Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]([OH:14])=O)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([C:47]2[N:56]=[C:50]3[CH:51]=[C:52]([NH2:55])[CH:53]=[CH:54][N:49]3[N:48]=2)[CH:44]=[CH:45][CH:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12](=[O:14])[NH:55][C:52]1[CH:53]=[CH:54][N:49]2[N:48]=[C:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([O:40][CH3:39])[CH:42]=3)[N:56]=[C:50]2[CH:51]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: COc1cccc(-c2nc3cc(N)ccn3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccc(OC)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.9 %

Procedure:
To a solution of 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (8.0 g, 40.4 mmol) in DMF (120 ml) were added HATU (34 g, 88.9 mmol), 2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (10.6 g, 44.4 mmol) and DIPEA (30 ml, 161.1 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water. The resultant precipitated solid was filtered, washed with water, dried azeotropically with toluene followed by vacuum to yield 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as white solid (7.8 g, 56%). LC-MS: m/z=421.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[N:10]=[C:11]2[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[N:12]2[C:13](=[O:18])[C:14]=1[C:15]([NH2:17])=[O:16].C[N:25](C)C=O>>[C:2]1([NH:1][N:25]=[C:22]2[C:11]3=[N:10][C:9]([CH3:8])=[C:14]([C:15]([NH2:17])=[O:16])[C:13](=[O:18])[N:12]3[CH:19]([CH3:23])[CH2:20][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2n(c(=O)c1C(N)=O)C(C)CCC2
Reactant: Nc1ccccc1
Reactant: CN(C)C=O
Product: Cc1nc2n(c(=O)c1C(N)=O)C(C)CCC2=NNc1ccccc1
Yield: 49.2 %

Procedure:
The process according to Example 6 is carried out with the difference that aniline and dimethylformamide solution of 2,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide is used. The crude 9-(phenyl-hydrazono)-2,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide melts at 235°-237° C., yield: 49.2%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[CH:18][CH:19]=1
Reactant: O=C(CCl)Nc1ccc(F)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-fluorophenyl)-2-chloroacetamide (38 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 45 mg (95%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (m, 4H), 3.18 (s, 2H), 3.58 (m, 4H), 6.63 (m, 1H), 6.83 (d, J=5 Hz, 1H), 7.14 (dd, J=8.7, 8.7 Hz, 2H), 7.55 (m, 1H), 7.66 (m, 2H), 8.18 (d, J=5 Hz, 1H), 9.80 (s, 1H); MS (ESI/APCI+) m/e 315 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Fc1ccc(F)c(CBr)c1
Product: O=Cc1cn(Cc2cc(F)ccc2F)c2ccccc12
Yield: 92.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 3.06 g of 2,5-difluorobenzyl bromide and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.46 g of 1-(2,5-difluorobenzyl)indole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 93%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:9](CC(O)=O)#[N:10].C(O[C:19](=[O:21])[CH3:20])(=O)C>>[NH2:10][C:9]1[N:6]([CH2:7][CH3:8])[C:4](=[O:5])[N:3]([CH2:1][CH3:2])[C:19](=[O:21])[CH:20]=1
Reactant: N#CCC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CCNC(=O)NCC
Product: CCn1c(N)cc(=O)n(CC)c1=O

Procedure:
12.69 grams (0.14 mol) of diethylurea and 11.90 grams (0.14 mol) of cyanoacetic acid were heated in acetic anhydride at 60° C. for 3 hours, under dry atmosphere. Thereafter, the acetic anhydride and remaining cyanoacetic acid were evaporated, 5% sodium hydroxide was added and the mixture was stirred and cooled. 20 grams of 6-amino-1,3-diethyluracil were obtained as a precipitate. 11.8 grams of sodium nitrite in 70 ml water were then added while cooling and stirring and the solution was then acidified by adding 70 ml acetic acid. The mixture was stirred at room temperature for additional 2.5 hours. The resulting precipitate was filtered, washed with water, ethanol and finally ether so afford 10.1 grams of 6-amino-1,3-diethyl-5-nitrosouracil, as a violet product.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]23[CH2:14][C:13](=[CH:15][C:16]([O:18]C)=[O:17])[CH2:12][N:11]2[C:10](=[O:20])[N:9]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:8]3=[O:29])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]23[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH2:12][N:11]2[C:10](=[O:20])[N:9]([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:8]3=[O:29])=[CH:30][CH:31]=1
Reactant: COC(=O)C=C1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1=CC2(Cc3ccc(Br)cc3)C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)N2C1
Reaction time: 2 h
Yield: 11.5 %

Procedure:
To a solution of 5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-7-methoxycarbonylmethylene-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.564 g) in THF (4 mL) and methanol (1 mL) at 0° C. was added 2N LiOH (1.20 mL). After 2 hours, the reaction mixture was concentrated and the residue was suspended in 1 N HCl and filtered. A solution of the filtrate (0.10 g) in thionyl chloride (5 mL) was refluxed for 30 minutes. The reaction mixture was concentrated and the residue was diluted with EtOAc and water. The organic solution was collected and dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: 4% MeOH/CH2Cl2, Chromatotron) afforded 0.063 g of the titled compound. MS (m/z) 509 (MH+), mp 101.5° C.
