Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([C:25]([C:30]2[N:31]=[CH:32][N:33]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:34]=2)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:18]3)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO.[OH-].[Na+]>C1COCC1.CO>[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C:25]([C:30]1[N:31]=[CH:32][N:33]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]=1)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:18]2
Reactant: CC(C)C(O)(c1ccc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-{6-[(Diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (15.0 g) was dissolved in THF (5 ml)-methanol (5 ml) and sodium acetate (285 mg) and hydroxylamine hydrochloride (181 mg) were added. The mixture was stirred at room temperature for 20 min. 0.1N aqueous sodium hydroxide solution was added and the mixture was extracted with ethyl acetate, washed with saturated brine and dried to give a crude product of 1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol as a pale-yellow oily substance. This product was dissolved in dichloromethane (100 ml), and pyridine (5.3 ml) and acetic anhydride (4.1 ml) were added. The mixture Was stirred at room temperature for 40 min. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane and dried. The solvent was evaporated and the residue was recrystallized from ethyl acetate to give the title compound (11.6 g) as pale-red crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[O:17][CH2:18][O:19][CH3:20].[CH:21]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=2)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH:21]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([O:17][CH2:18][O:19][CH3:20])[CH:12]=3)[CH:32]=2)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22]1
Reactant: COCOc1cc(O)ccc1-c1cc(OC)ccc1F
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OCOC)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 78 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-(methoxymethoxy)biphenyl-4-ol (1.29 g), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (1.26 g) and tributylphosphine (2.3 mL) in toluene (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.32 g), and the mixture was stirred at room temperature for 50 hr. To the reaction mixture was added hexane, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.84 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH2:21][C:22]#[N:23])(=[O:20])=[O:19]>>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:21](/[S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)(=[O:20])=[O:19])\[C:22]#[N:23])[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: N#CCS(=O)(=O)c1ccccn1
Product: Cc1cc(/C=C(\C#N)S(=O)(=O)c2ccccn2)cc(C)c1O

Procedure:
The titled compound was prepared with 3,5-dimethyl-4-hydroxybenzaldehyde and (pyrid-2-yl)sulphonyl acetonitrile under the similar conditions as described for EXAMPLE 1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1.Cl.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH2:33][NH2:34])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].ClC1C(C(F)(F)F)=CN=C(NCC2C=CC=C(S(C)(=O)=O)C=2)N=1>C1COCC1.C(Cl)Cl>[Cl:10][C:11]1[N:16]=[C:15]([NH:34][CH2:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CS(=O)(=O)c1cccc(CN)c1
Agent: CS(=O)(=O)c1cccc(CNc2ncc(C(F)(F)F)c(Cl)n2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(CNc2nc(Cl)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
Diisopropylethylamine (31.5 mL, 180 mmol) was added to a suspension of 2,4-dichloro-5-trifluoromethylpyrimidine (XL, 15.0 g, 69.4 mmol) and 1-[3-(methylsulfonyl)phenyl]methanamine hydrochloride (13.3 g, 60 mmol) in THF (300 mL) at 0° C., and the resulting mixture stirred at room temperature overnight. The mixture was then evaporated to dryness, the residue taken up in methylene chloride (100 mL) and the resulting solution washed with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue obtained was taken up in hot methylene chloride (35 mL) then left to stir overnight at room temperature. The separated solid was isolated by filtration (9.4 g) and determined to be a pure sample of the more polar component of the product mixture (4-chloro-N-[3-(methylsulfonyl)benzyl]-5-(trifluoromethyl)pyrimidin-2-amine XLIVb). The mother liquors were adsorbed onto silica gel and chromatographed over silica gel eluting with hexane:ethyl acetate 50:50 to afford 8.5 g of pure non-polar material (2-chloro-N-[3-(methylsulfonyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amine XLIVa) and a further 0.7 g of the polar component.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([O:12]CCCCC)=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].Cl>[OH-].[Na+]>[CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1cc(C(=O)OCCCCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of n-pentyl 3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoate (4.5 g) and 1N sodium hydroxide (70 ml) was heated on a steam bath for 1 hour. After cooling, the reaction mixture was adjusted to a pH of 2.5 by addition of 4N hydrochloric acid. The precipitated 3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. After drying in vacuo, the compound was obtained with a melting point of 223°-224°C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl.Br[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>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.O.C(COC)OC>[CH3:38][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:41]5[CH:46]=[CH:45][N:44]=[CH:43][N:42]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Brc1ccncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccncn5)cc4)CC3)n2CCS1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A reaction mixture of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 4-bromopyrimidine hydrochloride (234 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), potassium carbonate (276 mg, 2 mmol), dimethoxyethane (4 mL), and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was partially purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient). This partially purified product was dissolved in a 4 M solution (1 mL) of hydrochloric acid in 1,4-dioxane and methanol (4 mL), and the mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (67 mg, 17%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[N:26]=[C:25]([O:27]C)[C:24]([O:29]C)=[CH:23][N:22]=1>C1COCC1.[Pd]>[OH:29][C:24]1[C:25](=[O:27])[NH:26][C:21]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:22][CH:23]=1
Reactant: COc1cnc(Cl)nc1OC
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)ncc1O
Temperature: 150 °C
Yield: 3.9 %

