Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:32])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:33])[CH:8]=[CH:9][O:10]2)=[CH:5][CH:4]=1>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:32])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:19][CH2:20]2)=[C:11]2[C:6]([C:7](=[O:33])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)ccoc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)OCCC2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.4 %

Procedure:
42 mg of 1-(1-(2-(7-methoxy-4-oxo-4H-chromen-8-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide was dissolved in 3 ml of methanol. Thereafter, 15 mg of 10% palladium carbon was added to the reaction solution. The obtained mixture was then stirred at room temperature for 15 hours under hydrogen atmosphere. Thereafter, 15 mg of 10% palladium carbon was further added to the reaction solution. The obtained mixture was then stirred at the same temperature for 4 hours. Thereafter, palladium carbon was removed by filtration, and the filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate), so as to obtain 20 mg of the subject compound.
Reaction SMILES: [C:1]1([S:7](/[CH:10]=[CH:11]/[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1([CH3:31])[O:26][CH:25]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:24]2[O:23]1>C1(C)C=CC=CC=1>[C:1]1([S:7]([CH:10]2[CH:11]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:30]3[CH:29]=[CH:28][CH:27]2[CH:25]2[CH:24]3[O:23][C:22]([CH3:31])([CH3:21])[O:26]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OC2C=CC=CC2O1
Reactant: O=S(=O)(/C=C/S(=O)(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)OC2C3C=CC(C2O1)C(S(=O)(=O)c1ccccc1)C3S(=O)(=O)c1ccccc1

Procedure:
Trans-1,2-bis(phenylsulfonyl)ethylene (1.37 g, 4.45 mmol) was added to a solution of the compound obtained in Step (12) in toluene, and air in a vessel containing the mixture was replaced with nitrogen. After having been refluxed for 8 hours, the mixture was concentrated under reduced pressure. The resultant reaction product was purified by silica gel chromatography (50% EtOAc/Hexane), whereby 10,11-bis(phenylsulfonyl)-4,4-dimethyl-3,5-dioxa-tricyclo[5.2.2.02.6]undec-8-ene was obtained (2.0 g, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2].ClC1C=C2C(=CC=1)[NH:22]C=C2C1CCNCC1.C(N(CC)CC)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([NH2:22])=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: O=C(O)c1csc2ccc([N+](=O)[O-])cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1csc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitro-3-benzothiophencarboxylic acid 1b (20 g) was converted into the corresponding carboxylic acid chloride as in Example 2. The acid chloride was dissolved in THF (200 ml) and added dropwise to a solution of 5-chloro-3-(4-piperidinyl)-1H-indole, 9a (19 g) and triethylamine (10 ml) in THF (200 ml) at 0-5° C. The mixture was stirred overnight at room temperature. THF was evaporated. Water was added to the remaining oil. Extraction with dichloromethane (2×100 ml) and work-up of the organic extracts afforded the crude 5-nitro-3-benzothiophencarboxylic acid amide, which was subsequently purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:1). Yield 6.6 g, mp: 243-250° C. All of the amide was dissolved in 90% ethanol at reflux. Fe-powder (5 g) and concentrated aqueous HCl were added successively in small portions during 10 minutes. The mixture was refluxed for another 2.5 hours. Inorganic salts were filtered off and ethanol evaporated in vacuo. Water was added to the remaining oil and pH was adjusted to >9 by addition of diluted aqueous NH4OH. Extraction with dichloromethane (2×100 ml) and subsequent work-up of the organic phase yielded 4 g of the 5-amino-3-benzothiophencarboxylic acid amide as an oil. All of this oil was dissolved in methanol (100 ml). 