Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:36]I>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([I:36])[N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: II
Reactant: COc1ccc(F)cc1-c1ncnc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ncnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 3B (2.5 g, 6.52 mmol) in 50 mL tetrahydrofuran at −78° C. was added 2M lithium diisopropylamide (4.89 mL, 9.78 mmol) over 5 minutes. The solution was stirred at −78° C. for 30 minutes and a solution of iodine (3.31 g, 13.04 mmol) in tetrahydrofuran (50 mL) was added over 5 minutes. The mixture was stirred at −78° C. for 2 hours and quenched with 50 mL 1M sodium thiosulfate. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound, which was used without further purification. MS (ESI+) m/z 509.51 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35]C)=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:9])[CH2:4]1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([OH:35])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:20])=[O:21])=[O:9])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@H](C(=O)NCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CC[C@@H](C(=O)NCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 80 °C
Yield: 49.2 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-ylcarbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 195, 0.215 g) and lithium hydroxide monohydrate (0.170 g) was suspended in dioxane (5 mL) and water (5 mL) and the mixture was stirred and heated at 80° C. for 21 hours. The temperature was raised to 100° C. and the mixture was stirred and heated at that temperature for 2.5 hours. Further lithium hydroxide monohydrate (0.05 g) was added and the mixture was stirred and heated at 100° C. for 2 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and extracted with DCM. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-60% to give (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-ylcarbonyl)-amino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.103 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].O.C(=O)([O-])[O-].[K+:38].[K+]>CO>[K+:38].[C:20]([N:7]1[C@@H:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:5]([C:3]([O-:4])=[O:2])[O:9][CH:8]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2O[C@@H](C(=O)[O-])[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c(OC)c1
Reaction time: 1 h

Procedure:
A 100 mg (0.23 mM) quantity (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (Preparation 6, 5Ba) is stirred at room temperature under nitrogen in 3 mL MeOH. Added 0.1 mL water and 43 mg (0.31 mM) potassium carbonate. After 1 hour, TLC shows no starting material left. Stored in freezer overnight. The next morning the solvent is evaporated to give (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid potassium salt (6Ba). The residue is partitioned between methylene chloride and water containing 0.9 mL 1N HCl. The layers are separated and the aqueous layer reextracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated. This leaves (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid (7Ba) as a white solid.
Reaction SMILES: [C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:49])[C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)=[O:34])=[CH:29][CH:28]=2)[CH2:13][CH2:12]1)=[O:9].Cl.CO>>[C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:9])[O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]([CH3:49])[C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]3)=[O:34])=[CH:29][CH:28]=2)[CH2:15][CH2:16]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N2CCNCC2)cc1
Yield: 77.5 %

Procedure:
The compound (98 mg, 0.130 mmol) obtained in Example 92a and 2 N hydrochloric acid-methanol (1.30 mL, 2.60 mmol) were used to give the title compound (66 mg; yield, 78%) as a white solid according to the method described in Example 89e.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([F:23])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[CH2:12][CH2:11]1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:9][C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([F:23])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[CH2:12][CH2:11]1)=[O:28]
Reactant: COC(=O)c1cc2c(cc1F)CC[C@H]2N
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1F)CC[C@H]2NC(=O)c1ccccc1Cl
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Triethylamine (2.5 eq.) was added to a solution of (R)-methyl 3-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-11) (0.773 mmol, 1 eq.) in methylene chloride (6 ml) at 0° C. and the mixture was stirred for 10 min. 2-Chlorobenzoyl chloride (1.2 eq.) was added dropwise to the reaction mixture at the same temperature and the mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with methylene chloride (50 ml) and was then washed with NH4Cl solution (20 ml) and sat. NaCl solution (20 ml). The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The crude material was purified by column chromatography (silica gel, ethyl acetate/cyclohexane 2:1) to yield the desired product (B-15). Yield: 97%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].CC(C)([O-])C.[K+].O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:12]2[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=2[F:18])[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=CCCCCBr
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Chloro-benzenesulfonylmethyl)-1,3,4-trifluoro-benzene (1.0 g, 3.1 mmol, from example 8, step 2) and 6-bromo-1-hexene (1.5 g, 6.3 mmole) were dissolved in 20 mL THF and potassium t-butoxide (1M in THF, 6.2 mL) was added. The reaction mixture was stirred at room temperature for three hours. 50 mL water and 50 mL EtOAc were added. The organic layer washed with brine (50 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/Hexane as eluent (gradient from 0/100 to 25/75 in 40 minutes, 0.65 g, 52%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, j=8.05 Hz, 2H), 7.45 (d, j=8.05 Hz, 2H), 7.14 (m, 1H), 6.83 (m, 0.5H), 6.74 (m, 0.5H), 5.70 (m, 1H), 4.93 (m, 2H), 4.58 (d, j=5.1 and 6.5 Hz, 1H), 2.43 (m, 1H), 2.31 (m, 1H), 1.99 (m, 2H), 1.39 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: C[C@@:2]12[C@@:10](O)([C:11]([CH2:13]O)=[O:12])[CH2:9][CH2:8][C@H]1[C@@H]1CCC3[C@@](C)([C@H]1[C@@H](O)C2)C=CC(=O)C=3.C(NC(=O)[C@H](O)[C@]1(O)[C@]2(C)[C@H]([C@H]3[C@H]([C@@H:48]([OH:52])C2)[C@]2(C)C(=CC(=O)C=C2)CC3)CC1)CC.Cl(O)(=O)(=O)=[O:58]>>[C:11]([CH:10]([CH2:9][CH3:8])[C:2]([O:52][CH3:48])=[O:58])(=[O:12])[CH3:13]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CCCNC(=O)[C@H](O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: [O-][Cl+3]([O-])([O-])O
Product: CCC(C(C)=O)C(=O)OC

