Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:59])[CH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:40]2[C:39]3[C:34](=[CH:35][C:36]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:38]=3)[NH:33][C:32]=2[N:31]=[C:30]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52](=[N:57][OH:58])[C:53]([F:56])([F:55])[F:54])[CH:47]=2)[N:29]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:59])[CH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:40]2[C:39]3[C:34](=[CH:35][C:36]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:38]=3)[NH:33][C:32]=2[N:31]=[C:30]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52](=[N:57][O:58][S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:53]([F:54])([F:56])[F:55])[CH:47]=2)[N:29]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NOS(=O)(=O)c4ccc(C)cc4)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Ts-Cl (0.060 g, 0.315 mmol) was added portion-wise to a mixture of methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.184 g, 0.274 mmol), DMAP (3.35 mg, 0.027 mmol) and triethylamine (0.048 mL, 0.342 mmol) in DCM (12 mL) to give a tan solution. After 1 hour, the reaction mixture was diluted with DCM (12 mL), washed with water (3×12 mL) and the organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to afford methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (217 mg, 96% yield) as a tan foam: MS m/z 826.2 (M+H)+; HPLC 93.2% @ 220 nm and 91.3% @ 254 nm, RT=2.20 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH3:13])=[C:2]([NH:1][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(Br)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (4.5 g, 18.44 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (11.01 g, 55.33 mmol) in dichloroethane (50 mL), acetic acid (6.64 g, 110.6 mmol) was added and reaction stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (11.72 g, 55.28 mmol) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the desired compound (5.2 g, 66.24%).
Reaction SMILES: [CH2:1]([C@H:3]1[C:20](=O)[CH2:19][CH2:18][C@@:17]2([CH3:22])[CH:4]1[C@@H:5]([OH:24])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:23])[CH3:2].[ClH:25].Cl.[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32][NH2:33])[CH2:28]1>>[ClH:25].[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32]/[N:33]=[C:20]2/[C@H:3]([CH2:1][CH3:2])[CH:4]3[C@:17]([CH3:22])([CH2:18][CH2:19]/2)[C@@H:16]2[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]4)[CH2:6][C@@H:5]3[OH:24])[CH2:28]1
Reactant: NO[C@@H]1CCNC1
Reactant: CC[C@H]1C(=O)CC[C@@]2(C)C1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Product: CC[C@H]1/C(=N/O[C@@H]2CCNC2)CC[C@@]2(C)C1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
The title compound was obtained in 90% yield following the procedure described in Example 30 starting from 4β-ethyl-6α-hydroxyandrostan-3,17-dione (Preparation 27, 137 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 160 mg). The crude product was triturated with Et2O and the resulting precipitate was filtered to give the title compound I-bx.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[CH3:24]O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([O:19][CH3:24])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: CO
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (described in example 1j) (10.03 g, 37.1 mmol) in toluene (100 mL) was added thionyl chloride (4.05 mL, 55.7 mmol, 1.5 eq). The reaction was heated to reflux monitoring gas evolution with a bubbler of mineral oil. Gas evolution ceased after 30 min at which time the reaction was cooled slightly under nitrogen and a large excess of methanol (10 mL) was added. The solution was again heated to reflux for 1 h, cooled to room temperature under nitrogen, and stirred for 18 h. Aqueous NaOH (2.5N, 60 mL) was added and the aqueous phase was extracted with ethyl acetate (2×70 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to a solid. The reaction product was purified by flash chromatography over silica gel (250 mL, eluent: 15% ethyl acetate in hexane) to yield 10.2 g (97%) of the title compound as a highly crystalline white solid. TLC (Rf 0.45, 10% ethyl acetate in hexane). MS (CI, CH4) m/z 285 (M+1,100), 287 (31), 313 (M+29,11), 253 (14), 225 (14), 205 (8)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH3:20])[C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Br)cn(-c2cccc(C(F)(F)F)c2)c1=O
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 97) (150.0 mg) and potassium carbonate (181.6 mg) in N,N-dimethy formamide (4.0 ml) was added at room temperature, methyl iodide (0.042 ml) and the resulting mixture was stirred at 70° C. for two and a half hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (20.0 ml), and the resulting mixture was extracted with ethyl acetate (20 ml×2) and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-bromo-3-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (153.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.O.O.[F:23][C:24]([F:32])([F:31])[C:25]([C:27]([F:30])([F:29])[F:28])=[O:26]>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:25]([C:27]([F:30])([F:29])[F:28])([C:24]([F:32])([F:31])[F:23])[OH:26])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Clc1ccc(-c2cc[nH]c2-c2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OC(c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Yield: 83.7 %

