Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:35])=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:33]=3[F:34])[CH:27]=2)OC1.FC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1C1C(C#N)=CC=CC=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1>[Pd]>[F:35][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[F:34]
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cnccc3F)c2)OC1
Agent: [Pd]
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: Fc1ccncc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F
Yield: 36 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled to 3-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-4-fluoropyridine (prepared in an analogous manner to 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile in Example 1, using bis(neopentyl glycolato)diboron instead of bis(pinacolato)diboron in the final palladium coupling) using the procedure described in Example 65. 3-[4-Fluoro-3-(4-fluoropyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine was isolated as a yellow solid in 36% yield after purification on silica gel eluting with dichloromethane on a gradient of diethyl ether (2-15%): δH (400 MHz, DMSO) 7.48-7.55 (2H, m), 7.63 (1H, dd, J 10 and 9), 7.94 (1H, ddd, J 9, 5 and 2), 7.99 (1H, dd, J 7 and 2), 8.33 (1H, s), 8.73 (1H, dd, J 8 and 5.5), 8.85 (1H, d, J 10), 9.38 (1H, d, J 7); m/z (ES+) 377 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C@@H:11]1[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]([OH:15])[C@H:12]1[OH:13].[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[OH2:29]>N1C=CC=CC=1>[C:22]([O:13][C@@H:12]1[C@@H:14]([O:15][C:22](=[O:29])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:16]([O:17][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[O:19][C@H:11]1[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(OC)c1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-deoxy-1-(2,4-dimethoxyphenyl)-β-D-glucopyranose (0.47 g) in pyridine (10 mL) was added pivaloyl chloride (1.1 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether.
Reaction SMILES: C(O)=O.Cl[C:5]1[CH:6]=[C:7]([N:12]2[CH2:16][CH:15](C)[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]>O>[Cl:11][C:10]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:15][C:14]([NH:18][CH:19]=[O:20])=[N:13]2)=[CH:8][CH:9]=1
Reactant: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Solvent: O
Product: O=CNC1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Reaction time: 2 h

Procedure:
A mixture of 15.0 g. of the above crude product and 85.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to remain at room temperature for 2 hours. The reaction mixture is poured into water and filtered to collect the solid. The solid is wahsed with a solution of saturated sodium bicarbonate, then water. The material is dried, dissolved in dichloromethane, then is columnized and recrystallized as above to give 12.0 g. of the desired product as pale yellow crystals. A 5.0 g. amount of this material is recrystallized as above to give 4.70 g. of the desired product, m.p. 164°-166° C.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:28][CH2:27][CH2:26][C:25]([C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[NH2:17])=[O:30])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 402 as a red oil (99 mg, 54%) from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (100 mg, 0.47 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (152 mg, 0.70 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.95–2.15 (m, 7H), 2.37–2.57 (m, 5H), 2.67–2.85 (m, 3H), 2.90–3.05 (m, 3H), 3.24–3.33 (m, 2H), 6.27–6.39 (m, 2H), 6.41–6.50 (br, 2H), 6.64 (t, J=7.3 Hz, 1H), 6.85–6.94 (m, 2H), 7.77 (dd, J=9.2, 6.6 Hz, 1H) ppm.
Reaction SMILES: C([O-])C.[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:17]3[NH:18][CH:19]=[CH:20][CH:21]=3)=[N:15][N:16]=2)=[CH:8][CH:7]=1.ClCCl.CO>C(O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:18]3[CH:19]=[CH:20][CH:21]=[C:17]3[C:14](=[O:13])[NH:15][N:16]=2)=[CH:8][CH:7]=1
Reactant: Brc1ccc(-c2nnc(-c3ccc[nH]3)o2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(Br)cc2)n2cccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 0.469 g sodium ethanolate (6.89 mmol) dissolved in 20 ml ethanol was added 1.0 g 2-(4-bromophenyl)-5-(1H-pyrrol-2-yl)-1,3,4-oxadiazole (3.45 mmol) at room temperature under nitrogen and the mixture was stirred at room temperature for 5 minutes. The reaction was heated at 160° C. for 2 hours in a microwave (Biotage Initiator 2.5). The reaction was monitored by TLC dichloromethane/methanol=9/1. Additional equivalents of sodium ethanolate were added and additional heating was carried out until completion of the reaction according to TLC. The reaction mixture was concentrated under reduced pressure and adsorbed on silica gel. The product was purified by silica gel chromatography (gradient: cyclohexane/ethylacetate=0-100%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.85-7.78 (m, 2H), 7.76-7.69 (m, 2H), 7.39 (dd, J=1.3, 2.9, 1H), 7.16 (dd, J=1.4, 3.8, 1H), 6.77 (dd, J=2.9, 3.8, 1H). 13C NMR (400 MHz, DMSO-d6) δ 154.22, 136.46, 131.98, 130.90, 129.52, 124.07, 124.00, 118.80, 114.42, 111.01.