Reaction SMILES: [OH-].[Na+].O.CO.C([C@@:9]1([OH:28])[C@@H:13]([CH:14](C(=O)C)[OH:15])[O:12][C@@H:11]([N:19]2[CH:26]=[C:25]([F:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:10]1)(=O)C>C(O)(=O)C>[F:27][C:25]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[N:19]([CH:26]=1)[C@@H:11]1[O:12][C@H:13]([CH2:14][OH:15])[C@@H:9]([OH:28])[CH2:10]1
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
A solution of 15.55 g (0.389 mol) of sodium hydroxide in 200 ml of ino-exchanged water was mixed with 500 ml of methanol and cooled with ice. Then 42.18 g (0.128 mol) of 2'-deoxy-3',5'-diacetyl-5-fluorouridine (R is CH3 in the general formula (I)) was added to the solution under stirring, and stirring was continued at room temperature for 3.5 hr. As a result the reaction liquid became a clear solution. Then 20 g of acetic acid was added to the reaction liquid for neutralization, and the liquid was concentrated under reduced pressure. The solid residue was dissolved by adding 500 ml of water, followed by addition of 100 ml of a cation-exchange resin (IR 120-B), and the solution was left to stand for 1 hr. Then the resin was filtered out, and the addition of the cation-exchange resin and the subsequent treatment were repeated. After that the filtrate was concentrated and dried under reduced pressure. As the result a white solid was obtained. This solid product was recrystallized from ethanol to thereby obtain 24.80 g (yield 78.9%) of 2'-deoxy-5-fluorouridine. The melting point of this product was 149.5°-150.5° C., and the specific rotary power [α]D25 was +37.3° (C=1.06, H2O).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH2:19][CH2:20]I)[CH:16]=2)[C:11]([C:24]2[N:32]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=2)=[CH:10]1>>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH2:19][CH2:20][N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[CH:16]=2)[C:11]([C:24]2[N:32]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=2)=[CH:10]1
Reactant: OC1CCNCC1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCN1CCC(O)CC1
Yield: 92.4 %

Procedure:
1-{2-[1-methyl-5-methoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-6-yloxy]ethyl}piperidin-4-ol is prepared by following the procedure described in example 147b, but using 0.089 g of 4-hydroxypiperidine and 0.265 g of 2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. After purification by flash-pack chromatography (silica, 90/10 by volume dichloromethane/methanol as eluents, argon), 0.234 g of 1-{2-[1-methyl-5 methoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-6-yloxy]ethyl}piperidin-4-ol is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:40][N:14]4[CH2:15][CH2:16][N:17]([C:19](=[O:39])[CH:20]([NH:31][C:32](=[O:38])[O:33][C:34](C)(C)C)[C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.ClC(OC)=O.C(N(CC)CC)C>O1CCOCC1.Cl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:40][N:14]4[CH2:15][CH2:16][N:17]([C:19](=[O:39])[CH:20]([NH:31][C:32](=[O:38])[O:33][CH3:34])[C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1cccc(C(F)(F)F)c1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of the product from Example 180 (50 mg, 0.089 mmol) in 1,4-dioxane (0.5 mL) and 4 N HCl in 1,4-dioxane (0.5 mL, 2.00 mmol) was stirred at room temperature for 90 minutes and then concentrated in vacuo. Dichloromethane (1 mL) was added to the residue, followed by methyl chloroformate (7.6 μL, 0.098 mmol) and triethylamine (0.062 mL, 0.445 mmol). The resulting solution was stirred at room temperature for 90 minutes. The mixture was partitioned between water and dichloromethane (3×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane. The title compound was obtained as a semi-solid (18 mg, 39%). 1H NMR (300 MHz, CDCl3) δ ppm 0.82-1.02 (m, 4 H) 1.18-3.31 (m, 9 H) 3.50-3.89 (m, 5 H) 4.54-4.82 (m, 1 H) 5.17-5.38 (m, 1 H) 5.56-5.72 (m, 1 H) 6.25-6.41 (m, 1 H) 7.40-7.69 (m, 4 H) 7.85-8.05 (m, 2 H); MS (ESI) m/z 520 (M+H)+.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].O[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=N1.N1CCCCC1NC>O.CN(C=O)C.C(N(CC)CC)C>[NH:28]1[CH2:29][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:30][NH:26][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=1[CH3:20])=[O:23]
Reactant: On1nnc2ccccc21