Procedure:
A mixture of 2.9 g (0.01 mole) of 2,3-bis(4-chlorophenyl)-1H-pyrrole and 2.5 g (0.011 mole) of hexafluoroacetone trihydrate in 50 ml toluene was heated at reflux overnight. The mixture was concentrated on a rotary evaporation and the solid residue was chromatographed on 200 g silica gel (eluting with toluene), then recrystallized from hexane to give 3.8 g of product, m.p. 144°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8](=[O:23])[NH:9][N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.N>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:9]2[C:8](=[O:23])[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=3)=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[N:10]2)=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Reactant: Fc1ccc(I)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole (yield: 60 mg, 53%). mp 83–85° C. 1H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 6.89–7.03 (m, 4H), 7.15 (t, J=9 Hz, 2H), 7.65 (dd, J=9 Hz, 6 Hz, 2H), 7.83 (d, J=6 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 455 (M+H)+, 472 (M+NH4)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30](COCC[Si](C)(C)C)[N:29]=[C:28]3[NH:48][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:19]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:30][N:29]=[C:28]3[NH:48][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3)c(-c3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccccc3)c(-c3ccccc3)cc12
Yield: 9.1 %

Procedure:
17.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.5 g of N-[5,6-diphenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 40 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.5 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the product, which is still impure, is purified by HPLC (Hypersil column; C18, 5 μm; length 250 mm, diameter 21 mm, eluent: methanol/water (70/30 by volume) containing 0.1% trifluoroacetic acid; flow rate 10 cm3/min); after concentrating to dryness the fractions containing the expected product, the residue is taken up in 10 cm3 of diisopropyl ether, filtered off, washed with 2×5 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 100 mg of N-[5,6-diphenyl-1H-indazol-3-yl]butanamide in the form of white crystals melting at 210° C.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)=[C:30]([O:39]C)[N:29]=2)=[CH:10]\[C@@H:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[C:14](=[O:27])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.O>O1CCOCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6](/[C:9](/[C:28]2[NH:29][C:30](=[O:39])[C:31]([C:34]3[CH:38]=[N:37][NH:36][CH:35]=3)=[CH:32][CH:33]=2)=[CH:10]\[C@H:11]2[CH2:12][CH2:13][C:14](=[O:27])[N:15]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(OC)n2)c(OC)c1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(=O)[nH]2)c(OC)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
48% hydrobromic acid (1.25 mL) was added to a solution of (5R)-5-{(E)-2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (63 mg) in 1,4-dioxane (1.25 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 6-{(E)-1-(4-chlorophenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-(1H-pyrazol-4-yl)pyridin-2(1H)-one as a yellow amorphous (100 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:17]([NH:24][CH:11]1[CH2:12][CH2:13][C:7]2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(OC)c2c1CCC(=O)CC2
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OC)c2c1CCC(NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1,4-dimethoxy-5,6,8,9-tetrahydrobenzo-cyclohepten-7-one (670 mg) and benzylamine (0.5 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (0.5 g) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes before adding ethyl acetate and brine. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1,4-dimethoxy-5,6,8,9-tetrahydrobenzcyclohepten-7-yl)amine (600 mg).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: COc1ccccc1N
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Nc2ccccc2OC)[nH]c1=O
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (5 g) and 2-methoxyaniline (3.4 g) are added to DMF (20 ml), and the mixture is refluxed with stirring for 8 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (5 g). M.p. 217°-219° C.
Reaction SMILES: [Cl:1][C:2]1[N+:11]([O-])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([N:16](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]([C:14]#[N:16])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(Cl)c[n+]([O-])c1Cl
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(C#N)nc1Cl
Temperature: 70 °C
Yield: 84.2 %

