Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([CH3:36])([CH2:34][CH3:35])[CH2:8][C:9]1[N:10]=[C:11]([CH3:33])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1.[F:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:55]=[CH:54][C:47]([C:48](N(OC)C)=[O:49])=[CH:46][CH:45]=2)=[N:42][CH:43]=1>O1CCCC1>[CH3:6][C:7]([CH3:36])([CH2:34][CH3:35])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][C:48]([C:47]2[CH:46]=[CH:45][C:44]([C:41]3[CH:40]=[CH:39][C:38]([F:37])=[CH:43][N:42]=3)=[CH:55][CH:54]=2)=[O:49])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(F)cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
n-Butyllithium (2.5 M in hexanes) (0.53 mL, 1.32 mmol) was added to a solution of 4-(2,2-dimethylbutyl)-2-methyl-1-trityl-1H-imidazole (360 mg, 0.88 mmol) in tetrahydrofuran (15 mL) at −78° C. dropwise. After stirring at −78° C. for 40 min, 4-(5-fluoropyridin-2-yl)-N-methoxy-N-methylbenzamide (340 mg, 1.32 mmol) in tetrahydrofuran (5 mL) was added dropwise. After warming slowly to ambient temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-20% ethyl acetate/hexane afforded 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanone contaminated with an unidentified byproduct. This material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48]1([N:54]=[C:55]=[O:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:55]([NH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:56])[CH2:42][CH2:41]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccccc2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 53 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 53% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.38 (s, 1H), 9.35 (s, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.72 (s, 1H), 7.43 (d, 2H), 7.20 (m, 3H), 7.04 (m, 2H), 6.90 (m, 2H), 6.78 (d, 1H), 4.15 (d, 2H), 2.82 (m, 6H), 2.30 (d, 2H), 2.00 (m, 1H), 1.72 (m, 2H), 1.20 (m, 2H). LCMS for C32H33ClN7O2 (M+H)+: m/z=582.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+].Cl>C(Cl)Cl>[CH3:12][S:13]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a solution of methyl 6-aminonicotinate (1.0 g, 6.57 mmol) in CH2Cl2 (50 mL) with TEA (0.96 mL, 6.90 mmol) cooled in an ice bath is added MsCl (0.54 mL, 6.90 mmol) slowly. The crude is allowed to stir at room temperature for 2 hrs. The crude is then concentrated. The crude is dissolved in MeOH (20 mL) and to the crude is added 1 N NaOH (30 mL, 30 mmol). The crude is stirred at room temperature for 18 hrs. The crude is quenched with 1N HCl (32 mL, 32 mmol). The crude is concentrated to remove MeOH and some water is removed as well. The crude is diluted in CH2Cl2 and basified with 1 N NaOH (30 mL). The aq. layer is extracted with CH2Cl2. The aq. layer is acidified with concentrated HCl to bring the PH to 1 via PH paper indicator. The crude is diluted in EtOAc and the aq. layer is extracted with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated to give 6-(methylsulfonamido)nicotinic acid (421 mg) as a yellow solid. HPLC retention time=0.40 minutes (condition D); MS (m+1)=217.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:14])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)Cl)cc1

Procedure:
Meanwhile, the 4-methylbenzoyl chloride acylating agent was prepared by suspending 3.314 g (24.3 mmol) of ρ-toluic acid in 200 ml benzene. To this solution was added 2.0 equiv. (4.25 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at O° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Cl[C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1COCC1.CCOC(C)=O>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:2]=1
Reactant: COC(=O)CCCCCCC(=O)Cl
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of biphenyl-3-amine (180) (0.171 g, 1.01 mmol) in THF (3 mL) was cooled to 0° C. then treated with methyl 8-chloro-8-oxooctanoate (181) and stirred for 2 h. The reaction mixture was then diluted with AcOEt, washed with saturated NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent: 30 to 40% AcOEt in hexane), to provide title compound 182 (0.212 g, 69% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([CH2:28][N+:29]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>>[C:28]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10]1)#[N:29]
Reactant: CC(C)CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)CC1CC(C#N)CCN1C(=O)OC(C)(C)C

Procedure:
The compound was prepared as described in Reference Compound 1, Step 1 from 2-Isobutyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.55 g, 17.8 mmol), toluene-4-sulfonylmethyl isocyanide (5.2 g, 26.7 mmol) and potassium tert-butoxide (53.4 mL, 1 M in tert-butanol) which yielded crude tert-butyl 4-cyano-2-isobutylpiperidine-1-carboxylate. MS m/z 267 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)cc(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)cc(CBr)c1

