was added dropwise with stirring. After 40 min, LCMS indicated that the reaction was complete and the cold solution was quenched with saturated NaCl (ca 20 mL), transferred to a separation funnel and the organic phase extracted with EtOAc (3×20 mL). The combined organic portions were dried, decanted, concentrated and purified by silica gel ISCO chromatography. 2×120 g cartridge columns were used 0-60% EtOAc/hexanes over 20 min. A trace amount of minor diastereomer eluted first followed by the major diastereomer (R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.97 g, 72% yield). Rf 0.4 (Hexane:EtOAc 2:1) LCMS: 2.15 min [M+1] 499.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 4.15 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%; NMR: 400 MHz 1H (CDCl3) 8.65 ppm, d, 1H, J=2.6 Hz; 7.62 ppm, dd, 1H, J=2.6 and J=8.8 Hz; 7.36 ppm, 4H, m; 7.29 ppm, 1H, m; 7.24 ppm, 1H, m; 7.14 ppm, 2H, m; 6.99 ppm, 1H, d, J=10.1 Hz; 6.81 ppm, 1H, d, J=6.6 Hz; 4.09 ppm, 1H, d, J=13.2 Hz; 3.69 ppm, 1H, d, J=13.2 Hz; 1.18 ppm, 9H, s.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5](B2OC(C)(C)C(C)(C)O2)[C:4]([CH3:17])=[N:3]1.Br[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=2)[N:21]([CH2:29][CH2:30][CH2:31][O:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C:20]=1[C:43]([O:45]CC)=[O:44].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:29][CH2:30][CH2:31][O:32][C:33]1[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=1)[C:20]([C:43]([OH:45])=[O:44])=[C:19]2[C:5]1[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1c(Br)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(C)c1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (43.2 mg), ethyl 3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 134B as an intermediate) (43 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (15.01 mg) and K3PO4 (58.2 mg) in toluene (2.1 ml) was heated in a microwave reactor (CEM Discover) at 110° C. for 2 hours. The reaction was directly loaded into a silica cartridge, and eluted with 0%-25% ethyl acetate in dichloromethane. The collected desired ester was hydrolized with NaOH in tetrahydrofuran-methanol-H2O at 50° C. overnight to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.15 (d, J=8.90 Hz, 1H), 7.86 (d, J=7.36 Hz, 1H), 7.71 (dd, J=9.21, 4.30 Hz, 1H), 7.42-7.56 (m, 3H), 7.32-7.41 (m, 1H), 7.05-7.16 (m, 1H), 6.92 (dd, J=9.36, 2.61 Hz, 1H), 6.86 (d, J=7.36 Hz, 1H), 4.69-5.00 (m, 2H), 4.17 (t, J=5.83 Hz, 2H), 3.72 (s, 3H), 2.27-2.43 (m, 2H), 1.99 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[Cl-]>O>[NH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=[O:11])[C:6]([Cl:1])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: CON=C(C(=O)O)c1cccc(N)n1
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Product: CON=C(C(=O)O)c1nc(N)ccc1Cl

Procedure:
To a mixture of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer), acetic acid (350 ml.) and water (10 ml.) was introduced chloride gas for 1.5 hours. After the removal of the excess of the chlorine gas by bubbling air into the reaction mixture, the solvent was distilled off. The residue was pulverized in diethyl ether and collected by filtration. After the addition of water and ethyl acetate to the resultant powder (9.8 g.), the aqueous layer was separated and washed with ethyl acetate. The ethyl acetate layer and washings were combined together, and further extracted with water. The aqueous layers were combined together and adjusted to pH 4 with 1N aqueous solution of sodium hydroxide, and then the solvent was distilled off under reduced pressure. The remaining water in the residue was azeotropically removed with benzene three times to yield brownish powder which was dried in a desiccator to give 2-(6-amino-3-chloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (3.27 g.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH3:19])[S:6]([C:9]2[CH:10]=[N:11][C:12]([Sn](C)(C)C)=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:3][CH2:2]1.[NH2:20][C:21]1[C:26]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]3)=[CH:25][C:24](Br)=[CH:23][N:22]=1>>[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:12]2[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH3:19])(=[O:8])=[O:7])=[CH:10][N:11]=2)=[CH:25][C:26]=1[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]2
Reactant: CN(CC1CC1)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Reactant: Nc1ncc(Br)cc1-c1ccc2c(c1)CCNC2=O
Product: CN(CC1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)nc1
Yield: 45 %