0.5 g of Mg turnings were added. By heating to 35° C. an exothermic reaction started, Mg turnings were added in small portions (3×0.5 g) while keeping the temperature below 45° C. The mixture was finally poured into an aqueous NH4Cl solution and concentrated aqueous HCl (1 ml) was added. Extraction with dichloromethane (2×50 ml) and work-up of the organic extracts as above afforded 2 g of the 5-amino-2,3-dihydrobenzothiophen-3—carboxylic acid amide as an oil. To a suspension of LiAlH4 (0.6 g) in dry THF (50 ml) was added dropwise a solution of all of the carboxamide in THF (50 ml). The mixture was gently refluxed for 2 hours. After cooling to 10° C. water (2.4 ml) and a 15% aqueous NaOH solution were cautiously added to destroy excess LiAlH4. Inorganic salts were filtered off and washed extensively with THF. The combined THF solutions were evaporated leaving 1.9 g of 3-[1-(5-amino-2,3-dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:6]([OH:11])=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:4].[Br-].[Li+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C@H:22]2[CH2:35]OS(C)(=O)=O)=[CH:17][C:16]=1[F:41]>COCCOC.CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:23][C@H:22]2[CH2:35][N:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]#[N:4])[C:6]2=[O:11])=[CH:17][C:16]=1[F:41]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reactant: N#Cc1cccnc1O
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2cccc(C#N)c2=O)C1
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
60% Sodium hydride (0.274 g, 6.85 mmol) was added to a mixed solution of 3-cyano-2-hydroxypyridine (0.658 g, 5.48 mmol) in 1,2-dimethoxyethane (10 mL)-DMF (5 ml) under ice-cooling, and the mixture was stirred for 20 min. To the reaction solution was added lithium bromide (0.793 g, 9.13 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction solution was added a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (2 g, 4.57 mmol) in 1,2-dimethoxyethane (10 ml), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.757 g, 3.80 mmol, 83%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH:20]([C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1)Cl)=[O:6])[CH:2]=[CH2:3].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:14])[CH3:15])[CH2:9][C@H:8]1[CH2:20][C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(Cl)c1cncnc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1cncnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Under nitrogen atmosphere to a solution of 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl }-1-(pyrimidin-5-yl)-1-chloromethane (37.4 g) in toluene (750 ml) were added firstly tributyltin hydride (29.1 g) and secondly azoisobutyronitrile (0.45 g) at room temperature. After the reaction mixture was stirred at 80° C. for two hours, it was cooled and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (400 g) (solvent; hexane:ethyl acetate=4:1 to 2:1 to 1:2) to give (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(pyrimidin-5-ylmethyl) pyrrolidine (29.1 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:31])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[NH:24][CH2:25][C:26]([O:28]CC)=[O:27])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:31])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[NH:24][CH2:25][C:26]([OH:28])=[O:27])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CCOC(=O)CNc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(NCC(=O)O)c1
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of 1.65 g of ethyl [[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]amino]acetate in 10 mL of ethanol was added 14 mL of 2 mol/L sodium hydroxide solution at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added 15 mL of 2 mL of hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1.416 g of [[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]amino]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]([F:34])[CH2:13][O:14]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH:9]=1)[C:7]#[N:8].C1(C)C(CO)=CC=CC=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]([F:34])[CH2:13][OH:14])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1OC[C@@H](F)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N#Cc1cc(Cl)ccc1OC[C@@H](F)CO
Temperature: 60 °C
Reaction time: 18.5 h
Yield: 88 %

