Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2].CS(C)=O.[H-].[Na+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.C(O)(=O)C.O>[C:1]([NH:4][C:5]1([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: ClCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NC1(CCCCc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 0 °C
Yield: 1.8 %

Procedure:
The process is performed as in Example 44 but starting with 3 g of (10 RS)-10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 70 ml of dimethyl sulphoxide, 1.2 g of an 80% suspension of sodium hydride in oil and 2.7 g of 1-chloro-4-phenylbutane. The reaction medium is poured into a mixture of 250 g of ice, 435 ml of distilled water and 6 ml of acetic acid. 200 ml of ethyl acetate are added to the suspension obtained and the mixture is stirred, followed, after separation of the phases once settling has taken place, by removal of the ethyl acetate. The operation is repeated once. The precipitate is filtered off on a sinter funnel. The solid is crystallized from methanol. 80 mg of (10 RS)-10-acetamido-10-(4-phenylbutyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained in the form of a green solid melting above 260° C. (Analysis, % calculated C: 72.8, H: 5.9, N: 13.6, O: 7.8, % found C: 72.8, H: 6.0, N: 14.1, O: 7.9).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:37]([CH:34]1[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]1)=[O:38]
Reactant: COc1ccc(CNCc2cc(Br)c(Cl)cc2OC)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2cc(Br)c(Cl)cc2OC)C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of N-(5-bromo-4-chloro-2-methoxybenzyl)-1-(2,4-dimethoxyphenyl)methanamine (190 mg, 0.47 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (109 mg, 0.47 mmol), HATU (180 mg, 0.47 mmol) and Et3N (101 mg, 1 mmol) in DMF (5 mL) was stirred at room temperature for 4 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product. The crude product was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.ClCCCl.C(N(CC)CC)C.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:32](=[O:33])[O:34][C:35]4[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ncc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 125.6 %

Procedure:
To a suspension of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (0.5145 g, 2.039 mmol) in 1,2-dichloroethane (10 mL, 100 mmol) was added triethylamine (0.35 mL, 2.5 mmol) and p-nitrophenyl chloroformate (0.452 g, 2.24 mmol). The reaction mixture was stirred at room temperature for 16 hours and then pyridine (0.50 mL, 6.2 mmol) and p-nitrophenyl chloroformate (0.452 g, 2.24 mmol) were added. After an additional 2 hours, the reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated in vacuo. 1.069 g of 4-nitrophenyl 7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylcarbamate was obtained, and carried forward without purification. LCMS (ESI): M+H=poor ionization.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12](O)=O)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].Cl.[CH2:16]([O:18][C:19](=[O:33])[CH:20]([CH2:31][NH2:32])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH3:17].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.P(Cl)(Cl)(Cl)(Cl)Cl.[S]>C(Cl)Cl.C(O)C>[CH2:16]([O:18][C:19]([C:20]1[C:21]2[C:26](=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:12]([CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)=[N:32][CH:31]=1)=[O:33])[CH3:17]
Reactant: CCOC(=O)C(CN)c1ccc(OC)c(OC)c1
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(Cc2cccc(OC(C)C)c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a mixture of 3-isopropoxyphenyl acetic acid (3.79 g, 19.54 mmol) and α-aminomethyl-3,4-dimethoxybenzene-acetic acid ethyl ester hydrochloride (5.656 g, 19.54 mmol) in 150 ml of methylene chloride was added triethylamine (5.44 ml, 2.0 eq) and HBTU (8.15 g, 21.50 mmol). The mixture was stirred at room temperature overnight and then extracted with 3N hydrochloric acid and methylene chloride. The organic layer was washed with water and sodium bicarbonate solution. After the evaporation of solvents, an oil was obtained (10.20 g). This oil (10.2 g) was dissolved in 100 ml of methylene chloride. The solution was cooled in an ice bath and then phosphorus pentachloride (10.0 g, 47.96 mmol) was added. The mixture was stirred at room temperature overnight and then poured into ice. The mixture was extracted with methylene chloride. The organic layer was washed with concentrated sodium bicarbonate solution and then dried. After the evaporation of solvents, an oil was obtained. This oil (8.81 g, 21.43 mmol) was mixed with sulfur (755 mg, 23.6 mmol) and the mixture was put into an oil bath preheated to 165° C. and stirred at this temperature for 20 minutes. Then ethanol (100 ml) was added and the mixture was filtered. The filtrate was evaporated and the residue was suspended into ethyl acetate. The solid was removed by filtration and the filtrate was washed with sodium bicarbonate solution. After the evaporation of solvents, the residue was purified through a flash column chromatography using ethyl acetate and hexane (2/1 ratio) to give 1-(3-isopropoxybenzyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (4.40 g, 55% for 3 steps).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].CC(C)=[O:13]>O>[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7].[OH2:13]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CC(C)=O
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
In 50 volume parts of water are dissolved 19.0 parts of TRH. H2O and 7.5 parts of L-tartaric acid, followed by the addition of 700 volume parts of acetone. The resultant oil is rubbed with a glass rod and the crystals formed are recovered by filtration, washed with hot ethanol and dried under reduced pressure. The described procedure yields 24.5 parts of TRH tartrate-water as crystals melting at 127°C-129°C. [α]D25 =-49.45° (c=1.0 in water)
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])C(=O)OC(C)(C)C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:20][CH2:21][CH2:22][NH:23][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.8 %