Procedure:
General method D was applied to N-(cyclopropylmethyl)-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (233 mg, 0.6 mmol) and 6-(2-amino-5-bromopyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (190 mg, 0.6 mmol) to give 6′-amino-N-(cyclopropylmethyl)-N-methyl-5′-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (127 mg, 0.27 mmol, 46% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (d, J=1.5 Hz, 1H), 8.84 (d, J=2.3 Hz, 1H), 8.05-8.19 (m, 3H), 7.90-7.98 (m, 2H), 7.43-7.50 (m, 2H), 6.34 (s, 2H), 3.38-3.45 (m, 2H), 2.97 (t, J=1.0 Hz, 2H), 2.91 (d, J=6.8 Hz, 2H), 2.80 (s, 3H), 0.85-0.96 (m, 1H), 0.43-0.51 (m, 2H), 0.16-0.21 (m, 2H); MS (EI) m/z=464.5 [M+1]+.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]=O.[H][H]>[Pt]=O.C(O)C>[CH3:12][NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: C=O
Reactant: COC(=O)c1ccccc1N
Agent: O=[Pt]
Solvent: CCO
Product: CNc1ccccc1C(=O)OC

Procedure:
In a 250 mL Parr shaking glass pressure reactor was placed methyl anthranilate (37.75 g, 0.25 mol), 95% ethanol (80 mL), and platinum oxide (0.5 g). To this cooled mixture at 5° C. was added 37% formaldehyde solution (20 mL, 0.25 mol). This resultant mixture was immediately hydrogenated at room temperature at a hydrogen pressure of 50 psig. Over a period of 5 hours no hydrogen uptake was observed. The dimer, however, did form as evidenced by a solid precipitate, but no methyl N-methylanthranilate was produced.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([O:20][CH2:21][CH2:22][OH:23])(=[O:19])[CH2:16][CH2:17][CH3:18].CS(C)=O.CCN(CC)CC>C(Cl)Cl>[C:15]([O:20][CH2:21][CH:22]=[O:23])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)OCCO
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)OCC=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a mechanically stirred suspension of P2O5 (42.53 g, 150 mmol) in dry DCM (100 ml) at 0° C., was slowly added 30 (11.0 g, 83 mmol), followed by DMSO (13 g, 11.8 ml, 166 mmol). After stirring at 0° C. for 1 h, the ice bath was removed and the mixture further stirred at rt for 1.5 h. It was then cooled to 0° C., and then Et3N (42 g, 58 ml, 416 mmol) was slowly added. The reaction was then left with stirring for 6 hours at room temperature. The reaction was quenched by adding 1.0 M HCl (60 ml) at 0° C., and left with stirring for 30 minutes at 0° C. The organic layer was then washed with water (2×250 ml), dried, filtered and evaporated to afford 24 (6.60 g, 51 mmol, 61%) as a yellow liquid, that was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:35][CH2:34][CH2:33][NH:32][C:31](=[O:36])[O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)NCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 75 %