Procedure:
To a mixture of 0.05 g (0.26 mmol) 4-trifluoromethylphenylboronic acid, 0.02 g (0.009 mmol Pd EN Cat™ 30, and 0.65 mL 1 M aq Cs2CO3, was added a solution of 0.005 g (0.009 mmol) 1,1′-(bisdiphenylphosphino)ferrocene and 0.03 g (0.17 mmol) 2-chloro-4,5-dimethoxy-pyrimidine in 1 mL THF. The resulting mixture was heated by microwave to 150° C. for 10 minutes. After cooling, the aq layer was removed and the organic phase was filtered and concentrated. To the resulting residue was added 1 mL 33% HBr in AcOH, and the resulting mixture was heated by microwave to 160° C. for 5 min. The resulting solution was diluted with water (2 mL) and loaded onto an SCX column. After washing with MeOH (5 mL), the crude product was eluted off with 2 M ammonia in MeOH. Purification by automated mass-guided HPLC afforded 1.7 mg (4%) 5-hydroxy-2-(4-trifluoromethyl-phenyl)-3H-pyrimidin-4-one. NMR (499 MHz, DMSO-d6): δ 9.85 (br s, 1H); 8.22 (d, J=7.93 Hz, 2H); 7.85 (d, J=8.12 Hz, 2H); 7.63 (br s, 1H). High resolution mass spec (FT/ICR) calc (M+H)+=257.0533 found 257.0532.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:18](I)[CH3:19]>CN(C=O)C>[C:3]([N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)[CH2:18][CH3:19])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CCI
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 1.15 g, 29.5 mmol) i.l DMF (50 mL) at 0° C. was added a solution of 2-(N-Boc-amino)-6-picoline in DMF (30 mL). The reaction was stirred at 0° C. for 15 min; then ethyl iodide (4.6 g, 30 mmol) was added. The reaction mixture was stirred at RT overnight; then was concentrated in vacuum. The residue was diluted with H2O and extracted with CH2Cl2 (3×50 mL). Drying (MgSO4), concentration, and silica gel chromatography (20% EtOAc/hexane) gave the title compound as colorless oil: MS (ES) m/e 237 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:17]1[C:22]([Cl:23])=[N:21][C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1>[Cl:23][C:22]1[C:17]([N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([OH:36])=[O:5])[CH:14]([CH3:16])[CH3:15])=[N:18][C:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:21]=1
Reactant: CC(C)N(CCCCOCC(=O)OC(C)(C)C)c1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)N(CCCCOCC(=O)O)c1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
218 mg of 2-{4-[N-(3-chloro-5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester was dissolved in 2 ml of 1,4-dioxane and 2 ml of 1N hydrochloric acid was added, followed by stirring at 80° C. for one hour. The mixture was further stirred at 110° C. for 4 hours. The reaction solution was neutralized with 1N sodium hydroxide solution and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The resulting crude crystal was washed with a solvent of hexane-ethyl acetate (4:1) to obtain 120 mg of the desired product as a gray crystal having a melting point of 136 to 138° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH:30]1([CH2:33][C:34](O)=O)[CH2:32][CH2:31]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.C(#N)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:34][CH2:33][CH:30]4[CH2:32][CH2:31]4)[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Reactant: O=C(O)CC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(CCC4CC4)C3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of (S)-4-amino-5(piperidine-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin 2,2-dioxide hydrochloride (Example 2a, 694 mg, 2.0 mmol) in H2O/ACN (5 mL, 1:1) was added triethylamine (228 uL, 2.0 mmol). After stirring at room temperature for 5 min a solution of 2-cyclopropylacetic acid (200 mg, 2.0 mmol), HOBt (272 mg. 2.0 mmol), and EDCI-HCl (382 mg. 2.0 mmol) in H2O/ACN (5 mL, 1:1) was added to the mixture. An additional equivalent of triethylamine (228 uL, 2.0 mmol) was added and the reaction mixture was stirred at room temperature overnight. The product crashed out of solution and is collected by vacuum filtration. The compound was purified via preparative RP HPLC (10 to 90% EtOH in water) then diluted with 10 mL water and 200 mg of NaHCO3 was added. The solution was heated at 90° C. for 20 minutes until all the compound was dissolved then cooled to 0° C. and neutralized with 1N HCl solution. The product precipitated out and was collected by filtration and dried to provide the title compound (410 mg, 52.3%). 1H NMR (DMSO-d6, 400 MHz, 80° C.): 0.12 (br s, 2H), 0.44 (m, 2H), 0.96 (br s, 1H), 1.42 (m, 2H), 1.70 (m, 1H), 1.88 (m, 1H), 1.98 (br s, 1H), 2.09 (m, 1H), 2.26 (br s, 2H), 2.91 (m, 2H), 3.67 (br s, 0.5H), 3.85 (br s, 0.5H), 4.09 (m, 3H), 6.65 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 7.75 (br s, 1H), 8.16 (br s, 1H), 10.79 (s, 1H). M+H=393.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:35][C:32]1[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2N(Cc1ccncc1)Cc1nc2ccccc2[nH]1
Reaction time: 18 h
Yield: 70.2 %

