Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H:9]1([NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:15].Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>[Cu]I.O1CCOCC1>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH2:16])=[CH:19][CH:20]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(N[C@@H]2CCCC[C@H]2N)cc1
Temperature: 110 °C
Reaction time: 70 h
Yield: 63.6 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (190 mg, 0.998 mmol), K3PO4 (2.10 g, 9.89 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (0.60 mL, 5.00 mmol), 4-bromotoluene (0.70 mL, 5.69 mmol) and dioxane (3.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 70 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The black filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane saturated with aq NH3-methanol 50:1; 15 mL fractions). Fractions 9–11 provided 650 mg (64% yield) of the product as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.00–6.95 (m, 2H), 6.62–6.57 (m, 2H), 3.30 (br s, 1H), 2.96–2.86 (br m, 1H), 2.49 (td, J=10.4, 3.6, 1H), 2.23 (s, 3H), 2.17–2.08 (m, 1H), 2.02–1.94 (m, 1H), 1.79–1.66 (m, 2H), 1.44 (br s, 2H), 1.38–1.17 (m, 3H), 1.07–0.95 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 145.9, 129.7, 126.6, 113.9, 60.5, 56.1, 35.2, 32.4, 25.3, 25.0, 20.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:12][CH:11]([C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH2:10]2)[CH:3]=1.O.[NH2:24][NH2:25].C([O-])([O-])=O.[K+].[K+]>CC1OCCC1>[NH:24]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:12][CH:11]([C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH2:10]2)[CH:3]=1)[NH2:25]
Reactant: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: Cc1nc(NN)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Temperature: 85 °C

Procedure:
Compound 2-2 (900 mg, 2.87 mmol), hydrazine hydrate (431 mg, 8.6 mmol) and K2CO3 (1.2 g, 8.6 mmol) were suspended in 2-MeTHF (8 mL) in a vial that was capped and heated at 85° C. for 16 h. After cooling to room temperature, the reaction was filtered and the collected solids were washed with water and ether and dried over suction to give Intermediate 2 as a white solid. MS: m/z=310.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[S:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.BrC1C=C(F)C(F)=CC=1O.S1C=CC=C1B(O)O>>[S:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[OH:9])=[CH:11]1
Reactant: Oc1cc(F)ccc1Br
Reactant: OB(O)c1ccsc1
Agent: OB(O)c1cccs1
Agent: Oc1cc(F)c(F)cc1Br
Product: Oc1cc(F)ccc1-c1ccsc1

Procedure:
2-Bromo-5-fluorophenol is coupled with thiophene-3-boronic acid; 2-bromo-4,5-difluorophenol is coupled with thiophene-2-boronic acid; and 2-bromo-4,5-difluorophenol is coupled with thiophene-3-boronic acid in Suzuki reactions substantially as described for Epoxide 48, to yield 2-(thien-3-yl)-5-fluorophenol; 2-(thien-2-yl)-4,5-difluorophenol; and 2-(thien-3-yl)-4,5-difluorophenol, respectively. These phenolic products are reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxides.
Reaction SMILES: NCCCCN.C(O)(=O)CCCCCCC/C=C\C/C=C\C/C=C\CC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=[CH:45][C:46]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:72])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH:63][CH2:64][CH:65]=[CH:66][CH2:67][CH:68]=[CH:69][CH2:70][CH3:71])=[O:47])[CH:32]=[CH:33][C:34]=1[O:35]COCCOC.O1CCOCC1CC(O)=O.O>O1CCCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=[CH:45][C:46]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:72])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH:63][CH2:64][CH:65]=[CH:66][CH2:67][CH:68]=[CH:69][CH2:70][CH3:71])=[O:47])[CH:32]=[CH:33][C:34]=1[OH:35]
Reactant: CCC=CCC=CCC=CCCCCCCCC(=O)NCCCCNC(=O)C=CC=Cc1ccc(OCOCCOC)c(OC)c1
Agent: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: NCCCCN
Agent: O=C(O)CC1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CCC=CCC=CCC=CCCCCCCCC(=O)NCCCCNC(=O)C=CC=Cc1ccc(O)c(OC)c1

