Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccc(OC)cc12
Reactant: BrCc1ccccc1
Product: COC(=O)c1cn(Cc2ccccc2)c2ccc(OC)cc12

Procedure:
Prepare by a method similar to Example 48 using 5-methoxy-1H-indole-3-carboxylic acid methyl ester and benzyl bromide.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C([O-])([O-])=O.[Cs+].[Cs+].[C:11]([N:18]1[C:30]2[C:29]([OH:31])=[C:28]3[N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][C:38]=4[C:27]3=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[C:22]([F:47])[CH:23]=2)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(#N)C>[C:40]([N:32]1[C:28]2[C:29]([O:31][CH2:3][CH2:2][Br:1])=[C:30]3[N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:19]4[CH:20]=[CH:21][C:22]([F:47])=[CH:23][C:24]=4[C:25]3=[CH:26][C:27]=2[C:38]2[C:33]1=[CH:34][CH:35]=[C:36]([F:39])[CH:37]=2)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(OCCBr)c21
Yield: 77 %

Procedure:
To a solution of 1,2-dibromoethane (>5 equiv) in acetonitrile was added Cs2CO3 (2 equiv) and 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (1 equiv) under argon. The suspension was refluxed and the reaction was monitored by TLC. After completion of the reaction (1-3 hours), the solid was removed by filtration and washed with dichloromethane. The combined filtrate was concentrated and the residue was subjected to chromatography on silica gel, eluting with 8% ethyl acetate in hexanes to give 5,7-diBOC-2,10-difluoro-6-(2-bromoethoxy)indolo[2,3-b]carbazole (77%). 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (s, 1H), 8.06 (dd, J=9.0, 4.2 Hz, 2H), 7.68 (dd, J=8.4, 2.8 Hz, 2H), 7.17 (td, J=9.0, 2.8 Hz, 2H), 4.21 (t, J=6.8 Hz, 2H), 3.42 (t, J=7.0 Hz, 2H), 1.74 (s, 18H).
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[CH2:32][C:31]3[N:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH2:45][C:41]2[NH:42][CH:43]=[CH:44][N:40]=2)[CH:23]2[CH2:32][C:31]3[N:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]2)=[CH:19][CH:20]=1
Reactant: O=Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCc3cccnc3C2)cc1)Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3ncc[nH]3)C3CCc4cccnc4C3)cc2)nc1
Yield: 120.4 %

Procedure:
Using general procedure B: Reaction of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine (175 mg, 0.32 mmol), imidazole-2-carboxaldehyde (155 mg, 1.6 mmol) and NaBH(OAc)3 (137 mg, 0.64 mmol) in MeOH (3 mL) for 8 hours at 60° C., followed by purification of the crude material by column chromatography on silica gel (CHCl3/MeOH/NH4OH 20:2:1) gave the desired product (169 mg, 84%) as a yellow/green foam.
Reaction SMILES: O[C:2]1([CH:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCCCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCCCC2)c2ncc[nH]2)cc1
Reaction time: 18 h
Yield: 21.6 %

Procedure:
At 0°, 10 g of crude 4-[1-hydroxycyclohept-1-yl-1-(imidazolyl)methyl]benzonitrile is dissolved in 100 ml of dichloromethane and stirred with 10 ml of thionyl chloride for 4 hours. Then the mixture is concentrated to dryness under an oil pump vacuum, taken up in 100 ml of dichloromethane, and stirred with 40 ml of triethylamine for 18 hours at 25°. For working up purposes, the mixture is combined with water, extracted twice with dichloromethane, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus producing 2.03 g of 4-[1-cycloheptylidene-1(imidazolyl)methyl]benzonitrile as the oily, free base.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(O)(=O)C.O1CCCC1>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Temperature: 50 °C
Yield: 94.7 %

Procedure:
52.95 g (0.2 mol) of 7-amino-1-(ethoxycarbonylmethyl)-2,3(1H,4H)-quinoxalinedione and a spatula tip of 4-(N,N-dimethylamino)pyridine were suspended in a mixture of 500 ml of glacial acetic acid and 300 ml of tetrahydrofuran and heated to 50° C. Then 20.5 g (0.2 mol) of acetic anhydride were added dropwise and the mixture was heated at 50° C. for 2 h. The precipitate was filtered off with suction to yield 57.8 g (94%) of the product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[CH2:12].[H][H]>C(O)C.[Rh]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: C=CCc1cc(CO)ccc1O
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: CCCc1cc(CO)ccc1O
Reaction time: 0.5 h

