Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.FC(F)(F)C(O)=O.[NH:45]1[CH2:50][CH2:49][S:48](=[O:51])[CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:45]4[CH2:50][CH2:49][S:48](=[O:51])[CH2:47][CH2:46]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: O=S1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCS(=O)CC3)CC2)n1
Yield: 56 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (200 mg, 0.373 mmol), thiomorpholine 1-oxide trifluoroacetate (U.S. Pat. No. 6,372,773) (242 mg, 1.12 mmol), and DIPEA (0.45 mL, 2.61 mmol) was refluxed in THF (60 mL) for 4 days. The THF was removed under vacuum and the residue was dissolved in dioxane (60 mL). Additional thiomorpholine 1-oxide trifluoroacetate (161 mg, 0.745 mmol) and DIPEA (0.45 mL, 2.61 mmol) were added and the mixture was refluxed for 2 days. The solvent was removed under vacuum and the residue was diluted with water. The resulting precipitate was filtered, washed with water, and dissolved in CH2Cl2. The solution was dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (95:5), followed by recrystallization from CH2Cl2/hexane gave 138 mg (56% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-oxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (CH2Cl2/hexane) 229-231° C.; 1H NMR (CDCl3) δ7.85 (d, J=8.0 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.89 (br s, 4H), 3.79 (m, 4H), 3.38 (t, J=5.0 Hz, 4H), 3.15 (m, 4H), 2.99 (dd, J=8.8, 5.4, 2H), 2.79 (m, 6H); Anal. Calcd. for C26H35F2N9O5S2.0.2H2O: C, 47.4; H, 5.4; N, 19.1. Found: C, 47.3; H, 5.5; N, 18.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccccc1Cl
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: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2Cl)c1
Yield: 70.8 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.051 g (70%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([Mg]Br)[CH3:12].C(=O)=O.CC(C)=O>CCOCC>[O:4]=[C:2]([CH2:11][CH3:12])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)C(=O)OCC
Agent: O=C=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CC
Yield: 85.9 %

Procedure:
Diethyl oxalate (10 g; 68 mmol) was dissolved in Et2O (100 ml) and cooled to −78 C. Ethyl magnesium bromide (1.0 M in THF; 72 ml; 71.8 mmol; 1.05 equiv.) was added slowly via syringe. The dry ice/acetone bath was allowed to melt and warm to 10 C. Monitored the reaction by 1H NMR. The reaction was cooled to 0 C and quenched with saturated NH4Cl. Dilute with H2O and separate phases. The organic layer was dried over Na2SO4, filtered and concentrated. Isolation gave 7.6 g of a crude yellow oil in 86% yield. No further purification.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:16][C:14]([CH2:13][O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])=[O:15])[CH3:18]
Reactant: COc1cccc(C=O)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C=O)cccc1OC

Procedure:
A solution of 2-hydroxy-3-methoxybenzaldehyde (6.08 g), ethyl bromoacetate (4.9 ml) and potassium carbonate (12.14 g) in N,N-dimethylformamide (30 ml) was stirred for 2 hours at ambient temperature. Water was added to the reaction mixture, and the resulting precipitates were collected by filtration and recrystallized with ethanol to give 2-ethoxycarbonylmethoxy-3-methoxybenzaldehyde (5.04 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][CH:9]2[CH:11]=[CH:12][S:13][CH:8]2[CH:7]=1)=[O:5].[CH3:15][Mg]Br>C1COCC1>[S:10]1[C:6]([C:4](=[O:5])[CH3:15])=[CH:7][CH:8]2[S:13][CH:12]=[CH:11][CH:9]12
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1=CC2SC=CC2S1
Solvent: C1CCOC1
Product: CC(=O)C1=CC2SC=CC2S1
Temperature: 25 °C
Yield: 124.9 %

Procedure:
3a,6a-Dihydro-thieno[3,2-b]thiophene-2-carboxylic acid methoxy-methyl-amide (1.955 g, 8.60 mmol) was dissolved in THF. The stirred solution was cooled to 0° C. before methylmagnesium bromide (1.4 M in PhMe, 8.6 mL, 12.04 mmol) was added. The reaction was allowed to gradually warm to RT o/n, then it was quenched by addition of 10% HCl. The aqueous phase was extracted with diethyl ether. The organic phase was washed with brine then dried over MgSO4, filtered and concentrated to afford the title compound (1.98 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH2:18][CH2:19]1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3ncccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4ncccn4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 87.5 %

