Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[N:34]1([CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([O:47][CH2:48]/[CH:49]=[CH:50]\[CH2:51][NH2:52])[CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C=O.C(OCC)(=O)C>[N:34]1([CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([O:47][CH2:48]/[CH:49]=[CH:50]\[CH2:51][NH:52][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(O)c1cccs1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cccs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.4 %

Procedure:
240 mg of 2-thiophenecarboxylic acid, 390 mg of N,N'-dicyclohexylcarbodiimide and 275 mg of 1-hydroxybenzotriazole were added to a solution of 485 mg of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine in 10 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 17 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate, and the urea which precipitated was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give 499 mg (yield 73%) of the title compound as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH2:11][CH3:12])[C:8](=[O:13])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]1[CH3:18].[CH3:19][NH:20][CH3:21]>C(O)C>[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH2:11][CH3:12])[C:8](=[O:13])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]1[CH3:18]
Reactant: CNC
Reactant: CCN1CC(CCCl)N(C)c2ccccc2C1=O
Solvent: CCO
Product: CCN1CC(CCN(C)C)N(C)c2ccccc2C1=O

Procedure:
A solution of 30 g (0.112 mole) of 2-(2-chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one and 10 g (0.224 mole) of dimethylamine in 300 ml of ethanol was heated at 125° C. for 8 hrs and concentrated. The residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform was dried over anhydrous sodium sulfate, concentrated and distilled. Yield of product was 20.5 g (66.5%), b.p. 175°-178°/0.1 mm.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[N:12][NH:13][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[CH2:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:21][CH3:22].C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2[CH:11]=[N:12][N:13]([S:23]([CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24])[C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]ncc2n(CCCC)c1=O
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCn1c(=O)c2c(cnn2S(=O)(=O)CCC)n(CCCC)c1=O
Temperature: 23 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To 500 mg (2.6-2.8 mmol/g resin) of piperidinomethyl polystyrene resin in 25 mL CH2Cl2 was added 280 mg (1.06 mmol) of 4,6-dibutyl-1,4-dihydro-pyrazolo[4,3-d]pyrimidine-5,7-dione followed by 166 mg (1.17 mmol) of propanesulfonyl chloride. The resulting solution was stirred at 23° C. for 3 h after which time TLC showed that all starting material (4/1 CH2Cl2 /EtOAc; Rf =0.15) had been consumed. The reaction mixture was filtered, the filtered cake washed with 3×5 mL CH2Cl2, and the combined organics were evaporated to give crude yellow oil. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (40/1 to 10/1) gave 359 mg (0.97 mmol, a 92% yield) of the title compound as a yellow solid. mp: 44-48° C.; 1H NMR (300 MHz, CDCl3); δ 0.93-1.17 (m, 9H), 1.35-1.44 (m, 4H), 1.61-1.83 (m, 4H), 2.06-2.33 (m, 2H), 3.51-3.68 (m, 2H), 3.85 (t, J=7.5 Hz, 2H), 4.02 (t, J=7.4 Hz, 2H), 7.88 (s, 1H); IR (KBr, cm-1): 3231w, 2960m, 1719m, 1675s, 1620m, 1387m, 1289m, 1171m, 1066m; MS (ES) m/z (relative intensity): 371 (M+ +H, 100). Anal. Calcd. for C16H26N4O4S: C, 51.87; H, 7.07, N, 15.12. Found: C, 46.22; H, 6.65; N, 11.91
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.N1C=CC=CC=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O>O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(F)c(F)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a mixture of 2-chloro-3,4-difluorobenzamide (1.20 g), pyridine (1.01 mL) and N,N-dimethylformamide (18 mL) was added oxalyl chloride (0.82 mL) at 0° C. over 10 min. The mixture was stirred for 1 hr while raising the temperature to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane) to give the title compound as a solid (yield: 983 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:63]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:64]([C:69](OC1C=CC([N+]([O-])=O)=CC=1)=[O:70])[CH2:65][C:66](=[O:68])[NH2:67].C(Cl)(Cl)Cl.CO>O1CCCC1>[NH:63]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:64]([C:69]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:70])[CH2:65][C:66](=[O:68])[NH2:67]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 57 %

Procedure:
At 0° C. the solution of 1160 mg (1.26 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 50 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 500 mg (1.41 mmol) of Boc-Asn-ONp in 10 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 96 h and TLC (chloroform/methanol, 9:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The reaction mixture was evaporated to dryness and the residue was purified on sinica gel chromatography (CHCl3/CH3OH, 10:1) to provide 800 mg (57%) of the title compound as a glassy mass. Mp 86–88° C., FAB-MS (m/e) 1097[M+H]+.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][OH:20]>>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][O:20][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC1CCCCO1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc(OCC2CCCCO2)nc1
Reaction time: 1.5 h
Yield: 34 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 34% yield starting from ethyl 6-chloronicotinate and tetrahydro-2H-pyran-2-ylmethanol, the final reaction mixture was stirred for 1.5 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (d, 1 H), 8.13 (dd, 1 H), 6.91 (d, 1 H), 4.26 (d, 2 H), 3.87 (d, 1 H), 3.58-3.68 (m, 1 H), 3.37-3.44 (m, 1 H, obscured by H2O), 1.72-1.86 (m, 1 H), 1.62 (d, 1 H), 1.39-1.55 (m, 3 H), 1.23-1.36 (m, 1 H); MS (ESI) m/z 238[M+H+].
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cl-].[Hf+4:5].C(Cl)Cl.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]1([CH2:22][Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[CH2:15]([Hf:5]([CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: Cc1ccccc1
Reactant: [Hf+4]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(C[Hf](Cc2ccccc2)(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: -15 °C
Yield: 62 %