Procedure:
5-Chloro-2-[[(2R)-2-fluoro-3-(trityloxy)propyl]oxy]benzonitrile (460 g, 0.97 mol) was suspended in a toluene-methanol mixture (4.8 L/3.22 L) at room temperature and then concentrated sulfuric acid (3.1 mL, 0.06 mol) was added to the reaction mixture, followed by stirring the reaction mixture at the same temperature for 18.5 hours. A 1N sodium hydroxide aqueous solution was added to the reaction mixture at room temperature to adjust the pH to 14 or more, followed by subjecting the reaction mixture to vacuum concentration. Ethyl acetate (2.1 L) and water (1.2 L) were added to the residue to separate an organic layer, followed by washing the organic layer twice with water (1.2 L) before vacuum concentration. Ethyl acetate (0.7 L) was added to the resultant crude crystal, which was then heated to 60° C. for complete dissolution. Heptane (3.8 L) was then added to the reaction mixture, followed by cooling and the filtration of the precipitated crystal to obtain 196 g of the title compound (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12]Br.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH3:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:21][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[CH3:29])=[C:15]([Cl:14])[CH:20]=1
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Temperature: 80 °C

Procedure:
2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (2.0 g, 6.3 mmol), 2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-amine (1.7 g, 6.9 mmol), and K2CO3 (1.3 g, 9.4 mmol) were diluted with DMF (20 mL) and heated to 80° C. After 3 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][NH:3]1.Cl.[CH3:20][S:21]([CH2:24][CH2:25][NH2:26])(=[O:23])=[O:22].C(O)(=O)C.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.O>[CH3:20][S:21]([CH2:24][CH2:25][NH:26][CH2:17][C:15]1[O:16][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][NH:3][C:2]3=[O:1])=[CH:13][CH:14]=1)(=[O:23])=[O:22]
Reactant: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
To a suspension of the compound of formula (IX) (5 g, 21 mmol) and 2-(methylsulfonyl)ethanamine hydrochloride (4.1 g, 33 mmol) in THF (150 mL) was added acetic acid (5 g, 83 mmol) followed by DIPEA (10.5 g, 83 mmol). The mixture was stirred at 35° C. (internal temperature) for 2.5 h and was then cooled to 20° C. (internal temperature). Sodium tri-acetoxyborohydride (8.8 g, 42 mmol) was added and the mixture was stirred at ambient temperature the reaction was complete (TLC analysis). 25% Aqueous sodium hydroxide (10 mL) and water (50 mL) were added and the mixture was stirred for 30 min The liquid phases were separated and the aqueous layer was extracted with THF (50 mL). The extract was combined with the former organic layer and the mixture was washed with saturated aqueous NH4Cl (50 mL). The organic layer was concentrated under vacuum. The crude product was purified by column chromatography, eluting with 5% MeOH in DCM providing the compound of formula (XI) (3.1 g) after evaporation of the product containing fractions. The compound of formula (XI): 1H NMR (300 MHz, d6-DMSO): δ 2.94 (dt, J=13.8 Hz, J=7.05 Hz, 1H), 3.00 (s, 1H), 3.24 (t, J=6.75 Hz, 1H), 3.77 (s, 1H), 6.42 (d, J=3.3 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 8.06 (s, 1H), 8.09 (dd, J=8.55 Hz, J=2.25 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.CI.[C:15](=O)([O-])O.[K+]>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:10]([O:12][CH3:15])=[O:11])[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)C1(c2cccs2)CCC1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(c2cccs2)CCC1

Procedure:
1-(2-Thienyl)cyclobutanecarboxylic acid, methyl iodide, and potassium hydrogen carbonate were reacted in DMF at room temperature to obtain methyl 1-(2-thienyl)cyclobutanecarboxylate.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].CC(C)([O-])C.[K+].Cl[C:16]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[NH:39][C:38]4=[O:46])[CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[C:21]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:20][C:17]=1[C:18]#[N:19]>CC(N(C)C)=O>[NH2:7][C:6]1[N:8]=[C:18]([NH2:19])[C:17]2[CH:20]=[C:21]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[CH2:36][CH2:35][CH:34]([N:37]5[C:41]6[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=6[NH:39][C:38]5=[O:46])[CH2:33][CH2:32]4)=[CH:26][CH:25]=3)=[N:23][C:16]=2[N:5]=1
Reactant: N=C(N)N
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: O=C(O)O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2cc(-c3ccccc3)c(-c3ccc(CN4CCC(n5c(=O)[nH]c6ccccc65)CC4)cc3)nc2n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Guanidine carbonate (0.036 g, 0.2 mmol) was added to a suspension of potassium tert-butoxide (0.045 g, 0.4 mmol) in dimethylacetamide (1.0 mL). The mixture was stirred at 50° C. for 10 min. Then 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (11-5) (0.052 g, 0.1 mmol) was added. The mixture was then heated to 140° C. for 20 min in microwave. Purification directly with reverse phase HPLC (5–100% CH3CN/H2O+0.1% TFA) gave 1-{1-[4-(2,4-diamino-6-phenylpyrido[2,3-d]pyrimidin-7-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (11-6) as a off-white solid. 1H NMR (DMSO-d6) δ 8.59 (s, 1H), 8.45 (broad, 4H), 6.91–7.34 (m, 13H), 4.17–4.21(m, 1H), 3.60 (m, 4H), 3.34 (m, 2H), 2.38 (m, 2H), 2.12–2.23 (m, 2H). LRMS m/z (M+H) Calcd: 543.6, found: 543.2.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:8][C:9]1[C:10](Br)=[C:11]2[O:16][CH2:15][CH:14]([CH3:17])[N:13]3[CH:18]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:20](=[O:23])[C:21]([CH:22]=1)=[C:12]23.Cl>O1CCCC1>[F:8][C:9]1[C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]2[O:16][CH2:15][CH:14]([CH3:17])[N:13]3[CH:18]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:20](=[O:23])[C:21]([CH:22]=1)=[C:12]23
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)c1cn2c3c(c(Br)c(F)cc3c1=O)OCC2C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(-c4ccccc4)c(F)cc3c1=O)OCC2C
Temperature: -78 °C
Yield: 46 %