Procedure:
To a solution fo 880 mg (10 mmol) of 1,4-diaminobutane in tetrahydrofuran (20 ml) was added in an argon atmosphere a solutin fo 410 mg (1 mmol) of N-{5-(3-methoxy-4-β-methoxyethoxymethoxyphenyl)-2,4-pentadienoyl}-2-thiothiazolidine in tetrahydrofuran (10 ml) at room temperature over 30 min. The mixture was treated in the same way as in Example 3 to react with 390 mg (1.05 mmol) of α-linolenic acid thiazolidinethionamide. The reaction product was treated in the same way as in Example 3 to hydrolyze N-{5-(3-methoxy-4-β-methoxyethoxymethoxyphenyl)-2,4-pentadienoyl}-N'-9,12,15-octadecatrieneo yl-1,4-diaminobutane with 1,4-dioxane - acetic acid-water (5:4:1). The reaction product was treated in the same way as in Example 3 to give 195 mg (0.35 mmol) of N-{5-(3-methoxy-4-hydroxyphenyl)-2,4-pentadienoyl}-N'- 9,12,15-octadecatrienoyl-1,4-diaminobutane. Spectrophotometric data of the product support the structure shown below. ##STR31##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCO)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCOS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 300 mg (1.61 mmol) 5-(2-hydroxy-ethyl)-thiophene-2-carboxylic acid methyl ester in 10 mL DCM is added 0.90 mL triethylamine (6.44 mmol) and subsequently 312 μL (4.03 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and is diluted with 50 mL DCM. The organic phase is separated, washed three times with water and is dried over MgSO4. After filtration and evaporation of the solvent, the product is afforded.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:6][C:5]=12.[Cl:31]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:31][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:30])[C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)C(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)N1CCC(c2ccc(C(=O)NCc3ccn4c(Cl)cnc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(1-isobutyrylpiperidin-4-yl)benzamide (0.025 g, 0.062 mmol) in chloroform (1.030 ml) was treated with N-chlorosuccinimide (9.49 mg, 0.071 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated under a stream of warm nitrogen. The residue was purified by normal phase chromatography to give the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 8.67 (d, J=7.0 Hz, 1H), 8.11 (s, 1H), 7.89-7.83 (m, 2H), 7.81 (s, 1H), 7.57 (dd, J=7.1, 1.5 Hz, 1H), 7.43-7.37 (m, 2H), 4.80-4.75 (m, 2H), 4.75-4.67 (m, 1H), 4.25-4.16 (m, 1H), 3.28-3.18 (m, 1H), 3.07-2.88 (m, 2H), 2.79-2.66 (m, 1H), 2.02-1.85 (m, 2H), 1.75-1.53 (m, 2H), 1.17-1.08 (m, 6H); MS (ESI(+)) m/e 439 (M+H)+.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[N:11]([CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C[C@H](O)CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](O)CN=[N+]=[N-]
Reaction time: 2 h

Procedure:
To a mixture of ethyl (S)-4-chloro-3-hydroxybutyrate (1 93 g, 1.16 mol, optical purity:98.5% ee) and N,N-dimethylformamide (1.4 Lit.) is added sodium azide (151 g, 2.32 mol) and the mixture was stirred at 100°-110° C. for 2 hours. After cooling N,N-dimethylformamide was distilled off and to the residue was added water (1 Lit.). The mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate. By distillation off ethyl acetate under vacuo, there is obtained ethyl (S)-4-azido-3-hydroxybutyrate as a crude product (206 g). Then the crude product was dissolved in methanol (1 Lit.) and to it 5% palladium-carbon (10 g) was added. The mixture was stirred for 17 hours at room temperature under a hydrogen atmosphere. After the reaction was over, palladium-carbon was filtered off and the solvent was distilled off under vacuo. The resulting product was recrystallized from acetone-water to give (S)-4-hydroxy-2-pyrrolidone (99 g, 0.98 mol, yield:84%) as a colorless crystalline solid. Optical purity:98.3% ee, Specific rotation:[α]D22 -57.6°(c=1.00, H2O).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Yield: 92.4 %