Procedure:
Methyl 2,5-dichloronicotinate 1-oxide (16 g, 72 mmol) was dissolved in acetonitrile (200 mL) with triethylamine (15 mL, 110 mmol) and trimethylsilyl cyanide (24 mL, 180 mmol) was added. The mixture was heated to 70° C. for 30 minutes. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-30%) gave the desired compound (14 g, 82%). LCMS calculated for C8H5Cl2N2O2 (M+H)+: m/z=231.0. found: 230.8.
Reaction SMILES: Cl.CN.C1([CH2:10][NH2:11])CCCCC1.[O:12]=[C:13]1[C:21]2([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]2=3)[CH2:30][CH2:29][O:28]4)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:10][NH:11][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]3=4)[CH2:30][CH2:29][O:28]5)[C:13]2=[O:12])=[CH:42][CH:41]=1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: CN
Agent: Cl
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CNC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using methylamine hydrochloride to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-methyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (86%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.71 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.22-7.12 (m, 2H), 7.02 (t, J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.57-6.45 (m, 1H), 6.42 (s, 1H), 6.39 (s, 1H), 4.95 (ABq, 2H), 4.81 (ABq, 2H), 4.53-4.34 (m, 2H), 2.95 (d, J=4.0 Hz, 3H), 2.90-2.73 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.2, 167.5, 161.9, 161.4, 141.8, 139.0, 134.2, 132.5, 128.8, 127.6, 127.4, 124.0, 123.7, 120.0, 119.8, 118.7, 109.2, 93.3, 80.6, 72.4, 57.7, 43.8, 28.9, 26.8; MS (ES+) m/z 427.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.I[CH3:31]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:11]=[C:10]3[N:27]([CH3:31])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Clc1ccc(-c2nc3[nH]ncc3c(-c3ccc(Cl)nc3)c2-c2ccncc2)cn1
Product: Cn1ncc2c(-c3ccc(Cl)nc3)c(-c3ccncc3)c(-c3ccc(Cl)nc3)nc21

Procedure:
Following a similar procedure to that described in examples 73 and 74, but using 4,6-bis(6-chloropyridin-3-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 40) instead of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and iodomethane instead of 2-bromo-1,1-diethoxyethane, the title compounds were obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:34][CH2:35]1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)c(C)c1

Procedure:
91 mg (64%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.289 mmol), 1-(2,4-dimethylphenyl)piperazine (55 mg, 0.289 mmol), DIPEA (76 mL, 0.434 mmol) and NaBH(OAc)3 (184 mg, 0.868 mmol).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>ClCCl>[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=4)=[C:9]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:30]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Heat 300 mg (0.89 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 191.3 mg (1.16 mmol) of 3-aminophenylacetic acid methyl ester to 150° C. for 1.5 h. After cooling, add dichloromethane and filter off the resulting solid with suction, wash with dichloromethane and dry at 50° C. under high vacuum overnight. Purify the crude product by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 10:1). 273.2 mg (65.9% of theory) of the target product are obtained as a yellowish solid.
Reaction SMILES: Br[C:2]1[CH:3]([OH:8])[CH2:4][CH2:5][C:6]=1[CH3:7].[CH2:9]([Mg]Br)[CH3:10]>C1COCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([C:2]1[CH:3]([OH:8])[CH2:4][CH2:5][C:6]=1[CH3:7])[CH3:10]
Reactant: CC1=C(Br)C(O)CC1
Reactant: CC[Mg]Br
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC1=C(C)CCC1O
Temperature: 25 °C

Procedure:
The alcohol (Intermediate V2, 16 mmol) in THF (30 mL) at 0° C. was treated with ethyl magnesium bromide (40 mmol). The catalyst, 1,3-bis(diphenylphosphino)propane nickel (II) chloride (0.75 mmol) (NiCl2dppp) was added in one portion and the mixture was heated to reflux for 3 hours following the procedure of Organ et al. J. Org. Chem. 1997, 62, 1523, incorporated herein by reference.) The reaction mixture was cooled to rt and quenched with sat. NH4Cl solution. The mixture was filtered and partitioned between brine and diethyl ether. The organic layer was removed and dried over Na2SO4, filtered and concentrated under vacuum. The oil was purified by chromatography on SiO2 with 20% EtOAc:Hx to yield 2-ethyl-3-methyl-cyclopent-2-enol (Intermediate V3). Use of the alcohol (Intermediate V3) in the applicable steps of Method A and Method P produced 4-(2-ethyl-3-methyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 64). 1H NMR (300 MHz, CD3OD-d4): δ 6.03 (s, 1H), 2.88 (brs, 1H), 2.65-2.59 (m, 1H), 2.27-1.83 (series of m, 6H), 1.62 (s, 3H), 1.54-1.45 (m, 1H), 0.97 (t, J=6 Hz, 3H).