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CNC1CCCCN1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCC1CCCCN1
Temperature: 0 °C
Yield: 44.8 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were sequentially added to DMF (500 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then piperidin-2-yl-methylamine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 117.8 g (448 mmol) of N-[(piperidin-2-yl)methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 44.8%, m.p. 107-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CC(C)=O.O>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:11]([F:16])[CH:10]=2)[CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(Oc2ccc(N)c(F)c2)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ncn1
Reaction time: 3.5 h
Yield: 44 %

Procedure:
After dissolving 4-amino-6-(4-amino-3-fluorophenoxy)pyrimidine (730 mg) in acetone (60 ml)-water (30 ml), sodium hydrogencarbonate (335 mg) and benzyl chloroformate (0.550 ml) were added while cooling in an ice water bath and the mixture was stirred at the same temperature. After 3.5 hours, sodium hydrogencarbonate (140 mg) and benzyl chloroformate (0.120 ml) were added and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate (50 ml)-tetrahydrofuran (100 ml) and saturated aqueous sodium hydrogencarbonate (50 ml) were added to the residue, and the mixture was stirred. The organic layer was separated and washed with a small amount of brine, and then the organic layer was concentrated under reduced pressure. Ethyl acetate (25 ml) was added to the residue and the mixture was stirred. The precipitated insoluble portion was filtered prior to washing with ethyl acetate (5 ml×3). The filtrate was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2 to 1:4) to provide the title compound (514 mg, 44%) as pale brown powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:31])=[CH:12][C:13]([C:15]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)([CH3:23])[CH2:16][CH2:17][CH2:18]CCCC)=[CH:14][C:4]=2[O:3]1.[ClH:33].[N:34]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH2:38][CH2:37][CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:31][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:12][C:13]([C:15]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)([CH3:23])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCCCCCC(C)(c1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccc(F)cc1)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
3.21 g. (9.37 mmole) of 4,4-Dimethyl-9-hydroxy-7-(4-fluorophenyl-1-methyloctyl)-1,2,3,4-tetrahydrocyclopenta [c][1]benzopyran are combined with 1.82 g. (9.37 mmole) of γ-pyrrolidinobutyric acid hydrochloride and 2.06 g. (10.0 mmole) of dicyclohexylcarbodiimide in 150 ml. of methylene chloride and stirred at room temperature for 21/2 hours. The insoluble by-product of dicyclohexylurea is removed by filtration and the filtrate is evaporated to give a residue which crystallized upon standing. The material is triturated with ether and filtered. Recrystallization from benzene/ether gives the product as colorless crystals.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCC#Cc1ccc(CNCc2cccc(Cl)c2)cc1
Yield: 60 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-dec-1-ynylbenzaldehyde and 3-chlorobenzylamine gave the title compound as a colorless oil (60%). 1H NMR (CDCl3, 300 MHz) δ 7.37-7.19 (m, 8H), 3.75 (s, 2H), 3.74 (s, 2H), 2.37 (t, J=7.2 Hz, 2H), 1.64-1.52 (m, 2H), 1.48-1.37 (m, 2H), 1.36-1.19 (m, 8H), 0.91-0.81 (m, 3H). M+(LC/MS(ESI)): 368.4. HPLC (Condition A), Rt: 4.60 min (HPLC purity: 84.1%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10](=[O:20])[C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:8][C:9]1[C:10](=[O:20])[C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC1=CC(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