Procedure:
To a solution of 2-Methyl-4-nitro-benzoic acid methyl ester (3.08 g, 15.79 mmole) in 125 ml carbontetrachloride was added NBS (3.1 g, 17.38 mmole) and AIBN (390 mg, 2.38 mmole). The reaction mixture was heated at reflux under light for 22 hours. The reaction mixture was cooled down, concentrated to half, filtered off, solid was washed with 25 ml carbontetrachloride. The filtrate was concentrated to give 4 g crude product, containing about 20% unreacted starting material. This was used for next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].[OH-].[K+]>C(O)C.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[N:30][OH:31])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: ON=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 0 °C
Yield: 66.1 %

Procedure:
To a mixed solution (20 ml) containing 0.8 g of the 1-benzyl-4-[2-(4-pyrrolidinobenzoyl)ethyl]piperidine prepared in Example 59 and 0.7 g of hydroxylamine hydrochloride in ethanol was added a solution (7 ml) of 1.4 g of potassium hydroxide in methanol dropwise with warming at 50°-55° C. The mixture was further heated at 50°-55° C. for one hour, at the end of which time it was added to 200 ml of ice-water. The resulting precipitate was collected by filtration, rinsed and dissolved in dichloromethane. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude crystals. Recrystallization from dichloromethane-ether yielded 0.55 g of colorless crystals melting at 153°-158° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1.Cl[CH:24]([O:26]C)Cl.Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:22][C:18]1[CH:17]=[C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])[CH:21]=[CH:20][C:19]=1[CH:24]=[O:26]
Reactant: COC(Cl)Cl
Reactant: Cc1cccc(OCCc2nc(-c3ccccc3)oc2C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1C=O
Reaction time: 2.5 h
Yield: 52 %

Procedure:
A solution of 6.00 g of 5-methyl-2-phenyl-4-(2-m-tolyloxy-ethyl)-oxazole and 4.70 g of dichloromethylmethylether in 30 ml of CH2Cl2 was treated at 0° C. with 11.2 ml TiCl4 over 15 min and stirring was continued at 0° C. for 2.5 h. The red solution was treated at 0° with 600 ml of 1 N aqueous HCl, the organic layer was washed with 0.1 N aqueous NaOH and twice with brine. The organic layer was dried, the solvent evaporated and the residue was chromatographed on silica (n-hexane/AcOEt, 7:1) to give 3.42 g (52%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].C[Si]([N:18]=[N+:19]=[N-:20])(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[C:12](=[O:13])[NH:20][N:19]=[N:18]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cc(N=C=O)c(Cl)cc1F
Product: COc1cc(-n2nn[nH]c2=O)c(Cl)cc1F
Yield: 76.7 %