Procedure:
In yet another particular embodiment, the metal salt hafnium tetrachloride is slurried in a halogenated hydrocarbon such as methylene chloride or an aromatic diluent such as toluene. The adduct mixture can then be chilled to from 0 to −30° C. Four equivalents of the (benzyl)nMgX2-n compound such as C6H5CH2MgBr in ether are then added to the mixture. The resulting slurry can then be stirred for 30 min to several hours at this temperature. The solids can then be collected by filtration, and the filtrate evaporated. The resulting product can then be washed with a minimum amount of a hydrocarbon such as hexane or pentane. This procedure can afford from 62 to 90% yield of tetrabenzyl hafnium product.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:24][CH2:23]1)#[N:20]
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: O=C(O)c1cc2ccccc2s1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCN(C2CCOCC2)CC1
Yield: 64.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (0.4 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (0.6 g), the title compound (0.6 g) was obtained. melting point: >285° C.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:8]=1)[CH3:5])([OH:3])=[O:2].S(Cl)(Cl)=O.[C:24]1(C)C=CC=CC=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[N:9]1[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([O:3][CH3:24])=[O:2])[CH3:5])=[N:8]1
Reactant: CC(Oc1ncn(-c2ccc(Cl)cc2Cl)n1)C(=O)O
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2Cl)n1

Procedure:
Three g of the compound of Example 23 was added to 75 ml of toluene and 5 ml of thionyl chloride, and the solution was heated under reflux for 2 hours. It was then cooled and evaporated under vacuum. Fifty ml of toluene was added to the residue, and that solvent was also removed under vacuum. To the residue was then added 50 ml of methanol, and the solution was heated under reflux for 2 hours, cooled and evaporated under vacuum. The residue was recrystallized from toluene to obtain 0.68 g of the desired product, m.p. 74°-75°.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([F:17])[CH:9]=2)[CH2:5]1)#[N:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH:64]1([C@@H:70]([NH2:72])[CH3:71])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1>ClCCCl>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:5][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:72][C@H:70]([CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)[CH3:71])=[O:13])=[C:10]([F:17])[CH:9]=2)[CH2:7]1)#[N:2]
Reactant: C[C@H](N)C1CCCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)c(F)c5)C4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C1CCCCC1

Procedure:
The 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluorobenzoic acid (0.015 g, 0.027 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.016 g, 0.042 mmol), and (1S)-1-cyclohexylethanamine (0.0080 mL, 0.055 mmol, Aldrich: Cat. #336513) in dry 1,2-dichloroethane (0.501 mL) (not all in solution) was stirred for 30 minutes at 60° C., then 14 hours at room temperature (all in solution). LC/MS data showed that the reaction was complete and the desired product was formed. The product was used as is without further purification. LCMS (M+H)+: m/z=657.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][O:25][CH2:26][CH3:27].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>C(Cl)(Cl)Cl>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][O:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNS(C)(=O)=O
Reaction time: 1.5 h
Yield: 26.8 %

Procedure:
A solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) in chloroform (40 mL) was treated with triethylamine (1.62 mL, 11.6 mmol) and methanesulfonyl chloride (0.47 mL, 6.05 mmol). The reaction was stirred for 1.5 hours, and additional methanesulfonyl chloride (2 equivalents) was added. The reaction was stirred for 30 minutes, and then deionized water (15 mL) was added. A precipitate formed and was isolated by filtration, triturated once with methanol and twice with chloroform and 1% aqueous sodium carbonate, isolated by filtration, and dried overnight in an oven to provide 0.65 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide as a white solid, mp 233–235° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].CC([O-])=O.[Na+].[Br:16]Br.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[Br:16][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: BrBr
Reactant: Nc1ccncc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)cncc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 3-nitropyridin-4-amine (LXVIII) (10 g, 71.94 mmol) and acetic acid (120 mL) was added to a sealed tube followed by addition of NaOAc (29.50 g, 93.52 mmol) and dropwise addition of bromine (4.7 ml 359.7 mmol) under stirring. The sealed tube was heated at 100° C. for 28 h until TLC showed consumption of starting material. The reaction mixture was concentrated to obtain a solid which was dissolved in water, basified with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (LXIX) as a yellow solid (12 g, 55 mmol, 77% yield). 1H NMR (DMSO-d6) δ ppm 9.19 (s, 1H), 8.58 (s, 1H); ESIMS found for C5H4BrN3O2 m/z 217, 219 (M+, M+2).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:18]([C:15]2[N:16]=[N:17][C:12]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=4[C:2]([F:25])([F:1])[F:26])[CH2:11][CH2:10]3)=[CH:13][CH:14]=2)=[O:20])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(NC1CC1)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 4, Step 3 from 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine-3-carboxylic acid and cyclopropylamine. 1H NMR (400 MHz, acetone-d6): δ 0.71-0.82 (m, 4H), 1.91-1.99 (m, 2H), 2.13-2.19 (m, 2H), 2.96-3.02 (m, 1H), 3.91-4.07 (m, 4H), 5.04 (m, 1H), 7.13 (t, 1H), 7.37 (m, 2H), 7.62-7.68 (m, 2H), 7.91 (d, 1H), 8.09 (s, 1H). MS (+ESI) m/z 407 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:19]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=O)[CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[NH4+:41].[OH-].[NH4+:43]>C(O)(=O)C>[CH2:19]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[NH:41][C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:43]=2)[CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [NH4+]
Reactant: O=C(C(=O)c1ccc(Cl)c(Cl)c1)c1ccncc1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(Cl)c(Cl)c3)[nH]2)CC1
Temperature: 25 °C