Procedure:
The resulting tert-butyl N,N-bis(2-((Z)-octadec-9-enoyloxy)ethyl)carbamate (1.22 g, 1.66 mmol) was dissolved in dichloromethane (30 mL), and stirred at room temperature for 3.5 hours after adding trifluoroacetic acid (2.56 mL, 33.2 mmol). The aqueous layer was extracted with chloroform after adding a saturated sodium bicarbonate aqueous solution to the reaction solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 96/4) to give compound 73 (998 mg, 94.6%).
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:10])[C:4]=2[C:3]=1[CH:28]1[CH2:30][CH2:29]1.BrC1N(COCC[Si](C)(C)C)C2C=NN(COCC[Si](C)(C)C)C(=O)C=2C=1C.[F:59][CH:60]([F:83])[O:61][C:62]1[CH:63]=[CH:64][C:65](B2OC(C)(C)C(C)(C)O2)=[C:66]2[C:71]=1[O:70][C:69]([CH3:73])([CH3:72])[CH:68]=[CH:67]2.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[CH:28]1([C:3]2[C:4]3[C:9](=[O:10])[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:7]=[CH:6][C:5]=3[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:2]=2[C:65]2[CH:64]=[CH:63][C:62]([O:61][CH:60]([F:59])[F:83])=[C:71]3[C:66]=2[CH:67]=[CH:68][C:69]([CH3:72])([CH3:73])[O:70]3)[CH2:30][CH2:29]1
Reactant: CC1(C)C=Cc2c(B3OC(C)(C)C(C)(C)O3)ccc(OC(F)F)c2O1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C3CC3)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: Cc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CC1(C)C=Cc2c(-c3c(C4CC4)c4c(=O)n(COCC[Si](C)(C)C)ncc4n3COCC[Si](C)(C)C)ccc(OC(F)F)c2O1
Yield: 102.3 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(a) except for using 1.03 g (2.0 mmol) of 2-bromo-3-cyclopropyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 28-(b) in place of 2-bromo-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and using 1.40 g (3.97 mmol) of 2-(8-difluoromethoxy-2,2-dimethyl-2H-chromen-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(i) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 1.35 g of the title compound was obtained as a yellowish oil substantially quantitatively.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH2:15][C@H:16]1[CH2:19][N:18]([C:20]([NH:22][S:23]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[S:29][N:28]=2)(=[O:25])=[O:24])=[O:21])[C:17]1=[O:33].Cl.[Cl:35][CH2:36][C:37]([NH:39][C:40]1[S:41][CH:42]=[C:43](/[C:45](=[N:49]/[O:50][CH3:51])/[C:46](Cl)=[O:47])[N:44]=1)=[O:38]>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:35][CH2:36][C:37]([NH:39][C:40]1[S:41][CH:42]=[C:43](/[C:45](=[N:49]/[O:50][CH3:51])/[C:46]([NH:15][C@H:16]2[CH2:19][N:18]([C:20]([NH:22][S:23]([NH:26][C:27]3[CH:31]=[C:30]([CH3:32])[S:29][N:28]=3)(=[O:24])=[O:25])=[O:21])[C:17]2=[O:33])=[O:47])[N:44]=1)=[O:38]
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: Cc1cc(NS(=O)(=O)NC(=O)N2C[C@H](N)C2=O)ns1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CO/N=C(\C(=O)N[C@H]1CN(C(=O)NS(=O)(=O)Nc2cc(C)sn2)C1=O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
A solution of 436 mg (4.32 mmol) of triethylamine in 3.2 mL of dry DMF was cooled to -8° C. and 502 mg (1.2 mmol) of (S)-3-amino-N-[[(5-methyl-3-isothiazolyl)amino]sulfonyl]-2-oxo-1-azetidinecarboxamide trifluoroacetic acid salt was added. To the resulting solution was added dropwise a solution of 520 mg (1.2 mmol) of (Z)-[2-(chloroacetyl)amino-4-thiazolyl](methoxyimino)acetyl chloride hydrochloride in 4 mL of chloroform. The mixture was stirred cold for 15 minutes and at room temperature for three hours before concentrating under reduced pressure. Methylene chloride was added to the residue, and evaporation under reduced pressure was repeated. The residue was taken up in ethyl acetate and water, and the mixture adjusted to pH3 with N hydrochloric acid. The organic phase was washed with brine, dried (Na2SO4), decolorized with charcoal, and concentrated under reduced pressure to obtain 420 mg of the title compound.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH3:19])[CH2:12][C:13]2[N:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=O)=O)=CC=1.[C:21]([O-:24])(=[S:23])[CH3:22].[K+]>CC(C)=O>[C:21]([S:23][CH:11]([CH3:19])[CH2:12][C:13]1[N:14]=[N:15][CH:16]=[CH:17][CH:18]=1)(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cc2cccnn2)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SC(C)Cc1cccnn1
Reaction time: 4.5 h
Yield: 69.5 %