Procedure:
Following General Procedure B: To a solution of (1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (120 mg, 0.32 mmol) and 4-pyridinecarboxaldehyde (30 μL, 0.32 mmol) in CH2Cl2 (5 mL) was added sodium triacetoxyborohydride (136 mg, 0.64 mmol) and the reaction stirred for 18 h. The resulting crude material was taken up in neat TFA (1 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (5 mL) was added, and the resulting mixture was extracted with CH2Cl2 (3×10 mL) then the combined organic extracts were dried (MgSO4), and concentrated in vacuo. Purification of the crude material by radial chromatography (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) afforded the title compound (83 mg, 70%) as a white solid. 1H NMR (CDCl3) δ 1.68-1.72 (m, 1H), 1.97-2.06 (m, 2H), 2.26-2.30 (m, 1H), 2.74-2.77 (m, 1H), 2.80-2.86 (m, 1H), 3.77 (s, 2H), 3.92 (d, 1H, J=16 Hz), 4.09 (dd, 1H, J=9.7 Hz), 4.17 (d, 1H, J=16 Hz), 7.18-7.22 (m, 3H), 7.36 (d, 2H, J=6 Hz), 7.44 (dd, 1H, J=7.1 Hz), 7.52 (br d, 1H, J=7 Hz), 7.66 (br d, 1H, J=7 Hz), 8.46 (dd, 2H, J=5.2 Hz), 8.70 (dd, 1H, J=5.1 Hz); 13C NMR (CDCl3) δ 21.2, 23.8, 29.0, 49.1, 53.0, 60.5, 110.9, 118.8, 121.4, 121.9, 122.5, 123.3, 133.7, 134.7, 137.4, 144.2, 146.9, 148.7, 149.8, 155.4, 156.9. ES-MS m/z 370 (M+H). Anal. Calcd. for C23H23N5.0.2H2O.0.2CH2Cl2: C, 71.44; H, 6.15; N, 17.95. Found: C, 71.63; H, 6.30; N, 17.77.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:31])([CH3:30])[CH2:5][C:6]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH:7]2[NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][NH:18][C:19]2=[O:24].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:31])([CH3:30])[CH2:5][C:6]([OH:29])([C:25]([F:27])([F:28])[F:26])[CH:7]2[NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][NH:18][C:19]2=[O:24]
Reactant: COc1ccc2c(c1F)C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c1CNC2=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c2CNC3=O)c2ccc(O)c(F)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.7 %