Procedure:
In the manner of Example 2, Step E, the reaction of 3.2 g (0.016 mole) of 2-chloro-4-fluoro-5-methoxyphenyl isocyanate with 3.2 g (0.028 mole) of trimethylsilyl azide produced 3.0 g of 1-(2-chloro-4-fluoro-5-methoxyphenyl)-1,4-dihydro-5H-tetrazol-5-one.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:42][CH2:43][S:44]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)CCl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 35.4 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0853 g, 0.185 mmol) was dissolved in dichloromethane (3.0 mL), and the solution was treated with triethylamine (0.129 mL, 0.924 mmol) and chloromethanesulfonyl chloride (0.0490 mL, 0.554 mmol) to obtain 4-chloromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0376 g, yield 35%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[NH:8][C:9](=[O:17])[N:10]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH:11]=1)=[O:5])[CH3:2].[CH3:25][Si](C)(C)N[Si](C)(C)C.[K].CI.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:8]([CH3:25])[C:9](=[O:17])[N:10]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCOCN1C=C(C(=O)OCC)C(c2ccc(F)cc2)NC1=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [K]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCOCN1C=C(C(=O)OCC)C(c2ccc(F)cc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of 4-(4-Fluoro-phenyl)-2-oxo-1-propoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (152 mg, 0.39 mmol) in THF (3 mL) was added potassium hexamethyldisilazane (0.92 mL of 1M toluene solution, 0.46 mmol) at 0° C. under Ar. The mixture was stirred for 1 h at 0° C. Methyl iodide (0.23 mL of 2M solution in tert-butyl methyl ether) was added at 0° C., and the mixture was stirred at 0° C. overnight. Saturated aqueous NH4Cl was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried under Na2SO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash column (hexane/ethyl acetate gradient) gave 4-(4-fluoro-phenyl)-3-methyl-2-oxo-1-propoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (143 mg, 91%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2)([O-:22])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32]([C:27]2[NH:28][C:29]3[C:25]([CH:26]=2)=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)=[O:33])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2cc(CNC(=O)c3cc4cc([N+](=O)[O-])ccc4[nH]3)ccc2Cl)c1
Yield: 36.7 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-5-nitro-1H-indole-2-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 5-nitro-1H-indole-2-carboxylic acid, (0.025 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.36 (s, 1H), 9.34 (t, 1H), 8.67 (d, 1H), 8.04 (dd, 1H), 7.76 (t, 1H), 7.60 (d, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 7.41 (s, 1H), 7.35 (t, 1H), 7.28 (dd, 1H), 7.25 (d, 1H), 4.50 (d, 2H). MS: m/z 481.0 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:19])[N:5]([CH3:18])[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])[CH3:2].I[CH2:21][CH3:22]>C(O)C>[CH2:21]([S:19][C:4](=[N:3][CH2:1][CH3:2])[N:5]([CH3:18])[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])[CH3:22]
Reactant: CCI
Reactant: CCNC(=S)N(C)c1sc(-c2cccnc2)nc1C
Solvent: CCO
Product: CCN=C(SCC)N(C)c1sc(-c2cccnc2)nc1C
Yield: 39.2 %

Procedure:
A solution of 3-ethyl-1-methyl-1-(4-methyl-2-(pyridin-3-yl)thiazol-5-yl)thiourea (70 mg, 0.239 mmol) and iodoethane (74.7 mg, 0.479 mmol) in ethanol (5 mL) was heated at 80° C. for 6 h in a sealed tube. Upon cooling the solvent was removed under reduced pressure and the residue purified via silica gel chromatography (0 to 100% ethyl acetate/hexanes) to furnish the title compound as a clear oil (30 mg, 39%): 1H NMR (400 MHz, CDCl3) δ 9.10 (d, J=2.0 Hz, 1H), 8.64 (dd, J=4.6 Hz, 1.4 Hz, 1H), 8.20 (d, J=4.2 Hz, 1H), 7.41-7.37 (m, 1H), 3.63 (q, J=7.6 Hz, 2H), 3.22 (s, 3H), 2.72 (q, J=7.8 Hz, 2H), 2.38 (s, 3H), 1.28-1.17 (m, 6H); ESIMS m/z 321 (M+1).
Reaction SMILES: [C:1]([CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH:21]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[OH:32])([CH3:23])[CH3:22]>CC(=O)CC>[CH:21]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[O:32][CH2:3][C:1]#[N:2])([CH3:23])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OCC#N)cc1
Reactant: COc1ccc(O)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(OCC#N)c(C(C)C)c1
Reaction time: 96 h