Procedure:
3-[2-(4-Toluenesulfonyloxy)propyl]pyridazine (2.53 g) was dissolved in acetone (50 ml). To the solution was added potassium thioacetate (1.48 g), and the mixture was stirred for 4.5 hours under reflux. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water (30 ml), which was subjected to extraction with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate, which was concentrated under reduced pressure. The concentrate was purified by a silica gel column chromatography (developing solvent: ethyl acetate-hexane 4:1→1:0) to afford the title compound (1.18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]=1[CH3:35].O.[OH-].[Li+].Cl>CO.O.C(OCC)(=O)C>[OH:14][C:5]1[C:4]([CH2:25][C:26]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]=2[CH3:35])=[C:3]([O:2][CH3:1])[C:11]([CH3:12])=[C:10]2[C:6]=1[C:7](=[O:13])[O:8][CH2:9]2
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1c(C)c2c(c(O)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Reaction time: 4 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid obtained in Example ZC-1G was dissolved in a mixture of methanol (8 mL) and water (2 mL) and treated with lithium hydroxide monohydrate (0.15 g). After 4 hours, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the product was washed out of the combined organic layers with 2M NaOH. Acidification of the basic layers with 5% hydrochloric acid and extraction of the product into ethyl acetate was followed by drying the organic layer with magnesium sulfate. Filtration and solvent removal was followed by two flash chromatographies (hexanes/ethyl acetate, 4/1 with 1% HOAc; then methylene chloride/methanol 25/1) to provide 3-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid (0.010 g) m.p. 153°-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:8]=2[CH:9]=1)=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)c1cc2cc(OC)ccc2o1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1Cc2cc(OC)ccc2O1
Yield: 62.4 %

Procedure:
5-Methoxy-benzofuran-2-carboxylic acid methyl ester (2.2 g, 10 mmol) and 10% Pd-C (0.44 g) in ethanol (50 mL) were agitated under hydrogen (45 psi) for 72 hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 8:2 hexane:ethyl acetate to give 1.3 g 5-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[I-:28].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[I:28][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Yield: 128.9 %

