Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH:30]([F:32])[F:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:41]2[CH:53]=[CH:52][C:44]([CH2:45][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:43][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:31][CH:30]([F:32])[CH2:29][N:22]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:4]1[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH:20]=[C:2]([C:41]2[CH:42]=[CH:43][C:44]([CH2:45][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:52][CH:53]=2)[CH:3]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(CC(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(CC(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
In a 2 necked RBF, 5-bromo-3-[(2,2-difluoroethyl)(oxan-4-yl)amino]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-methylbenzamide (200 mg, 0.39 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (130 mg, 0.43 mmol) in dioxane (3.0 ml) were treated with a solution of Na2CO3 (145 mg, 1.4 mmol) in water (1.0 ml). The mixture was briefly sonicated and nitrogen was bubbled through the resulting suspension with a long needle for 5 minutes. The suspension was then treated with palladium-triphenylphosphane (1:4) (45 mg, 0.04 mmol) and nitrogen was bubbled through the resulting suspension for a further 5 minutes. The reaction mixture was then heated to 100° C. for 8 hours and stirred at room temperature for 16 hours. The reaction mixture was treated with water (20 ml) and 10% MeOH/CH2Cl2 (15 ml). The layers were separated and the aqueous layer was extracted with 10% MeOH/CH2Cl2 (3×15 ml). The combined organics were washed with brine (55 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-5% MeOH/CH2Cl2) and treated with ether (10 ml), briefly sonicated, warmed in a water bath and cooled on ice. The resulting white solid was collected by filtration and washed with ether (5 ml). The solid was dried in-vacuo at 40° C. for 35 hours to give the title compound (159 mg, 67%) as an off-white solid. LC-MS 100%, 3.09 min (7 minute LC-MS method), m/z=609.15; 1H NMR (500 MHz, Acetone) δ 10.72 (s, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 7.54 (t, J=5.2 Hz, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 5.91 (s, 1H), 5.76 (ttt, J=56.4, 30.4, 4.4 Hz, 1H), 4.44 (d, J=5.5 Hz, 2H), 3.89 (dd, J=11.4, 3.9 Hz, 2H), 3.65-3.55 (m, 6H), 3.50 (s, 2H), 3.29 (t, J=11.3 Hz, 2H), 3.07 (tt, J=11.5, 3.6 Hz, 1H), 2.40 (s, 4H), 2.37 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H), 1.82-1.75 (m, 2H), 1.61 (qd, J=11.9, 4.1 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[N:31][CH:30]=4)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccnnc1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4ccnnc4)c3)C(C)(C)C2=O)cc1
Temperature: 90 °C
Yield: 5.5 %

Procedure:
To a solution of 0.872 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) of Example 7 in 25 mL of dioxane are successively added, under argon, 430 mg of 4-aminopyridazine, 2.8 g of caesium carbonate, 156 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) [xantphos] and 50 mg of palladium diacetate. The reaction mixture is heated at 90° C. for 6 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (98/2 by volume) to give 55 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-{[2-(pyridazin-4-ylamino)pyridin-4-yl]-methyl}imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=2[O:27]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:31]2[CH:30]=[CH:29][C:28]3[O:27][CH2:26][O:34][C:33]=3[CH:32]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc3c(c2)OCO3)c2c(c1)ncn2-c1ccccc1

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3,4-methylene dioxyphenylboronic acid (83 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and product was crystallised from dichloromethane/diethyl ether to the title compound (75 mg, 44%) m/z, 339.8 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.C1([C@H]([N:18]2[CH2:23][CH2:22][O:21][C@H:20]([C@H:24]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:19]2)C)C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl>[C:36]1([C@H:24]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:33])([F:34])[F:35])[C@H:20]2[O:21][CH2:22][CH2:23][NH:18][CH2:19]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@H]([C@@H](Sc2ccccc2C(F)(F)F)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1S[C@@H](c1ccccc1)[C@@H]1CNCCO1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To a suspension of polymer supported Hünig's base (0.11 g, 0.40 mmol) and 52 (0.03 g, 0.066 mmol) in dry dichloromethane (1 ml) was added α-chloroethyl chloroformate (0.09 g, 0.066 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature over the weekend then filtered and concentrated in vacuo. This was taken up in methanol, heated at 70° C. for 2 hours, cooled, and purified by SCX chromatography (eluent: ammonia/methanol 1/1 [v/v]) to give 9 as a colourless oil (0.01 g, 43%). The spectroscopic data for 9 obtained by the route outlined here was identical to the data for 9 obtained as described above.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1