Procedure:
To a solution of 0,370 g (2.25 mmol) of the product of Step E dissolved in 25 mL of absolute ethanol was added 53 mg of a 5% rhodium on carbon catalyst and the mixture was shaken under a 40 psig pressure of hydrogen on a Parr apparatus. After 30 minutes, the reaction mixture was removed, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=S)=[CH:5][CH:4]=1.O.[NH2:22][NH2:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7](=[N:22][NH2:23])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=S)Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=NN)Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 10 g of 4-methoxy-4'-nitrothiobenzanilide [prepared by process of Ann. Chem., Vol. 716 (1968), p. 209-211], 100 ml of ethanol and 15 ml of hydrazine hydrate was heated to reflux and then was allowed to return to room temperature and was filtered. The product was washed with ethanol and dried at 80° C. under reduced pressure to obtain 7.9 g of 4-methoxy-N-(4-nitrophenyl)-benzene-carbohydrazonamide melting at 104° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)=[C:4]([O:15]C(C)C)[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)=[C:4]([OH:15])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)Oc1cc(F)ccc1-n1nnn(C)c1=O
Agent: O=S(=O)(O)O
Product: Cn1nnn(-c2cc([N+](=O)[O-])c(F)cc2O)c1=O
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A solution of 1-(4-fluoro-2-isopropoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (3.50 g, 13.9 mmol, 1 equiv) in H2SO4 (35 mL) was cooled in ice/water bath. To the cooled solution, was added HNO3 (fuming>90%; 715 uL, 15.3 mmol, 1.1 equiv) dropwise, and the cooled reaction mixture was allowed to warm to RT over 2 h. The reaction mixture was quenched with ice, and extracted with EtOAc 3×. The organic layer was then extracted with saturated NaHCO3 3×. The basic aqueous layer was acidified to pH<3 with 6N HCl. Then, the acidic layer was extracted with EtOAc 3×, and the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 1-(4-fluoro-2-hydroxy-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (2.94 g, 83%) as brown solid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 12.5 (bs, 1H), 8.41-8.44 (d, 1H, J=8.7 Hz), 7.04-7.08 (d, 1H, J=13 Hz), 3.59 (s, 3H); 19F NMR (282 MHz; d6-DMSO) δ −111.3 (q); m/z=256 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]#[N:16])=[C:13]([S:17][CH3:18])[S:12][C:11]=2[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:34]([NH2:37])([CH3:36])[CH3:35].O.Cl>C(Cl)Cl>[C:15]([C:14]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH:37][CH:34]([CH3:36])[CH3:35])=[CH:5][CH:6]=2)=[C:11]([C:19]([OH:21])=[O:20])[S:12][C:13]=1[S:17][CH3:18])#[N:16]
Reactant: CC(C)N
Reactant: CSc1sc(C(=O)O)c(-c2ccc(C(=O)O)cc2)c1C#N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CSc1sc(C(=O)O)c(-c2ccc(C(=O)NC(C)C)cc2)c1C#N
Reaction time: 8 h
Yield: 27 %