Procedure:
With 300 mg of the compound obtained in Step 45-1 and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 402 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[C:15](I)=[CH:14][N:13]=[CH:12][N:11]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)O1.COCCOC>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:9][C:10]1[C:15]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)=[CH:14][N:13]=[CH:12][N:11]=1
Reactant: Clc1ncncc1I
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Cl)CC1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a sealable tube was added potassium phosphate (1.308 g, 6.16 mmol), dppf (0.051 g, 0.092 mmol), palladium (II) acetate (0.014 g, 0.062 mmol), 4-chloro-5-iodopyrimidine (0.741 g, 3.08 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.23 mmol) followed by DME (17.60 mL) and water (2.93 mL) before sealing the reaction under argon and stirring at 85° C. for 4 h. It was cooled to room temperature and diluted with water before extracting with dichloromethane drying over magnesium sulfate, filtering, and concentrating under reduced pressure to a dark brownish-orange residue that was used without purification. MS (ESI, pos. ion) m/z: 296.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25](O)=[O:26])([O-:3])=[O:2].C(Cl)Cl.ClC(OC)=O.[NH3:36]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25]([NH2:36])=[O:26])([O-:3])=[O:2]
Reactant: N
Reactant: O=C(O)CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
88 g of N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-3-aminopropionic acid (compound 3) are added to 500 ml of methylene chloride with 34.3 ml of triethylamine at -25° C. With stirring, 22.8 ml of methyl chloroformate are run in over 30 minutes and stirring is continued at -10° to -20° C. After 2 hours, 40 ml of ammonia solution are added and the reaction mixture is warmed to room temperature. The mixture is then washed with water and the organic phase is concentrated. The residue is recrystallised from ethyl acetate/hexane. The product has a melting point of 137°-138° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH3:12][O:13][Na]>CO>[CH3:12][O:13][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CO[Na]
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Solvent: CO
Product: COCc1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with CH3OH (50 mL), 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (8.8 g, 40 mmol) and CH3ONa (4.3 g, 80 mmol). The reaction mixture was heated at reflux for 2 h. After this time the reaction was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate (60 mL) and water (60 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with brine (50 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to afford 176a as a yellow oil (6.1 g, 90%). LCMS: [M+H]+ 172.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:3]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)#[N:2]
Reactant: CS(=O)(=O)Nc1cc2occ(C=NO)c(=O)c2cc1Oc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2occ(C#N)c(=O)c2cc1Oc1ccccc1
Yield: 84 %

Procedure:
3.0 g of 3-hydroxyiminomethyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 30 ml of acetic acid. Thereto was added 900 mg of sodium acetate. The mixture was refluxed for 3 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from a mixed solvent of ethyl acetate and ethanol to obtain 2.4 g (yield: 83.9%) of 3-cyano-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 219.5°-220.5° C.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=2)[O:12][C:11]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1[CH2:38][CH2:37][CH2:36][CH2:35]1>[Cl-].[Zn+2].[Cl-]>[CH2:2]([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH2:35][CH2:36][CH:37]([CH3:38])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:13])[CH2:19][CH2:10][CH2:11][CH:22]([CH3:27])[CH3:23])=[CH:16][CH:17]=2)[O:12][C:11]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Product: COc1cc(-c2oc3cc(CCC(C)CCCC(C)CCCC(C)C)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Temperature: 50 °C
Reaction time: 25 h
Yield: 15 %

Procedure:
To a stirring suspension of zinc chloride (0.367 g, 2.7 mmol, 3 eq) and magnesium (0.100 g, 4.1 mmol, 4.7 eq) in tetrahydrofuran (2.5 ml) under argon was added 7 (1.268 g, 3.8 mmol, 4.2 eq) in tetrahydrofuran (2.5 ml). The reaction was heated to 50° C. for 19 hours then cooled. 34 (0.481 g, 0.8 mmol) in tetrahydrofuran (7 ml) and dichlorobis-[tri-(o-tolyl)-phosphinyl]palladium (0.063 g, 0.08 mmol, 0.09 eq) added and the reaction stirred for 25 hours. The reaction was then quenched with 3 N HCl (10 ml), diluted with water and extracted into ethyl acetate (3×). The combined aqueous layers were dried (MgSO4) and concentrated in vacuo to give a purple oil. Column chromatography (silica gel, petrol:EtOAc 9:1>2:1) yielded 48 (0.082 g, 15%) as a pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=2)[CH:15]=[C:16]([C:18]([O:20]C)=[O:19])[CH:17]=1.[OH-].[Na+]>O1CCOCC1>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=2)[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=1
Reactant: COC(=O)c1cc(N[C@@H]2c3ccccc3C[C@H]2O)c2nc(C)c(C)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c(N[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)O)cn2c1C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
2.0 g (5.7 mmol) methyl 8-(trans-2,3-dihydro-2-hydroxy-1-indenylamino)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxylate are suspended in 100 ml dioxane and 20 ml 2N aqueous sodium hydroxide and heated to reflux. After 1 h the reaction mixture is cooled down, evaporated in vacuo to ¼ of its volume and 50 ml water are added. The pH of the mixture is adjusted to pH=7 by adding 2N hydrochloric acid and the flask is placed in an ice bath. After 30 min, the precipitate is collected, washed with water and dried in vacuo at 50° C. to yield 1.4 g (73%) of the title compound (m.p. 246-249° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>ClCCl.CCOCC.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CCCS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 25.7 %