Procedure:
A solution of 3,5-dimethylanisole (1.11 g, 8.15 mmol), N-bromosuccinimide (1.52 g, 8.55 mmol), and 2,2′-bisisobutyronitrile (27 mg, 0.16 mmol) in carbontetrachloride (10 mL) was refluxed for 2 hrs. The reaction mixture was cooled, filtered and concentrated in vacuo to afford 1-bromomethyl-3-methoxy-5-methyl-benzene as a slightly yellow oil (1.66 g). This material was used without further purification: 1H NMR (300 MHz) compatible.
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1.O>[CH:19]1([C:25]([N:9]2[CH2:10][CH:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:12]3)[CH2:8]2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(C1CCCCC1)N1CC2CC2(c2ccccc2)C1

Procedure:
A 6.4 g. portion of 1-phenyl-3-azabicyclo[3.1.0]hexane is added to 60 ml. of benzene. A 4.2 g. portion of sodium carbonate in 40 ml. of water is added with stirring. A 5.9 g. portion of cyclohexylcarbonyl chloride in 40 ml. of benzene is added and the mixture is stirred overnight. The oily solid in the aqueous layer is extracted with chloroform. The extracts are washed with water and dilute hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The oily residue is extracted with ether giving a white solid as the product, mp 81°-82° C.
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.C([O-])([O-])=O.[K+].[K+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N+:36]([CH2:38][C:39]([O:41][CH3:42])=[O:40])#[C-:37]>CN(C=O)C>[C:9]([O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]1[O:6][CH:37]=[N:36][C:38]=1[C:39]([O:41][CH3:42])=[O:40])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CCC(=O)[O-]
Reactant: [C-]#[N+]CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To an ice-cooled mixture of mono-tert-butyl succinate (5.0 g, 28.7 mmol) and K2CO3 (15.9 g, 114.8 mmol) in DMF (40 mL) were added diphenylphosphoryl azide (11.06 g, 40.2 mmol) and methyl isocyanoacetate (3.41 g, 34.4 mmol). After being stirred at room temperature for 16 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica-gel, 9:1-3:7 hexane/ethyl acetate) to give the title compound (6.20 g) as a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[C:15]1([C:21]2[S:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.COCCOC.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>[C:15]1([C:21]2[S:25][C:24]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of sodium carbonate (799 mg), tetrakis(triphenylphosphine)palladium(0) (218 mg), 3-bromopyridin-2-amine (652 mg) and 5-phenylthiophen-2-ylboronic acid (1000 mg) in water (10 mL) and 1,2-dimethoxyethane (50 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (579 mg) as a dark yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: CC1(C)OB(c2occc2-c2ccccc2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3occc3-c3ccccc3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (140 mg, 0.48 mmol) in dioxane (5.0 mL) and water (3 drops) was added 4,4,5,5-tetramethyl-2-(3-phenylfuran-2-yl)-1,3,2-dioxaborolane (270 mg, 1.00 mmol), K3PO4 (211 mg, 0.99 mmol) and Pd(PPh3)4 (28 mg, 0.02 mmol) with stirring for 1 h at 95° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(3-phenylfuran-2-yl)quinoxaline-6-carboxylate as a light yellow solid (140.0 mg, 73%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:14])[CH2:13][C:23]([C:18]3[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=3)([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
0.50 g (2.69 mmol) of 1-(4-(1H-imidazol-1-yl)phenyl)ethanone, 0.65 g (2.69 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.31 g of toluene and 0.15 g (0.81 mmol) of tributylamine were fed and the mixture was stirred for 8 hours at 60° C. After leaving the reaction mixture for one night at room temperature, the solid was filtered under reduced pressure to obtain 0.94 g of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid (yield 85.7%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][CH2:11][C:12](O)=[O:13].FC(F)(F)S(O)(=O)=O.C(Cl)(Cl)Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:12](=[O:13])[CH2:11][CH2:10][Cl:9]
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)CCCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCl)c1ccc(O)cc1O
Temperature: 80 °C
Yield: 66.9 %

Procedure:
To a stirred mixture of resorcinol (200 g, 1.82 mol) and 3-chloropropionic acid (200 g, 1.84 mol) was added trifluoromethane sulfonic acid (1 kg) in one portion. The solution was heated slowly over about 45 minutes at about 80° C. then cooled to room temperature over about 15 minutes and poured into chloroform (4.0 L). The organic portion was slowly poured into water (4.0 L) and the layers separated. The aqueous layer was extracted with chloroform (2×2.0 L). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gave an orange semi-solid (244.1 g) which was used crude in the next step. 1H-NMR (300 MHz, CDCl3): 12.56 (1H, s), 7.63 (1H, d, J=7.6 Hz), 6.37-6.46 (2H, m), 3.92 (2H, t, J=6.3 Hz), 3.41 (2H, t, J=6.3 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1oc2ccc(CN3CCCC3)cc2c1-c1ccccc1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with pyrrolidine in ethanol to provide yellow crystals of 2-nitro-3-phenyl-5-(1-pyrrolidylmethyl)benzofuran, m.p. 111°-112.5° C., having the structure ##STR9##
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].C(OP([CH2:19][C:20]#[N:21])(=O)OCC)C.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[N:35]=[C:34]([C:36]3[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=3)[CH:39]=O)[CH:33]=[N:32][CH:31]=2)[CH2:25][CH2:24]1>C1COCC1>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[N:35]=[C:34]([C:36]3[CH:37]=[C:38](/[CH:39]=[CH:19]/[C:20]#[N:21])[CH:41]=[CH:42][CH:43]=3)[CH:33]=[N:32][CH:31]=2)[CH2:25][CH2:24]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CN1CCCN(c2cncc(-c3cccc(C=O)c3)n2)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: CN1CCCN(c2cncc(-c3cccc(/C=C/C#N)c3)n2)CC1
Yield: 62 %