Procedure:
Compound 27 cc, N-{2-(Coumarin-3-carboxylamido)ethyl}-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide, was synthesized by the method depicted in FIG. 6. Briefly, indomethacin was complexed with tert-Butyl-2-aminoethylcarbamate for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF). A yellow solid of tert-Butyl 2-[2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamido]ethylcarbamate was produced as a yellow solid at 75% yield. This product was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(2-Aminoethyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide hydrochloride as a brown solid with a yield of 98%, which was reacted with N,N-diisopropylethylamine (DIPEA) in dichloromethane for 5 minutes at room temperature prior to the addition of Coumarin-3-carboxylic acid, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and N,N-diisopropylethylamine (DIPEA) in dichloromethane. The reaction proceeded for 16 hours at room temperature and produced Compound 27cc as a yellow solid (35% yield).
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([NH:7][C:8]([O:10]C(C)(C)C)=O)=[CH:5][CH:4]=1)#N.S.[C:18]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[S:34])[NH2:33])=[CH:28][CH:27]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>N1C=CC=CC=1.CO>[C:21]([O:20][C:18](=[O:19])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:34][CH:16]=[C:3]([C:4]3[C:8](=[O:10])[NH:7][C:6]4[C:5]([CH:5]=3)=[CH:4][CH:3]=[CH:16][CH:15]=4)[N:33]=2)=[CH:30][CH:31]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(N)=S)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Agent: S
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(-c3cc4ccccc4[nH]c3=O)cs2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-cyano-tert-butyloxycarbonylaniline (2.20 g, 10.0 mmol) in 20 mL of pyridine and 5 mL of TEA was purged with H2S gas for 7.0 h. Solvents were removed under vacuum. The resulting crude 4-Boc-aminobenzene-thiocarboxamide (yellow residue, 70% purity) was used directly in the next step. A solution of 4-Bocamino-benzenethiocarboxamide (205 mg, 70% pure, 0.57 mmol) and 3-(2-bromoacetyl)hydroquinolin-2-one (Example 27b, 78 mg, 0.29 mmol) in 50 mL of MeOH was heated at reflux for 4 h. After cooling to RT, the precipitates were collected by filtration to provide the title compound as an off-white solid. MS m/z: 420.2 (M+1). HRMS m/z: 420.1358 (M+H+, C23H21N3O3S Calc'd 420.1376).
Reaction SMILES: Br[C:2]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4][CH2:3]1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH:30]([CH2:3][C:2]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:13])[Cl:14])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: CC1(Br)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Yield: 48 %

Procedure:
2,2,2,-Trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (1.10 g) was dissolved in methylene chloride (15 ml) and to this solution was added aniline (0.28 g). And to the solution was added silver fluoroborate (0.45 g) under stirring under ice-cooling and the mixture was stirred for 4 hours at the same temperature. After the reaction was completed, the reaction mixture was filtered. The filtrate was washed with a dilute aqueour solution of phosphoric acid and then with water, dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml and the second to eighth fractions were collected and then the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g), mp 148° to 149° C.
Reaction SMILES: C([O:4][C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2occc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(O)c2occc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Ethyl 7-(Acetyloxy)-1-benzofuran-5-carboxylate was dissolved in absolute ethanol (200 mL). Potassium carbonate (7 g, 50 mmol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (2:1) to give the desired product 2.8 g (13 mmol, 38%) as a cream solid. 1H NMR (DMSO-D6): δ ppm 1.35 (s, 3H), 4.20 (qt, 2H), 7.15 (m 1H), 7.39 (m, 1H), 7.77 (m, 1H), i8.04 (m, 1H); MS (APCI, pos): 241.1.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C[O:7][C:8]([C:10]1[O:11][C:12]([Br:15])=[CH:13][CH:14]=1)=O.Cl>C1COCC1>[Br:15][C:12]1[O:11][C:10]([C:8](=[O:7])[CH2:4][C:3]#[N:5])=[CH:14][CH:13]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(Br)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Br)o1
Yield: 74.7 %