Procedure:
A solution of phenyl lithium (2.7M) in etherbenzene [(3:7), 1.5 ml, 4 mmol] was added to dry tetrahydrofuran (10 ml) and the resulting solution was cooled to -78° C. with stirring under a nitrogen atmosphere. A solution of freshly fused zinc chloride (0.54 g, 4 mmol) in dry tetrahydrofuran (10 ml) was added dropwise over 5 minutes. The clear, colorless solution was warmed to -30° C. over 20 minutes. Ethyl 9-fluoro-10-bromo-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate (1.0 g, 2.7 mmol) was added in one portion; then dichlorobis(triphenylphosphine) nickel (0.13 g, 0.2 mmol) was added in one portion. The reaction mixture was gradually warmed to ambient temperature and stirred for 24 hours. The dark brown mixture was poured onto a 1N hydrochloric acid solution (100 ml) and the aqueous mix was stirred for 15 minutes. Three extractions with chloroform (50 ml), drying the combined organic layers over magnesium sulfate, treatment with decolorizing charcoal and filtration through diatomaceous earth gave a yellow solution. Removal of solvent in vacuo afforded a bright yellow solid. Trituration with ether, filtration and drying in vacuo gave a pale yellow solid (0.67 g, 46% yield): m.p. 270°-272° C. NMR (CDCl3, 250 MHz): 8.42 (s, 1H), 7.85 (d, 1H, J=10 Hz), 7.55-7.40 (m, 5H), 4.42 (q, 2H, J=7 Hz), 4.50-4.35 (m, 3H), 1.62 (d, 3H, J=8 Hz), 1.45 (t, 3H, J=7 Hz).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28][N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[CH2:10][CH3:11]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: O=C1CCCCCN1
Product: CCCc1c(OCCCN2CCCCCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one was prepared as for Example 10 from caprolactam and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12](Cl)=[O:13])=[CH:3]1.Cl.C([O:20][C:21](=[NH:34])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]([CH3:33])[CH:24]=1)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:33][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[C:23]([C:22]2[C:21](=[O:34])[NH:20][C:12](=[O:13])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:24]1
Reactant: Cc1ccc2c(CC(=N)OC(C)C)cn(C)c2c1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of the known (1-methyl-1H-indol-3-yl)-oxo-acetyl chloride (183 mg, 0.83 mm) and 2-(1,6-dimethyl-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride (233 mg, 0.83 mm) in CH2Cl2 (6 mL) which had been cooled to 0° C., was added Et3N (0.46 mL, 3.3 mm). The reaction was allowed to warm to room temperature overnight, then diluted with CH2Cl2 (20 mL), and extracted with H2O(15 mL) and 0.5N HCl(15 mL). The organic fraction was dried over MgSO4, filtered and evaporated, and the residue combined with toluene (3 mL). After cooling to 0° C., para-toluene sulfonic acid (pTsOH) (174 mg, 0.91 mm) was added, and the mixture was stirred at room temperature for 3 hours. The red solids which precipitated were collected and partitioned between CH2Cl2 (50 mL) and H2O(25 mL). The organic fraction was washed with saturated NaHCO3 (25 mL) solution, then dried over MgSO4, filtered and evaporated. The residue was washed with cold CH2Cl2 to yield 3-(1,6-dimethyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3yl)-pyrrole-2,5-dione; mp=264°-266° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]3[N:17]=[C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]4[CH:25]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38](C)[CH:39]=O>O>[CH3:37][N:38]([CH:1]=[N:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]3[N:17]=[C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]4[CH:25]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)[CH3:39]
Reactant: CC(=O)Nc1nc2ccc(CCc3cn4ccc(C)cc4n3)cc2o1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccn2cc(CCc3ccc4nc(N=CN(C)C)oc4c3)nc2c1

Procedure:
2-Acetamido-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (2.20 g) was added in small portions to a solution of phosphorous oxychloride (1.79 ml) in N,N-dimethylformamide (20 ml) at ambient temperature with stirring. After being stirred for 1 hour, the mixture was diluted with water (200 ml) and stirred for an additional 30 minutes. The mixture was made alkaline with aqueous potassium carbonate and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give dark brown amorphous powder. The crude material was chromatographed on silica gel by eluting with chloroform-methanol (50:1, V/V), followed by recrystallization from a mixture of methanol and diisopropyl]ether to give 2-dimethylaminomethyleneamino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.31 g).