Procedure:
1-(6-Chloro-pyrazin-2-yl)-4-methyl-[1,4] diazepane (360 mg, 1.59 mmol), (intermediate C prepared in example 3), 3-formylphenylboronic acid (235 mg, 1.58 mmol) and bistriphenylphosphinepalladium(II)chloride (21 mg, 0.03 mmol) were dispersed in 10 mL DMF in a reaction tube. Subsequently 1.5 mL of 2M Na2CO3 was added. The tube was sealed and the reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was then filtered through a plug of celite, diluted with ethyl acetate and water (25 mL), and the organic phase was separated. The aqueous phase was extracted with 2×10 mL ethyl acetate. The organic extracts were combined, washed with brine, dried and concentrated. The residue was purified by flash chromatography. Intermediate L (337 mg, 72%; MS analysis electrospray, 297, M+H) was isolated by concentration of the solvents and used directly. Sodium hexamethyldisilazane (0.22 mL, 1M in THF, 0.22 mmol) was added to a solution of cyanomethyl-phosphonic acid diethyl ester (0.034 mL, 0.21 mmol) in 1 mL THF under an atmosphere of N2. The mixture was stirred for 2 h after which time a solution of 3-[6-(4-methyl-[1,4] diazepan-1-yl)-pyrazin-2-yl]-benzaldehyde in 2 mL THF was added. After 15 min. the solvents were evaporated and the residue was diluted with 5 mL water and extracted with ethyl acetate (2×5 mL). The organic extracts were combined, washed with brine, dried and concentrated. The residue was purified by flash chromatography to provide the title compound (40 mg, 62%); MS analysis electrospray, 320 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:15]I>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cn(C)c2ccccc12
Reaction time: 0.5 h

Procedure:
3-Acetyl-1H-indole (4.00 g, 0.025 mol) was dissolved in dry THF (100 ml), and treated with 80% sodium hydride (0.794 g, 0.0263 mol) with stirring under At. After 0.5 h, methyl iodide (2.36 ml, 0.038 mol) was added. After 20 h, the reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was then dried (Na2SO4), and evaporated under reduced pressure to give the title compound as a pale brown oil which crystallised on standing (4.20 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:3]1[C:4]2[N:5]=[CH:6][NH:7][C:8](=[O:11])[C:9]=2[S:10][C:2]=1[Cl:1]
Reactant: O=c1[nH]cnc2cc(Cl)sc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c(Br)c(Cl)sc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43.9 %

Procedure:
A solution of 1.12 g (0.006 mole) of 6-chlorothieno[3,2-d]pyrimidin-4(3H)-one and 15 ml of acetic acid at 80° C. was treated with 2.88 g (0.92 ml, 0.018 mole) of bromine. Heating was continued for 2.5 hours during which time solids precipitated. After cooling to room temperature, the mixture was filtered and washed with acetic acid, water and acetone. There was obtained 0.70 g (44%) of the title compound: m.p. above 280° C.; mass spectrum 264 (molecular ion and parent peak with expected isotope pattern), 239 (-27), 186 (some starting material) among others; 1H-nmr (trifluoroacetic acid) delta 7.5 ppm (starting material, s 0.1H), 9.3 (s, 1.0H). The nmr spectrum indicates that the reaction product is about 90% of the desired product; the remainder is starting material. This material is sufficiently pure for use in further reactions.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][CH:27](OCC)OCC)[CH3:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1C=CC=CC=1>[C:1]([N:9]1[C@@H:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:17][CH:27]1[O:26][CH2:24][CH3:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1OC(OCC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1

Procedure:
[R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (1.16 mmol) is suspended in benzene (10 ml), and triethoxymethane (3.44 mmol) and PPTS (72 mg) are added. Heating to reflux provides the title compound.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31]C>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:30][CH3:31])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: CCC=O
Product: CCc1c2c(nc3cc(F)cc(F)c13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 100 is treated with propionaldehyde according to a procedure similar to that in Stage 95e to produce the expected solid (m.p. 255° C.).