Procedure:
Treatment of (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (4.2 g, 9.34 mmol) with sodium azide (2.4 g, 37.38 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.32 g, 5 wt. %) generally according to the procedure described for Example 1 provided 2.16 g (72%) of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 198-200° C.; Anal. calcd. for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.5; H, 4.39; N, 4.16.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH:27][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1
Reactant: CC(C)[C@H](N)CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
p-Toluoyl chloride (0.48 ml, 3.63 mmol) was added to a solution of 1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (1 g, 3.0 mmol) and triethylamine (0.633 ml, 4.54 mmol) in methylene chloride under nitrogen atmosphere. After 1 h, the product was extracted into ethyl acetate and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography with hexanes/ethyl acetate (1:2) gave N-{1(S)-[4-(3,4-dichlorobenzyl)-piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (1.2 g) as an oil. The free amine was dissolved in ether and 3.5 equivalents of 1N ethereal HCl solution (10.7 ml) was added. Filtration of the resulting solid provided N-{1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (1.2 g) as the bis hydrochloride salt, mp 227.8-228.9° C.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][NH2:18])[C@H:14]([O:19][C:20](=[O:22])[CH3:21])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1>>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][NH:18][C:29]([C:27]2[S:28][C:24]([Cl:23])=[CH:25][CH:26]=2)=[O:30])[C@H:14]([O:19][C:20](=[O:22])[CH3:21])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(=O)c1ccc(Cl)s1

Procedure:
79.4 Using general procedure E, (3S,4R)-3-acetoxy-4-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester acetate was coupled with 5-chlorothiophene-2-carboxylic acid to give (3S,4R)-3-acetoxy-4-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Brown oil. MS 347.0 ([M-iso-butene+H]+)
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:58](Br)[CH3:59]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:58][CH3:59])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCBr
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
48.0 mg of compound (6) was dissolved in 0.4 ml of dry dimethylformamide, and about 5 mg of sodium hydride was added under cooling with ice. After 15 minutes, 19 μl of ethyl bromide was added, and the reaction solution was stirred under cooling with ice. After 50 minutes, the reaction solution was brought back to room temperature and allowed to react for another 90 minutes under stirring. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×25 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 36.8 mg of compound (27) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11]Br.[F:18][C:19]([F:34])([F:33])[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([OH:32])=[C:28]([CH2:29][CH2:30][CH3:31])[C:23]=2[O:22][N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:32][C:27]1[CH:26]=[CH:25][C:24]2[C:20]([C:19]([F:34])([F:33])[F:18])=[N:21][O:22][C:23]=2[C:28]=1[CH2:29][CH2:30][CH3:31]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: COC(=O)Cc1ccc(NCCCBr)c(Cl)c1
Product: CCCc1c(OCCCNc2ccc(CC(=O)OC)cc2Cl)ccc2c(C(F)(F)F)noc12

Procedure:
Using the method in example 17 step D substituting Methyl 3-chloro-4-(3-bromopropylamino)phenylacetate and 3-trifluoromethyl-7-propyl-6-hydroxybenz-[4,5]-isoxazole as the starting materials, the titled compound was obtained.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN.CO>[C:1]1([C:7]2([CH2:12][CH2:13][CH2:14][NH2:15])[O:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC1(c2ccccc2)OCCO1
Agent: CN
Solvent: CO
Product: NCCCC1(c2ccccc2)OCCO1
Temperature: 50 °C
Yield: 47 %

Procedure:
Dissolve 2-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propyl]-isoindole-1,3-dione (38 g, 112.91 mmol) in 2 M methylamine solution in methanol (300 mL) and heat in a sealed tube for 3 h at 50° C. Cool the solution to RT, concentrate and purify (silica gel chromatography, eluting with 25:75 DCM:2 M ammonia in methanol) to give the title compound as an oil (11 g, 47%).
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([F:20])[F:19])[NH2:13].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[F:8][C:9]([F:21])([F:22])[C:10]1[CH:11]=[C:12]([NH:13][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:7])[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([F:19])[F:20]
Reactant: CC1(C(=O)O)CC1
Reactant: Nc1ccc(OC(F)F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(C(F)(F)F)c2)CC1
Yield: 81.6 %

Procedure:
To a solution of 1-methylcyclopropanecarboxylic acid (1.0 g) in tetrahydrofuran (50 ml), 3-trifluoromethyl-4-difluoromethoxyaniline (2.25 g) was added, and a solution of N,N'-dicyclohexylcarbodiimide (DCC) (2.2 g) in tetrahydrofuran was dropwise added while stirring. After several minutes, the by-produced N,N'-dicyclohexylurea (DCU) was eliminated by filtration. To the filtrate, acetic acid (2 ml) was added to decompose excessive DCC, followed by elimination of DCU. The resultant filtrate was extracted with ether, and the extract was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The crude crystals (2.85 g) were recrystallized from ethanol to give N-(3-trifluoromethyl-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (2.5 g). M.P., 39°-40° C.
Reaction SMILES: C([O:8][C:9](=[O:29])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:26]=[N+]=[N-])C1C=CC=CC=1>CO.[Pd]>[NH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([OH:29])=[O:8]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCOCCOCCOCCOCCOCC(=O)O
Reaction time: 2.5 h