Procedure:
Combine 3-(4-Carboxy-phenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid (0.1 g, 1.0 eq) in CH2Cl2 (5.0 mL) and stir. Add carbonyldiimidazole (2.0 eq). Stir the mixture overnight. Add isopropylamine (1.0 eq) and stir overnight at room temperature. Add 1N HCl water solution. Filter the precipitate to provide the title compound (0.03 g, Yield 27%). MS (ES+, m/e): 361 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][N:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(I)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(I)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11 g of 2-iodopyridine-5-carboxylic acid were suspended in 300 ml of dichloromethane and 4 8 g of benzyl alcohol, 10 g of dicyclohexylcarbodiimide and 100 mg of 4-dimethylaminopyridine were added. The mixture was stirred at room temperature and, after 2 hours, filtered. The filtrate was evaporated and the residue was chromatographed on silica gel using firstly ethyl acetate/petroleum ether (1:9) and then ethyl acetate/petroleum ether (1:6) for the elution. There were obtained 12.2 g of benzyl 2-iodopyridine-5-carboxylate which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]12[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:32]C(=O)O[C:28]2=[O:29].CCCCCC>C1(C)C(C)=CC=CC=1>[NH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=1[C:28]([NH:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4])=[O:29]
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: Nc1ccccc1C(=O)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of (3aR*,l0aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (420 mg, 1.2 mmol) and isatoic anhydride (196 mg, 1.2 mmol) was stirred for 30 minutes in xylene at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, which was recrystallized from ethanol-hexane to give 345 mg (yield 58%) of the titled compound. This compound was in good agreement in
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:30])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)CCC>[CH3:13][O:12][C:9]1[C:8](=[O:14])[N:7]([CH3:15])[C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:16]3[CH2:21][CH2:20][C:19]4([C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][C:22]4=[O:30])[CH2:18][CH2:17]3)[C:11]=2[N:10]=1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: COc1nc2c(Cl)ncnc2n(C)c1=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1nc2c(N3CCC4(CC3)C(=O)Nc3ccccc34)ncnc2n(C)c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Into a 100 mL round bottomed flask were placed 4-Chloro-6-methoxy-8-methylpteridin-7(8H)-one (2.00 g, 8.83 mmol, 1 equiv) and spiro[indoline-3,4′-piperidin]-2-one (2.14 g, 10.6 mmol, 1.2 equiv). Anhydrous n-butanol (20 mL) and triethylamine (2.46 mL, 2 equiv) were added and reaction mixture was heated to 80° C. with stirring. The reaction was complete as monitored by LC/MS after 5 hours. The solvent was stripped by rotary evaporation, and the residue rinsed with water (5 mL) to yield a tan precipitate, which was collected by vacuum filtration and rinsed with water to afford the desired product which was used directly without any further purification. 1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.39 (s, 1H), 7.49 (d, 1H), 7.20 (d, 1H), 6.97 (t, 1H), 6.87 (t, 1H), 4.53-4.45 (m, 4H), 3.80 (s, 3H), 3.55 (s, 3H), 1.93-1.80 (m, 4H). MS (EI) for C20H20N6O3: 393 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:12]([Cl:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([OH:14])[CH:5]=1.Cl[CH2:16][CH2:17][S:18][CH3:19]>CN(C)C=O>[NH2:3][C:4]1[C:12]([Cl:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:14][CH2:16][CH2:17][S:18][CH3:19])[CH:5]=1
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Reactant: CSCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCOc1cc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
A cooled (5° C.) suspension of 60% sodium hydride oil dispersion (0.52 g, 13 mmole) in anhydrous dimethylformamide (15 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid (0.94 g, 5 mmoles) stirred for 15 minutes at 25° C., treated with (2-chloroethyl)methyl sulfide (1.66 g, 15 mmoles), and heated to 100°±5° C. for 18 hours. The solution was cooled, concentrated in vacuo to remove most of the dimethylformamide and water (25 ml) was added. The aqueous solution was extracted with ether (2×25 ml), and the combined extracts were dried (MgSO4), concentrated in vacuo, taken up in 50% aqueous ethanol (50 ml), treated with potassium hydroxide (5.0 g), and refluxed for one hour. The mixture was concentrated to remove most of the ethanol, diluted with water to 75 ml total volume, extracted with ether (2×35 ml), and acidified to pH 3 with concentrated HCl. The resultant precipitate was filtered, washed with water, air dried, and recrystallized from ethyl acetate to yield 0.75 g (57%) of fine voluminous white needles, mp 137.5°-139.5° C.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[C:9]1([CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Br)C.P([O-])([O-])([O-])=O>C1COCC1>[C:18]1([C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH2:2][CH3:3])[C:16]#[N:17])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
173 ml (0.259 mol) of a 1.5 M solution of LDA in THF were added dropwise to a solution of 50.0 g (0.259 mol) of diphenylacetonitrile in 500 ml of THF (abs.) at −78° C. under argon, and the mixture was then stirred at −30° C. for one hour. Then, at −78° C., 28.23 g (0.259 mol) of ethyl bromide were added. The mixture was allowed to reach room temperature and was stirred for 16 hours. Subsequently, 80 ml of phosphate buffer (pH 7) were added and the mixture was evaporated. The residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was stripped off under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/acetic acid (20:1). 38.2 g (67%) of 2,2-diphenylbutyronitrile were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH:16]([N:21]=[C:22]=[S:23])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][CH:16]([NH:21][C:22]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[S:23])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:24][CH:25]=1
Reactant: Nc1cccnc1
Reactant: Cc1ccc(C(=O)NC(N=C=S)C(F)(F)F)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)NC(NC(=S)Nc2cccnc2)C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
A solution of 3-aminopyridine (145 mg, 1.54 mmol) in benzene (8 mL) at ambient temperature was treated with a solution of Example 1C (500 mg, 1.54 mmol) in benzene (1.5 mL). The reaction mixture was stirred for 1.5 hours, then concentrated to a nominal volume. The white solids which precipitated from solution were collected by filtration and were washed with diethyl ether. Recrystallization from 25% ethyl acetate/hexanes provided the desired product as a white solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])[CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2cccc(O)c2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 79.2 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 1, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added 3-aminophenol (11.8 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 79% (29 mg, 0.057 mmol) of the title compound.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]2[CH2:21][C:22]3=[O:27])=[CH:15][CH:14]=1.I[CH3:29]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]2[CH:21]([CH3:29])[C:22]3=[O:27])=[CH:17][CH:18]=1
Reactant: CI
Reactant: COc1ccc(N2CC3CCC2CC3=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CC3CCC2C(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
LHMDS (2.2 mL, 2.16 mmol, 1.0 equiv, 1.0 M in THF) was added to an oven-dried flask under N2 and cooled to −78° C. A solution of 2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2]octan-5-one (2-1, 500 mg, 2.16 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (8.6 mL) was added dropwise via cannula, and the resulting mixture was allowed to stir for 20 min at −78° C. Following this duration, the enolate mixture was added via cannula to a solution of iodomethane (0.68 mL, 10.8 mmol, 5.0 equiv) in anhydrous tetrahydrofuran (2.2 mL). After 1 h, the reaction contents were removed from the −78° C. bath and allowed to gradually warm to RT. After 18 h, LCMS showed complete consumption of starting material. The reaction was quenched with saturated NH4Cl (15 mL), added to ethyl acetate (20 mL) and diluted with water (5 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange solid. Purification by normal-phase HPLC (0-40% CH3CN:0.1% TFA in H2O) provided 7-1 as a pale yellow solid (inconsequential 1:1 mixture of diastereomers).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)=O.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1>>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:19]3[N:18]([C:17]([CH3:16])=[N:21][CH:20]=3)[CH2:2][CH2:3][CH:4]=2)=[CH:8][CH:9]=1)[CH3:15]
Reactant: Cc1ncc[nH]1
Reactant: CCOc1ccc(C(=O)CCCCl)cc1
Product: CCOc1ccc(C2=CCCn3c2cnc3C)cc1