Reaction SMILES: Cl.[CH3:2][OH:3].[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([C:13]#N)=[N:10][C:11]=1[CH3:12])[CH3:5].[OH2:15]>>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([C:13]([O:3][CH3:2])=[O:15])=[N:10][C:11]=1[CH3:12])[CH3:5]
Reactant: CO
Reactant: CCc1ccc(C#N)nc1C
Reactant: O
Agent: Cl
Product: CCc1ccc(C(=O)OC)nc1C
Temperature: 25 °C
Reaction time: 30 h
Yield: 87 %

Procedure:
Dry HCl (gas) was bubbled through a MeOH (30 mL) solution of 2-cyanopyridine from Step 1 (1.4 g, 9.6 mmol) at 0° C. until saturation. The flask was sealed with a new rubber septum and the reaction mixture was stirred 30 hours at r.t. After careful depressurisation, H2O (5 mL) was added and the MeOH was evaporated. The aqueous residue was neutralized with saturated aq. NaHCO3 and extracted with EtOAc (3×). The organic extracts were dried over MgSO4, concentrated in vacuo, and the residue was purified by flash chromatography (from 30% to 50% EtOAc in hexanes) to give 1.49 g (87%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[C:39]([NH:41][CH:42]3[CH2:44][CH2:43]3)[N:38]=[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:36]=2)[CH:32]=[N:33][CH:34]=1>COCCOC.CCOC(C)=O>[CH:42]1([NH:41][C:39]2[N:38]=[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:36]=[C:35]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH:7]=4)[CH:30]=3)[CH:40]=2)[CH2:44][CH2:43]1
Reactant: CN(C)CCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CN(C)CCOc1cccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)c1

Procedure:
To a solution of Dimethyl-(2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl)-amine (2 eq, 0.272 mmol, 0.079 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (3 eq, 0.408 mmol, 0.204 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 50 mg) and PdCl2dppf (0.1 eq, 0.014 mmol, 11 mg). The reaction mixture is heated using microwave radiation at 90° C. for 90 minutes. The reaction mixture is dissolved in EtOAc and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 452.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18]Br.C(N(C(C)C)CC)(C)C.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:18][C:17]2[CH:20]=[CH:21][C:22]([F:23])=[C:15]([F:14])[CH:16]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a methylene chloride (10 mL) solution of (3S)-3-(tert-butoxycarbonylamino)pyrrolidine (916 mg), 3,4-difluorobenzylbromide (0.7 mL) and IPEA (2.2 mL) were added one by one, and the reaction solution was agitated at room temperature for 20 hours. A saturated sodium bicarbonate water was added to the reaction solution after the reaction ended, and the organic layer was partitioned. It was dried over anhydrous magnesium sulfate and the obtained organic layer was concentrated under reduced pressure. 1.55 g of the title compound was obtained by purifying the residue by silica gel chromatography (elution solvent: heptane:ethyl acetate=1:1). The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1.[Br:18]Br>C(O)(=O)C>[BrH:18].[Br:18][CH:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:17]
Reactant: COc1ccc(C(=O)Cc2cccnc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
1-(4-Methoxyphenyl)-2-(3-pyridyl)ethanone (6.85 g) was dissolved in acetic acid (36 mL), bromine (1.7 mL) was added to the solution and the resulting mixture was stirred at 80° C. for 3 h. After the mixture was cooled with ice-water, the crude crystalline mass was collected by filtration. The crude crystalline was recrystallized from ethanol-ethyl ether to afford the title compound (10.4 g, yield 89%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][OH:11].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl.O>[Si:21]([O:11][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH:6]=[O:7])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: O=Cc1ccc(F)c(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
1.6 g of 4-Fluoro-3-hydroxymethylbenzaldehyde was dissolved in 20 ml of dichloromethane, and 1.4 g of imidazole and 1.75 g of t-butyldimethylchlorosilane were added under ice-cooling, then the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (18% ethyl acetate-hexane), to give 2.6 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[C:27](Cl)[N:26]=1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:27]3[C:28]([Cl:32])=[CH:29][C:30]([Cl:31])=[C:25]([Cl:24])[N:26]=3)[CH2:22][CH2:23]2)=[O:17])=[CH:12][CH:11]=1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(Cl)c(Cl)cc3Cl)CC2)cc1