595 g (5.89 moles) of triethylamine are added dropwise in 30 minutes to a suspension of 500 g (2.87 moles) of 2-hydroxy-1,4-naphthoquinone (lawsone) in 2200 ml of ethyl acetate, cooled to +5° C., maintaining the temperature below +10° C. At the end of the dripping a dark red solution is obtained. The solution is kept at +5-10° C. for 30 minutes. 550 g (5.39 moles) of acetic anhydride are added dropwise in 30 minutes, maintaining the temperature between +5 and +10° C. At the end of the dripping, the mixture is left under agitation at +5° C. for 4 hours. The solid is filtered and washed with a mixture of 250 ml of ethyl acetate and 250 ml of hexane pre-cooled to +5° C. The damp product is dried at +40° C. at reduced pressure for 6 hours providing 496 g (yield 80%) of 2-acetoxy-1,4-naphthoquinone (acetyl-lawsone) as a yellow solid with melting point −131°-134° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]([CH:13]=1)=[N:10][O:11][N:12]=2.[CH3:14][NH2:15]>C(O)C>[BrH:1].[CH3:14][NH:15][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]([CH:13]=1)=[N:10][O:11][N:12]=2
Reactant: CN
Reactant: BrCCOc1ccc2nonc2c1
Solvent: CCO
Product: Br
Product: CNCCOc1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 5-(2-bromoethoxy)benzofurazan (0.84 g, 3.4 mmol) in ethanol (45 ml), contained within a Fisher-Porter pressure vessel cooled with ice/acetone was added methylamine (45 ml). The vessel was sealed, the bath removed and the solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue flushed with ethanol. Recrystallization from ethyl acetate-hexane gave 5-(2-methylaminoethoxy)benzofurazan hydrobromide (0.75 g, 81%); 1H NMR (DMSO) δ2.68 (s, 3H), 3.45 (t, 2H), 4.43 (t, 2H), 7.34 (m, 2H), 8.04 (d, 1H, J=9.6 Hz), 8.76 (bs, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@@H:30]([CH3:58])[C@@H:31]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[C:50]([Cl:56])[C:49]=1[CH3:57])[C:32]([NH:34][NH:35][C:36]([C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[CH:41]2)=[O:37])=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[NH:43]1[C:44]2[C:40](=[CH:39][C:38]([C:36]3[O:37][C:32]([C@H:31]([NH:47][C:48]4[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[C:50]([Cl:56])[C:49]=4[CH3:57])[C@@H:30]([O:29][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH3:58])=[N:34][N:35]=3)=[CH:46][CH:45]=2)[CH:41]=[CH:42]1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc3[nH]ccc3c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc4[nH]ccc4c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Polymer supported Triphenylphosphine (640 mg, 1.58 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (401 mg, 1.58 mmol) and TEA (0.59 mL, 4.24 mmol) at 0° C. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-1H-indole-5-carbohydrazide (450 mg, 1.06 mmol) in 20 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The reaction mixture was allowed to warm to room temperature and stirred for additional 10 minutes. The reaction was quenched with 20 mL saturated sodium thiosulfate and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3×60 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography [EtOAc-hexanes (1:1) as eluent] to provide the title compound (0.403 g, 72%). 1H NMR (500 MHz, Acetone d6, δ in ppm): 10.71 (br s, 1 H), 8.25 (br s, 1H), 7.78 (d, J=9 Hz, 1 H), 7.61 (d, J=9 Hz, 1 H), 7.49-7.47 (m, 1 H), 6.86 (d, J=9 Hz, 1 H), 6.64-6.62 (m, 1H) 5.55 (d, J=9 Hz, 1 H), 5.23 (d, 9 Hz, 1 H), 4.76-4.74 (m, 1 H), 2.44 (s, 3H), 1.48 (d, J=6 Hz, 3 H), 0.87 (s, 9 H), 0.12 (s, 3 H), −0.15 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:31](C)[C:32](=O)OC(C)(C)C)=[CH:27][CH:26]=3)=[CH:21][N:20]2[CH:40]=1.Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=3)=[CH:21][N:20]2[CH:40]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3cn4cc(-c5ccc(N(C)C(=O)OC(C)(C)C)cc5)cnc4n3)c2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1ccc(-c2cnc3nc(-c4cc(NC(=O)c5ccc(C)o5)ccc4Cl)cn3c2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
tert-butyl (4-(2-(2-chloro-5-(5-methylfuran-2-carboxamido)phenyl)imidazo[1,2-a]pyrimidin-6-yl)phenyl)(methyl)carbamate was treated with 4.0M HCl in dioxane (2 eq.) and was stirred overnight at 50° C. At completion, the reaction mixture was concentrated in vacuo and the residue was redissolved in methanol. Purification of the compound was done via mass-triggered reverse phase column chromatography preparative system (15% to 65% (B)), m/z (ESI) for 33: 460 (M+H+), 1H NMR (400 MHz, DMSO-D6) δ 10.32 (s, 1H), 9.19 (d, J=2.5, 1H), 8.90 (d, J=2.5, 1H), 8.69 (d, J=2.6, 1H), 8.56 (s, 1H), 7.93 (dd, J=2.7, 8.8, 1H), 7.53 (dd, J=1.7, 8.7, 3H), 7.34 (d, J=3.3, 1H), 6.68 (d, J=8.7, 2H), 6.35 (d, J=3.3, 1H), 6.00 (q, J=4.9, 1H), 2.73 (d, J=5.0, 3H), 2.40 (s, 3H).