Procedure:
Combine 150 g (0.66 mol) of 4-chloro-4'-ethoxybutyrophenone with 300 g (3.65 mol) of 2-methylimidazole and heat to 175° C. for 18 hr. Crystallization from ethyl acetate provides the title compound.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=[CH:2]1.C1C2C(C3CC2CC3NC(=O)[O:31]C(C)(C)C)CC=1>C1(C)C=CC=CC=1>[OH:31][CH:2]1[CH2:3][CH:4]2[CH:9]([CH:8]3[CH2:10][CH:5]2[CH:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:7]3)[CH2:1]1
Reactant: CC(C)(C)OC(=O)NC1CC2CC1C1C=CCC21
Reactant: CC(C)(C)OC(=O)NC1CC2CC1C1CC=CC21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CC2CC1C1CC(O)CC21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.87 g of a mixture of tert-butyl (3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)carbamate and tert-butyl (3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)carbamate were dissolved in 30 ml of toluene (anhydrous) and, at RT, 20 ml of a 2 M solution of borane/dimethyl sulfide complex in toluene were added using a syringe. The mixture was stirred at RT for 24 hours, a further 10 ml of a 2 M solution of borane/dimethyl sulfide complex in toluene were added using a syringe, and the mixture was stirred at RT for another 6 hours. The volatile components were then removed under reduced pressure, 200 ml of CH2Cl2 and 33 ml of a 3 N aqueous NaOH solution were added, and the mixture was slowly admixed with 7 ml of a 30% strength aqueous H2O2 solution. The mixture was stirred at RT for 10 minutes, and a further 100 ml of a 3 N aqueous NaOH solution and 20 ml of a 30% strength aqueous H2O2 solution were added. The reaction mixture was stirred at RT for another 10 minutes and then extracted three times with, in each case, 200 ml of CH2Cl2. The extracts were dried over MgSO4 and the solvent was removed under reduced pressure. Chromatography over silica gel using MTB gave 2.9 g of an amorphous solid which was still contaminated by regioisomers.