Yield: 82.2 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-methoxymethyl-3-[4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (972 mg) described in Preparation Example 165 and 2,3,5,6-tetrachloropyridine (990 mg), the title compound (1.25 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:12]=2)=[O:9])[CH:3]=1.[CH:26]1([CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34])[CH2:28][CH2:27]1>>[ClH:1].[NH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([N:30]([CH2:29][CH:26]3[CH2:28][CH2:27]3)[CH2:31][CH2:32][O:33][CH3:34])[N:7]=[CH:6][N:5]=2)=[O:9])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)c2cc(Cl)ncn2)cc1
Reactant: COCCNCC1CC1
Product: COCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN)cc2)ncn1
Product: Cl

Procedure:
Following the general method as outlined in Example 72 (Steps 1 and 2), starting from tert-butyl (4-{[(6-chloropyrimidin-4-yl)carbonyl]amino}benzyl)carbamate (Intermediate 22) and N-(cyclopropylmethyl)-2-methoxyethanamine, the title compound was obtained as a pale yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [BrH:1].C(O)(=O)C.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=2[F:6])[N:18]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(F)c1F
Solvent: CC(=O)O
Solvent: O
Product: Fc1cccc(-c2csc(Br)n2)c1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (40 ml) solution was added to a solution of 2-(2,3-difluorophenyl)-2-oxoethyl thiocyanate (5.67 g, 26.6 mmol) in acetic acid (40 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.74 g (91.8%) of the desired product as a solid.
Reaction SMILES: COC(C1C=CC(C(O)=O)=NC=1)=O.C(N)C1C=CC=CC=1.[CH2:22]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][N:33]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]=1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2ccccc2)nc1
Agent: COC(=O)c1ccc(C(=O)O)nc1
Solvent: NCc1ccccc1
Product: O=C(O)c1ccc(C(=O)NCc2ccccc2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylamine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 300 mg of 6-(benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield-benzyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. MS (Q1) 443.1 (M)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:8][CH3:9].CS[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][N:19]=1>>[CH2:7]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][N:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9]
Reactant: CCCN(CCCCN)c1ccccn1
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Product: CCCN(CCCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(4-aminobutyl)-N-propylamino]pyridine (1.24 g) and 2-methylthio-5-(4-fluorobenzyl)pyrimid-4-one (1.25 g) were fused together on an oil bath at 160° C. for 2.5 hr. On cooling the residue was crystallized from ethanol/water to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]-5-(4-fluorobenzyl)pyrimid-4-one 1.25H2O, 0.56 g (26%) m.p. indeterminate.
Reaction SMILES: [N+:1]([CH2:4][C:5](=[O:9])[CH2:6][CH2:7][CH3:8])([O-:3])=[O:2].[OH-].[Na+].[C:12](=S)=[S:13].CI.[CH3:17][S:18]([CH3:20])=O>>[C:5]([C:4]([N+:1]([O-:3])=[O:2])=[C:17]([S:13][CH3:12])[S:18][CH3:20])(=[O:9])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(=O)C[N+](=O)[O-]
Reactant: S=C=S
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CCCC(=O)C(=C(SC)SC)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 13.1 g of 1-nitro-2-pentanone in 200 ml of dimethylsulfoxide was added dropwise 44 g of 20% sodium hydroxide solution at 10°-20° C. 12 g of carbon disulfide was then added dropwise to the solution at 10° C. and the mixture was stirred for 2 hours at 0°-10° C. 57 g of methyliodide was dropped into the mixture with ice cooling and the reaction mixture was allowed to stand overnight at room temperature. This was then poured into ice water and the organic layer was extracted with dichloromethane. The extract was washed with water a few times, and after removing the solvent the residue was purified by chromatography on a silicagel column to give desired 1-butyroyl-1-nitro-2,2-bis(methylthio)ethylene. The yield is 3.0 g.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:14]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)([O:17][IH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)(=[O:16])=[O:15].C(OCC)C>C(O)(=O)C>[S:14]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)([O-:17])(=[O:16])=[O:15].[C:1]1([C:22]2[CH:21]=[C:20]([IH+:18])[CH:25]=[CH:24][CH:23]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O[IH](=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)oc1ccccc12