Procedure:
To 1.95 g (48.8 mmol, 60% dispersion in mineral oil) sodium hydride in a 2-necked flask fitted with a reflux condenser was added dropwise 30 ml THF and the mixture was then heated to reflux. A solution of 6.4 ml (122 mmol) acetonitrile and 5.00 g (24.4 mmol) 5-bromo-furan-2-carboxylic acid methyl ester in 20 ml dry THF was added dropwise and the reaction mixture heated at reflux for 5 hours. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixture was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 2/3) afforded 3.90 g (75%) 3-(5-bromo-furan-2-yl)-3-oxo-propionitrile as a yellow crystalline solid. EI-MS m/e (%): 215 (M{81Br}+, 27), 213 (M{79Br}+, 28), 175 ([M{81Br}—CH2CN]+, 100), 173 ([M{79Br}—CH2CN]+, 100), 38 (59).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][N:20]4[N:23]=[CH:24][C:25]([CH:26]=O)=[C:19]4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1.[NH:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[O:30].N1CCCCC1>CCO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][N:20]4[N:23]=[CH:24][C:25]([CH:26]=[C:34]5[NH:28][C:29](=[O:30])[NH:31][C:32]5=[O:33])=[C:19]4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2ccc(Nc3cccc(OCCN4CCOCC4)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(OCCN5CCOCC5)c4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(3-(2-morpholinoethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (81 mg, 0.221 mmol) in EtOH was added hydantoin (27 mg, 0.270 mmol) and piperidine (22 μL, 0.221 mmol). The mixture was heated at 70° C. for 48 hr. The solution was then purified by HPLC to yield 5-((5-(3-(2-morpholinoethoxy)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=450)
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.[OH-].[Na+]>CO.O>[CH:15]1([NH:21][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CNC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (9.6 g, 152 mmol) to a solution of 4-cyanobenzaldehyde (5 g, 38 mmol), cyclohexylamine (3.8 g, 38 mmol) and acetic acid (0.46 g, 7.6 mmol) in methanol (100 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Add water (100 mL) and adjust the pH to 10 with 3N aqueous NaOH. Extract with DCM and wash the organic phase with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (500 g) eluting with hexane/EtOAc (1:0 to 1:1 gradient) to obtain the desired intermediate (6.9 g, 86%). MS (APCI+) m/z: 215 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)C.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[Cl:14][C:11]1[N:10]=[C:9]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:16])=[CH:4][CH:3]=2)=[CH:13][N:12]=1
Reactant: Clc1ncc(Cc2ccccc2)c(Cl)n1
Reactant: CN1CCNCC1
Reactant: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(Cc2cnc(Cl)nc2N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A solution of 5-benzyl-2,4-dichloropyrimidine (9.66 g, 38 mmoles), triethylamine (Aldrich) (4.15 g, 41 mmoles), and ethanol (20 mL) was stirred at ice bath temperature for 10 minutes. 1-Methylpiperazine (Aldrich) (3.83 g, 38 mmoles) in ethanol (10 mL) was added, and the reaction was stirred at ambient temperature for 16 hours. The solution was spin evaporated in vacuo at 40° C. to give a residue that was partitioned between dichloromethane (50 mL) and water (70 mL). The dichloromethane phase was separated and washed with water (2×7 mL), and finally with brine (50 mL). The dichloromethane solution was dried over sodium sulfate, filtered and applied to a column (4×20 cm) of Silica Gel 60 (230-400 mesh) that was equilibrated with dichloromethane. The column was eluted with dichloromethane (400 mL) by flash chromatography to remove impurities. The product was eluted with 2% methanol-dichloromethane, and the combined fractions were spin evaporated in vacuo to give 9.89 g (cc % yield) of 2-chloro-5-(4-methylbenzyl)-4-(4-methylpiperazino)pyrimidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH2:3][CH2:2]1.C=O.[C:34](O)(=O)C.CO[BH-](OC)OC.[Na+]>O1CCCC1.CO>[CH3:34][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH2:3][CH2:2]1
Reactant: CCNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCNCC3)c2)ccn1
Reactant: CC(=O)O
Agent: C=O
Agent: CO[BH-](OC)OC
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCN(C)CC3)c2)ccn1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid piperidin-4-ylamide (36 mg, 0.085 mmol, Example 181) was dissolved in tetrahydrofuran (2.0 ml) and methanol (1.0 ml); and a 37% aqueous formaldehyde solution (0.036 ml, 0.43 mmol) and acetic acid (0.0098 ml, 0.17 mmol) were added thereto. While stirring at room temperature, sodium trimethoxyborohydride (27 mg, 0.13 mmol) was added; and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; the obtained crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (25 mg, 0.057 mmol, 67%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C(NCC)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:21][N+:18]([O-:20])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccccc1)c1ccc(Br)cc1
Reactant: C[N+](=O)[O-]
Solvent: CO
Solvent: CCNCC
Product: O=C(CC(C[N+](=O)[O-])c1ccccc1)c1ccc(Br)cc1
Yield: 85.7 %

Procedure:
In a 1 L flask, 46.9 g (154 mmol) of (2E)-1-(4-bromophenyl)-3-phenylprop-2-en-1-one were dissolved in 450 g of methanol, admixed with 46.9 g (768 mmol) of nitromethane and 56.2 g (768 mmol) of diethylamine and refluxed for 16 h. The solvent was half distilled off in vacuo and the precipitated solid was separated off and dried to constant weight in vacuo to obtain 46 g (132 mmol) of 1-(4-bromophenyl)-4-nitro-3-phenylbutan-1-one.