Procedure:
A stirred slurry of toluene-4-sulfonic acid cyanomethyl ester (13.0 kg), potassium carbonate (13.0 kg) and 2-isopropyl-4-methoxyphenol (9.57 Kg) in 79.7 kg of 2-butanone was heated to 55-60 degrees C. for 4 days, then heated to reflux for 18 hours. The resultant slurry was cooled and filtered to remove solids. The filtrate was concentrated under reduced pressure and the residue was redissolved in toluene. The toluene solution was extracted with 1N KOH, and the organic phase was concentrated by distillation to give 20.6 g of a 1:1 (by weight) solution of (2-Isopropyl-4-methoxy-phenoxy)-acetonitrile in toluene, which was used directly in the next step. An aliquot (96.7 g) of this solution was concentrated to dryness to give 50.9 g of crude (2-Isopropyl-4-methoxy-phenoxy)-acetonitrile, projecting to a yield of 10.9 kg in the bulk solution: MS (M+H)=206; 1H nmr (CDCl3) delta: 1.25 (d, J=6.9 Hz), 3.31 (septet, 1H, J=6.9 Hz), 3.82 (s, 3H), 4.76 (s, 2H), 6.73 (dd, 1H, J=8.8 Hz, 3.1 Hz), 6.87 (d, 1H, J=3.1 Hz), 6.91 (d, 1H, J=8.8 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[Cl:35][C:36]1[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[C:37]=1[S:43]([NH2:46])(=[O:45])=[O:44]>>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:46][S:43]([C:37]3[C:38]([CH3:42])=[N:39][N:40]([CH3:41])[C:36]=3[Cl:35])(=[O:45])=[O:44])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: Cc1nn(C)c(Cl)c1S(N)(=O)=O
Product: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)c3c(C)nn(C)c3Cl)cnn12
Yield: 85.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.18 mmol) obtained in Example 39, step 2 and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide (0.18 g, 0.88 mmol), the title compound (0.10 g, 90%) was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([NH2:15])=O)=[N:11][CH:12]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:15])=[N:11][CH:12]=1
Reactant: NC(=O)c1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Br)cn1
Temperature: 0 °C
Yield: 82.7 %

Procedure:
Phosphorus oxychloride (111 g, 0.720 mol) was added to a mixture of 5-bromopicolinamide (D8) (58 g, 0.288 mol) in dry toluene (300 ml) The mixture was heated to reflux for 2 hours. The mixture was poured into ice/water, and basified to pH=12 with 2N NaOH. The resulting mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 10:1. Collected fractions, after solvent evaporation afforded the title compound (D9) (43.6 g) as a yellow solid.
Reaction SMILES: FC1C=CC([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:20])[N:9]=2)=CC=1C.C(C1C=CC=CC=1)(=O)C.COCCOC1C=CC=CC=1C(OC)=O.[F:46][C:47]1[CH:55]=[CH:54][C:50](C(O)=O)=[CH:49][C:48]=1[CH3:56]>>[F:46][C:47]1[CH:55]=[CH:54][C:50]([N:11]2[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][CH:8]=[N:9][C:10]2=[O:20])=[CH:49][C:48]=1[CH3:56]
Reactant: Cc1cc(-c2cc(-c3ccccc3)[nH]c(=O)n2)ccc1F
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: COCCOc1ccccc1C(=O)OC
Solvent: CC(=O)c1ccccc1
Product: Cc1cc(-n2c(-c3ccccc3)ccnc2=O)ccc1F

Procedure:
Using the same or analogous synthetic techniques described in Example 1, 4-(4-fluoro-3-methylphenyl)-6-phenylpyrimidin-2(1H)-one was prepared by replacing 1-[(4-hydroxy-3-methyl)phenyl]ethanone with commercially available acetophenone and methyl 2-{[2-(methyloxy)ethyl]oxy}benzoate with commercially available 4-fluoro-3-methylbenzoic acid.