Procedure:
5-(4-Aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (98 mg, 0.5 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (87 μL, 0.6 mmol) was added. Propane sulfonyl chloride (62 μL, 0.55 mmol) was added and the mixture was stirred 16 hours. The mixture was diluted with 50% ether in ethyl acetate and washed with water, saturated NaHCO3, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]propane-1-sulfonamide (0.039 g).
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[NH:8][C:7]2=O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]2[C:11](=[C:2]([I:1])[C:3]([CH3:14])=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(I)c(C)ccc2c(=O)[nH]1
Product: Cc1nc(Cl)c2ccc(C)c(I)c2n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
8-Iodo-2,7-dimethylquinazolin-4(3H)-one (0.300 g, 1.00 mmol) was treated with phosphorus oxychloride (10 mL, 107 mmol) and the mixture stirred at 120° C. for 4 h. During this time, the reaction went from being a milky white suspension to a clear solution. The mixture was concentrated under vacuum and the residual phosphorous oxychloride was azeotroped with toluene. The residue was taken up in DCM and washed with cold water (2×) followed by washes (2×) with aqueous saturated sodium bicarbonate and brine. The organic solution was then dried with sodium sulfate and concentrated under vacuum to give 4-chloro-8-iodo-2,7-dimethylquinazoline (0.30 g, 94%) as an orange solid. MS (M+H)+ 319.
Reaction SMILES: [C:1]1([C:7]2[C:16]([CH3:17])=[CH:15][C:14]3[C:9](=[C:10]([C@H:18](OS(C)(=O)=O)[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]1>C(Cl)(Cl)Cl>[C:1]1([C:7]2[C:16]([CH3:17])=[CH:15][C:14]3[C:9](=[C:10]([C@@H:18]([N:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C@H:34]4[CH3:33])[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc2cccc([C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)c2nc1-c1ccccc1
Reactant: C[C@@H]1CCCCN1
Solvent: ClC(Cl)Cl
Product: Cc1cc2cccc([C@H](CO[Si](C)(C)C(C)(C)C)N3CCCC[C@H]3C)c2nc1-c1ccccc1
Yield: 45 %

Procedure:
A solution of 7 g (17.8 mmol) of 2-phenyl-3-methyl-8-(1-(S)-methanesulfonyloxy-2-[tert-butyldimethylsilyloxy]ethyl)quinoline 8.8 g (88 mmol) of 2-(R)-methylpiperidine in 50 ml of anhydrous chloroform is brought to 60° C. for 6 hours. The reaction mixture is concentrated under vacuum and the residue obtained is purified by silica gel chromatography (eluent: dichloromethane/methanol 9/1) to provide 3.8 g of 2-phenyl-3-methyl-8-(1-(R)-[2-(R)-methylpiperidino]-2-[tert-butyldimethylsilyloxy]ethyl)quinoline in the form of a colorless oil. (Yield: 45%)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[C:17](Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[C:17]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Solvent: c1ccncc1
Product: CCCCCC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 82 %

Procedure:
3-Caproyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with caproyl chloride in pyridine.
Reaction SMILES: [O:1]=[C:2](O)[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O=C(O)[C@@H]([C@@H]([C@@H](CO)O)O)O.O=C[C@@H]([C@@H]([C@@H]([C@@H](CO)O)O)O)O.O=C[C@H]([C@@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@H](O)[C@H](O)CO

Procedure:
In another aspect of the second embodiment, D-arabinonic acid reactant 90 may be prepared by decarboxylation 80 of a D-glucose starting material 60 by one or more reactions. Referring to FIG. 2, the starting material can be converted to an arabinonic reactant 90 or a ribonic acid reactant 40 by one or more reaction steps. Preferably, a suitable C-6 sugar starting material is decarboxylated at the C-1 position. Optionally, a starting material comprising D-(+)-allose or D-(+)-altrose can undergo a decarboxylation reaction 35 to produce an intermediate comprising D-(−)-ribose (aldehyde) that can subsequently undergo an oxidation reaction 37 to produce the desired reactant 40 comprising D-ribonic acid. Similarly, a starting material comprising D-(+)-glucose or D-(+)-mannose can undergo a decarboxylation reaction 85 to produce an intermediate comprising D-(−)-arabinose (aldehyde) that can subsequently undergo an oxidation reaction 87 to produce the desired reactant 90 comprising D-arabinonic acid. U.S. Pat. No. 4,515,667 describes a process for the photochemical decarboxylation of an alpha-hydroxy carboxylic acid to the corresponding alcohol which process comprises irradiating a mixture of a solution of an alpha-hydroxy carboxylic acid and a metal titanate.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([C:18]([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:19]#[N:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-:33].[Na+]>C(Cl)(Cl)Cl>[C:21]1([C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH:15]2[CH2:16][CH2:17][N:13]([CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:14]2)[C:19]([NH2:20])=[O:33])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1
Reaction time: 16 h

Procedure:
To 250 ml of concentrated sulfuric acid under agitation was added, slowly at 70° C., 170 g (0.48 mole) of α-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile. Stirring was continued for 16 hr at 75°-80° C. The solution was cooled and poured into a mixture of ice, 50% sodium hydroxide solution and chloroform. The chloroform layer was separated and the aqueous phase extracted three more times with chloroform. The combined chloroform layers were dried and concentrated in vacuo to give 188 g of residual oil. A portion of the oil was crystallized in isopropanol and the solid recrystallized from a mix of isopropanol and isopropyl ether to give a light brown solid, m.p. 135°-138° C.