Procedure:
109.8 mg (0.250 mmol) of (rac.) 4-{[5-fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one is mixed with 3.4 ml of a 1 M solution of BBr3 in dichloromethane and stirred for four hours at room temperature. The batch is mixed at 0° C. with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic extracts are dried on sodium sulfate. After the desiccant is filtered off, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 15.6 mg (14.7%) of the final product is isolated.
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15](N)=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.Cl.C(O)(=[O:28])C>>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([OH:16])=[O:28]
Reactant: CC(C(N)=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Reactant: CC(=O)O
Agent: Cl
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 70 %

Procedure:
11.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is refluxed for 2 hours in 70 ml. of acetic acid and 105 ml. of concentrated hydrochloric acid. The mixture is cooled and diluted, then extracted with ether. The ethereal solution is extracted with aqueous sodium carbonate and the extract acidified and extracted with ethyl acetate to afford a 70% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[NH2:12][NH2:13]>C(O)C>[N:9]1[CH:10]=[CH:11][C:6]([C:2]2[NH:13][N:12]=[C:4]([NH2:5])[CH:3]=2)=[CH:7][CH:8]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccncc1
Solvent: CCO
Product: Nc1cc(-c2ccncc2)[nH]n1
Yield: 21 %

Procedure:
To 3-oxo-3-(pyridin-4-yl)propanenitrile (3.40 g; Example 7, Step 1) suspended in 230 mL ethanol was added 2.92 mL hydrazine. The mixture refluxed for 3 hours and concentrated to dryness. The residue was purified by chromatography, eluting with a mixture of 10% methanol in dichloromethane to yield 0.80 g (21% yield) product as a light yellow solid. MS showed a M+1 molecular ion of m/z 161.3 by positive APCI.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1
Reactant: Brc1ccccn1
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2n1
Product: Cc1ccn2c(-c3cccc(-c4ccccn4)c3)cnc2n1
Yield: 36.1 %

Procedure:
7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)phenyl]-imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 2-bromopyridine (55 μl, 0.59 mmol) as described in Example 26 to give 7-methyl-3-[3-(pyridin-2-yl)phenyl]imidazo[1,2-a]pyrimidine as a white solid (30 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 6.79 (1H, d, J 7), 7.30 (1H, m 7.55-7.65 (2H, m), 7.77-7.81 (2H, m), 7.87 (1H, s), 8.00 (1H, dd, J 8 and 1.6), 8.19 (1H, d, J 1.5), 8.57 (1H, d, J 7), 8.71 (1H, d, J 1.6); m/z (ES+) 287 (M++H).
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.C[O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:32].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.[OH-].[Na+].Cl>CN(C=O)C>[CH3:32][C:24]1[N:25]([S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:34])=[CH:36][CH:37]=2)(=[O:43])=[O:42])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:31]2[C:23]=1[CH2:22][C:21]([OH:20])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)cc1
Reaction time: 0.75 h

Procedure:
A solution of BEMP (90 μL, 0.31 mmol) in DMF (400 μL) is added to a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (40 mg, 0.20 mmol) in DMF (400 μL). After 40-50 minutes, a solution of 4-methyl-benzenesulfonyl chloride (60 mg, 0.31 mmol) in DMF (400 μL) is added. After a further 30 minutes, 1M aqueous NaOH (800 μL) is added, and the reaction is shaken mechanically for 105 minutes, then 1M aqueous HCl (800 μL) is added. The reaction is partitioned between water and CH2Cl2. The organic phase is loaded directly onto a pre-packed Isolute™ silica column and eluted with EtOAc to give crude product which is triturated with water to afford [2-methyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=345.