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: [IH+]c1cccc(-c2cccc3oc4ccccc4c23)c1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A mixture of 16.8 grams (0.1 mole) dibenzofuran and 39.2 grams (0.1 mole) phenyliodoso tosylate in 150 ml glacial acetic acid was stirred for 3.5 hours at 50° C. There was added to the mixture, 200 ml diethyl ether which resulted in the precipitation of 3-dibenzofuranyl phenyl iodonium tosylate. The mixture was suspended in water to remove unreacted phenyliodoso tosylate then filtered and dried. A 62.5% yield of the above salt was obtained having a melting point of 188°-190° C.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[Cl:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[O:3][CH2:2][N:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[N:15][C:16]1=[O:19]
Reactant: ClCOc1ccc(Cl)cc1Cl
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COc1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 by the addition of a solution of 1-chloromethoxy-2,4-dichlorobenzene (see preparation 6) (5 mmol) in dichloromethane (25 ml) to a solution of 5-chloropyrimidin-2-one (5 mmol) and triethylamine (5 mmol) in dichloromethane (75 ml). The mixture was stirred at room temperature for 2 h and at 40° C. for 7 h before being worked up as above; yield 1.30 g (80%), isomer ratio 3:1. The title compound crystallized from DMSO: m.p. 170° C. 1H NMR (TFA): δ 6.10 (CH2),, 6.9-7.4 (Ph), 9.0-9.2 (H-4, H-6). IR (KBr): 1680 cm-1 (CO). MS (70 eV, m/z (% rel. int.)): 304 (l,M), 162 (3), 145 (35), 143 (100), 116 (28 ).
Reaction SMILES: [CH3:1][C:2]([O:4]I1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[S:23]1[CH:27]=[CH:26][C:25]2[CH:28]=[CH:29][C:30](CCO)=[CH:31][C:24]1=2.C([O-])(O)=O.[Na+].C(Cl)[Cl:41]>>[Cl:41][C:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[S:23][C:27]=1[CH2:1][CH:2]=[O:4]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: OCCc1ccc2ccsc2c1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=CCc1sc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dess-Martin period inane (1.570 g, 3.70 mmol) was added to an ice-cold solution of 2-(benzo[b]thiophen-6-yl)ethanol (649 mg, 3.05 mmol) in CH2Cl2 (8 mL). The reaction was allowed to warm to room temperature and after 2 h, was poured into a mixture of 50 mL saturated NaHCO3/50 mL 5% NaHSO3 solution. The resulting mixture was stirred for 30 minutes and then was extracted with CH2Cl2 (3×40 mL). The combined organic solution was dried (Na2SO4), filtered and evaporated to give the title compound which was used directly in the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](=[O:21])C)[CH3:17]>CN(C=O)C>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)=[O:21])[CH3:17]
Reactant: O=C1CCNCC1
Reactant: CCN(CC)C(C)=O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of piperidin-4-one in DMF was added triethylamine (1.5 eq.) and N,N-diethylacetamide chloride (1.5 eq.). The resulting solution was stirred at room temperature for 5 hours or until completion observed by TLC. The solvent was evaporated and the residue was partitioned in H2O and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by a CombiFlash chromatography system using silica gel cartridge and CH2Cl2/MeOH gradient eluent to afford 4-oxo-piperidine-1-carboxylic acid diethylamide, which was subsequently reacted with 3-hydroxybenzaldehyde (2.5 eq.) in acetic acid (99.7%) and purged with HCl gas (0.5-1 h). After stirring at room temperature for 3 hours, the solvent was evaporated and the crude was purified by a Combiflash chromatography system with hexanes/EtOAc as eluent, followed by crystallization from MeOH, to afford Compound 12 as a yellow crystalline solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CC1N(C2C=CC(OC(F)(F)F)=CC=2C#N)C=NC=1>>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:2]2[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=2[C:4]#[N:5])[CH:20]=1
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(OC(F)(F)F)ccc1F
Agent: Cc1cncn1-c1ccc(OC(F)(F)F)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(OC(F)(F)F)cc2C#N)cn1

Procedure:
As described for example 84a, 2-fluoro-5-trifluoromethoxy-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. Aqueous workup afforded a 3:1 mixture of the title compound and its regioisomer [2-(5-methyl-imidazol-1-yl)-5-trifluoromethoxy-benzonitrile] as a light brown viscous oil (yield: 100%). 1H-NMR (300 MHz, DMSO): δ=2.19 (s, 3H), 7.37 (s, 1H), 7.75-7.90 (m, 2H), 8.02 (s, 1H), 8.27 (d, J=2.7 Hz, 1H).