Procedure:
The Compound 6 obtained in Production Example 9 (1.94 g, 4.72 mmol) was dissolved in methanol (50 ml), 10% Pd—C (500 mg) was added, and catalytic hydrogenation was conducted at room temperature for 2.5 hours. The solid was removed by Celite filtration and washed with methanol, and the filtrate and the washings were combined and concentrated under reduced pressure to yield the desired [2-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]acetic acid (Compound 7; 1.4 g, quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl.[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: COCCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCOCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of 8-(tert-butoxycarbonylamino)-2-naphthol, as described in Example 6, Step A, (1.80 g, 6.94 mmol) in dry THF (50 mL), at 0° C., under argon, was added NaH (305 mg of a 60% oil dispersion, 7.64 mmol). The resulting mixture was stirred for 30 min, then 2-methoxyethoxymethyl chloride (0.95 mL, 8.33 mmol) was added. The mixture was allowed to warm slowly and then stirred at ambient temperature for 18 hrs. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) and CH2Cl2 (250 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane −20% to 50% EtOAc to yield the desired product as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[C:9]([C:11]1[C:16]([F:17])=[CH:15][C:14]([O:18][CH3:19])=[CH:13][C:12]=1F)#[N:10].C(OCC)C>CN(C)C=O.O1CCCC1>[C:9]([C:11]1[C:12]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])=[CH:13][C:14]([O:18][CH3:19])=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: OCC(F)(F)F
Reactant: COc1cc(F)c(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(F)c(C#N)c(OCC(F)(F)F)c1
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
Sodium hydride (1.6 g, 60%, 0.040 mol) was added to a solution of trifluoroethanol (4.0 g, 0.040 mol) in dimethylformamide (50 ml) and the solution stirred for 90 minutes. This solution was then added to 4-cyano-3,5-difluoroanisole [Grey et al, Mol Cryst Liq Cryst, 172, 165-189 (1989)] (6.30 g, 0.037 mol) in tetrahydrofuran (50 ml) and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured into diethyl ether (250 ml) washed with water (2×150 ml) and then brine (50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure, then triturated with diethyl ether:hexane to give the subtitle compound as white crystals (5.92 g, 59%). Rf 0.14 (dichloromethane:hexane, 1:2, v/v). MS m/z 267 (MNH4)+.
Reaction SMILES: ClC1C=C(C=CC=1)C=O.Cl[C:11]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:12]=1[CH2:13][NH:14][CH:15]1[CH2:17][CH2:16]1>>[Cl:22][C:21]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH2:13][NH:14][CH:15]1[CH2:16][CH2:17]1
Reactant: Clc1cccc(CNC2CC2)c1Cl
Agent: O=Cc1cccc(Cl)c1
Product: Clc1cccc(CNC2CC2)c1

Procedure:
1C was synthesized from 3-chlorobenzaldehyde (20.0 g, 142.3 mmol) using the procedure described for 1A as clear liquid. ESI-MS:m/z 182.08 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2>[Pd].CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccco3)c2n2ccnc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccco1)c1ccccc1-2

Procedure:
A mixture of 10-(2-furylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 100 ml of dimethylformamide and 0.15 g of 10% palladium on charcoal is hydrogenated by flushing with a stream of hydrogen at a temperature in the region of 20° C. for 2 hours. The catalyst is then filtered off under inert atmosphere and the solvent is evaporated off. The brown solid obtained (2 g) is purified by trituration in 50 ml of acetone, filtration and crystallization of the insoluble material obtained (1 g) in 80 ml of methanol. After filtration and drying at 80° C., 0.48 g of 10-(2-furylmethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one is obtained, in the form of a light brown solid melting above 260° C. (Analysis % calculated C: 71.28, H: 4.32, N: 13.85, O: 10.55, % found C: 71.5, H: 4.2, N: 14.0).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)([N:13]1C=CN=C1)=O.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH2:13])=[O:8]
Reactant: Cn1ncc(I)c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(I)c1C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.9 %

Procedure:
A round-bottom flash was charged with 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid (297 g, 1.18 mol), DCM (2.97 L), and 1,1′-carbonyldiimidazole (CDI) (207 g, 97% by mass, 1.24 mol). The reaction mixture was stirred at room temperature for 45 min. Ammonium chloride (189 g, 3.53 mol) and triethylamine (498 mL, 3.53 mol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was suspended in H2O (˜3 L) and granulated at room temperature for 1 h. The solid was collected via filtration, washed with H2O, and dried in a vacuum oven to afford 4-iodo-1-methyl-1H-pyrazole-5-carboxamide as a colorless solid (222 g, 75% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:10]=[C:11]([CH2:21][OH:22])[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14]=1[N+:15]([O-:17])=[O:16]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14]=1[N+:15]([O-:17])=[O:16])[CH:21]=[O:22]
Reactant: Cc1cc(CO)cc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)cc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
In a flame-dried flask, manganese (IV) oxide (36.0 g, 414 mmol) was azeotropically dried with toluene. Then, a solution of (3-methyl-4,5-dinitrophenyl)methanol (3.2 g, 15 mmol) in chloroform (100 mL) was transferred to the flask containing the manganese dioxide. The reaction mixture was heated at 50° C. with stirring for 3 h. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite® to remove manganese dioxide and the Celite was washed with chloroform several time. The filtrate was evaporated to give the title compound (1.4 g, 44% yield). 1H-NMR (CDCl3, 300 MHz) δ 10.09 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H), 2.51 (s, 3H).