Procedure:
(S)-tert-Butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (1 g, 2.31 mmol) was dissolved in 25 mL anhydrous dioxane in a Schlenk vessel. Sodium iodide (1.38 g, 3.9 mmol), copper(I) iodide (0.13 g, 0.68 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.2 g, 1.41 mmol) were added under argon conditions and the mixture was further submitted to three vacuum-argon cycles. The reaction vessel was sealed and the mixture was heated at 120° C. for 7 h. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The organic phase was washed with 1N hydrochloric acid, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 1.43 g (88% yield) of the title compound as a oil. Purity 68%.
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
465 mg of 2-nitroresorcinol was dissolved in 9.3 ml of ethanol, and 230 mg of 10% palladium/carbon was added, and stirred under hydrogen atmosphere at room temperature for 1 hour. After the insoluble matter was filtered off, solvent was distilled off under reduced pressure to yield 338.5 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([S:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH2:16][CH2:17][OH:18])[CH:10]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH:28]=[C:29]([OH:31])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])=[N:3][CH:4]=1
Reactant: OCCSc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: COC(=O)c1cc(N)cc(O)c1
Product: COC(=O)c1cc(O)cc(Nc2ncc(Cl)c(Nc3cccc(SCCO)c3)n2)c1
Yield: 99 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using 2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethanol and methyl 3-amino-5-hydroxybenzoate as the starting materials in 99% yield. LCMS for C20H20ClN4O4S (M+H)+: m/z=446.9.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][N:7]=1.Cl[CH:20]([CH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)[CH:21]=O>C(O)C>[CH3:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:20]([CH2:23][C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)=[CH:21][N:1]=3)[N:4]=2)=[CH:9][C:10]=1[CH3:18]
Reactant: O=CC(Cl)Cc1ccc2ncccc2c1
Reactant: CNC(=O)c1ccc(-c2cnc(N)nn2)cc1C
Solvent: CCO
Product: CNC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of 4-(3-amino-1,2,4-triazin-6-yl)-N,2-dimethylbenzamide (Step 3, 0.30 g, 1.2 mmol) and 2-chloro-3-quinolin-6-ylpropanal (Step 4, 0.32 g, 1.5 mmol) in ethanol (2.5 mL) in a sealed tube was stirred at 120° C. overnight. After cooling, the reaction mixture was purified by RP-HPLC (pH=2) to afford the desired product (150 mg) as the TFA salt. LCMS (M+H)+: m/z=409.3. 1H-NMR (400 MHz, CD3OD): 9.64 (s, 1H), 9.21 (d, J=5.0, 1H), 9.18 (d, J=8.0 Hz, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.32 (d, J=9.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.12 (dd, J=9.0, 5.0, Hz, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 4.86 (s, 2H), 2.92 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:41].[N:42]1([CH2:48][CH2:49][C:50](O)=[O:51])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.Cl>CCOCC.C(Cl)Cl>[ClH:41].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:50](=[O:51])[CH2:49][CH2:48][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
2.8 g. (8.2 mmoles) of 4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran, 1.77 g. (8.6 mmoles) of dicyclohexylcarbodiimide and 1.65 g. (8.5 mmoles) of β-piperidinopropionic acid hydrochloride (m.p. 216°-220°C., J. Am. Chem. Soc. 73, 3168 (1951) were combined with 125 ml. of methylene chloride and stirred at room temperature for about 20 hours. The reaction mixture was filtered and the methylene chloride removed using a rotary evaporator. The residue was treated with benzene and filtered to remove a small quantity of insoluble material. The benzene was evaporated and the dark, viscous residue was chromatographed using 100 g. of 60-100 mesh activated magnesium silicate (Florisil) and methanol/chloroform graded solvent mixtures. Chromatography gave a small quantity of orange oil which was dissolved in ether and treated with a solution of ethereal HCl. The desired compound appeared as white crystals which were filtered and washed with additional ether. The colorless crystals (86 mg., m.p. 106°-107°C.) were pure by thin layer chromatography (10% MeOH/CHCl3) and the nuclear magnetic resonance and infrared spectra were in agreement with the proposed structure.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[O:17])[CH2:5]1)(=[O:3])[CH3:2].[CH:18](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([O:17][CH3:18])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)N(C(C)=O)CC2=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc2c(OC)cn(C(C)=O)c2c1

Procedure:
Methyl 1-acetyl-2,3-dihydroindol-3-one-6-carboxylate (233 mg, 1 mmol), trimethyl orthoformate (10 ml) and p-toluene sulphonic acid (20 mg) were heated under reflux for 3 h. in methanol (10 ml). The reaction mixture was concentrated under reduced pressure, poured into water and extracted with chloroform. After drying and evaporation, the product was purified by prep hplc;