Procedure:
1-(3,4-Dichlorophenyl)-2-pyridin-4-yl-ethane-1,2-dione (2.8 g, 10 mmol), 4-formylpiperidine-1-carboxylic acid benzyl ester (2.47 g, 10 mmol) and ammonium acetate (7.7 g, 100 mmol) were dissolved in acetic acid (65 mL) and heated to reflux for 2.5 hour and allowed to cool to ambient temperature. The reaction mixture was then poured over an ammonium hydroxide (100 mL) and ice mixture. This aqueous layer was extracted with ethyl acetate (3×200 mL) and the organic layers were combined, washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was chromatographed on silica gel eluting with 97:3 dichloromethane:methanol to give the imidazole as a foam (2.3 g).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].Cl[C:20]1([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[NH:22][C:21]1=[O:30]>>[Cl:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:30])[C:20]2([N:10]1[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:6][CH:5]1[C:3]([N:2]([CH3:18])[CH3:1])=[O:4])[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[O:38][CH3:39]
Reactant: COc1ccc(C)cc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Product: COc1ccc(C)cc1C1(N2CCN(C(=O)OC(C)(C)C)CC2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Yield: 43.5 %

Procedure:
With 2.43 g of the compound obtained in Step 109-3 and 2.43 g of the compound obtained in Step 109-4 as starting materials, 1.78 g of the title compound was obtained by a similar method to Step 4-2.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C=C(O)C=CC=1O)(C)(C)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=C(C)C(=O)OCCO
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of 2-t-butylhydroquinone (polymerization inhibitor) were added. The mixture was heated to keep about 130° C. for 3 hours in nitrogen atmosphere with distilling 22 ml (0.38 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 64.8 g (yield 76.5%) of 2-ethoxalyloxyethyl methacrylate (bp 84°-125° C./0.4 mmHg).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1ccc(C2=Cc3ccc(O)cc3OC2)cc1

Procedure:
As shown in Scheme 2, 7-benzyloxy-3-(4-methoxyphenyl)-2H-1-benzopyran (compound 1) was reacted with n-Bu4NI/BCl3 and BCl3 to give haginin E (compound 2a) at a yield of 79% and 7-hydroxy-3-(4-methoxyphenyl)-2H-1-benzopyran (4′-O-methyl haginin E, compound 2b) at a yield of 81%, respectively. Treatment of compound 1 with Pd(OH)2/C (Pearlman's reagent) and cyclohexene in refluxing ethanol promoted O-debenzylation and reduction of the chromene ring in one step, giving 7-hydroxy-3-(4-methoxyphenyl)-1-benzopyran (compound 3a) at a yield of 94%. Compound 3a was subsequently demethylated by use of n-Bu4NI/BCl3 to give equol (compound 3b) at a yield of 95%.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH3:9][Li:10]>C(OCC)C>[C:2]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)([CH3:9])([CH3:8])[CH3:1].[Li+:10]
Reactant: [Li]C
Reactant: CC(C)=C1C=CC=C1
Solvent: CCOCC
Product: CC(C)(C)[c-]1cccc1
Product: [Li+]

Procedure:
To a solution of 4.18 g (39.4 mmol) 6,6-dimethylfulvene in 80 mL diethylether at 0° C. were added 22.9 mL of a 1.72M (39.4 mmol) methyl lithium solution in ether. The resulting slurry was stirred several days, then filtered, washed with pentane and dried under vacuum.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][C:12]1=[O:24])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH2:15][N:11]([CH:4]([CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10])[C:3]([OH:25])=[O:2])[C:12](=[O:24])[CH:13]=1
Reactant: COC(=O)C(CCC(C)(C)C)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CCC(C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid methyl ester (34 mg, 0.093 mmol) in tetrahydrofuran (2 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (8 mg, 0.19 mmol) in water (2 mL). The mixture was then stirred for 1.5 h at 25° C. and then treated with a 1N aqueous hydrochloric acid solution to pH=2 and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid (32 mg, 98% as a light yellow solid.