Procedure:
Prednisolone with 20-hydroxy and 20-carboxamide groups are known, e.g., (VI) (20R)-21-(n-propylamino)-11β,17, 20-trihydroxy-3,21-dioxo-1,4-pregnadiene; and (VI) is reacted with an alkyl acetylalkanoate or alkyl formylalkanoate in the presence of catalytic amount of perchloric acid to produce the corresponding 17,20-carboxycyclic acetal pregnane derivatives, e.g., when methyl acetylbutyrate is used the product is (VII) (20R)-21-(n-propylamino)-11β-hydroxy-3,21-dioxo-17,20-(methyl, methoxycarbony-n-propyl)methylenedioxy-1,4-pregnadiene.
Reaction SMILES: CCl.[NH2:3][CH2:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:12](N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>ClCCl>[CH3:12][O:9][C:8](=[O:10])[CH2:7][CH2:6][C:5]([CH2:4][NH:3][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)CCC(=O)O
Reactant: CCN(CC)CC
Agent: CCl
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC(=O)CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-aminolevulinic acid methyl hydrochloride (1.0 g, 5.5 mmol) and triethylamine (2.3 mL, 16.5 mmol) in dichloromethane (50 mL) was cooled to 0° C., and benzoyl chloride (0.7 mL, 6.1 mmol) was then added to the solution. The obtained mixture was stirred at room temperature for 3 hours. Thereafter, water was added to the reaction solution, and it was then extracted with ethyl acetate. The organic layer was washed with a saturated saline and was then dried over sodium sulfate. The solvent was distilled away, and the obtained residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain the title compound (1.29 g, yield: 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[CH2:15]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:31][CH:32]=2)[CH2:23][CH2:24]1)[CH2:16][CH2:17][CH3:18]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CCCCN1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCN1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 155 °C
Yield: 13 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (6) (1.19 mmol) in DMA (10 mL) was added 4-(4-butylpiperazin-1-yl)benzaldehyde (5) (1.09 mmol), NaHSO3 (1.30 mmol), and p-TsOH (0.10 mmol). The resulting solution was heated to 155° C. for 4 hours and cooled to room temperature. The solution was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting with 10% to 50% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the compound 7 (0.06 g, 13%). 1H NMR (300 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.09 (d, J=8.9 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.17-3.42 (m, 4H), 2.39-2.58 (m, 4H), 2.23-2.37 (m, 2H), 1.37-1.56 (m, 2H), 1.26-1.37 (m, 2H), 0.84-0.94 (m, 3H). APCI MS m/z 423 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.Br[CH2:37][C:38]#[N:39]>>[C:38]([CH2:37][N:23]1[C:24]2[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=2)[C:30](=[O:31])[N:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)[C:22]1=[O:35])#[N:39]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: N#CCBr
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(CC#N)c4=O)CC3)c2cc1OC
Yield: 27 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and bromoacetonitrile was used in place of methyl iodide. As a result, 87.3 mg (yield: 27%) of Compound 7 was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH:18][CH:19]1[CH:23]=[CH:22][S:21](=[O:25])(=[O:24])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:19]1[CH:23]=[CH:22][S:21](=[O:25])(=[O:24])[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=S1(=O)C=CC(NCc2ccccc2)C1
Solvent: c1ccccc1
Product: O=C(NCc1ccccc1)N(Cc1ccccc1)C1C=CS(=O)(=O)C1
Yield: 73.3 %

Procedure:
Benzylisocyanate (2.26 g, 17.0 mmol, 135 mol %) was added to a mixture of amine 3 (2.80 g, 12.6 mmol) in a benzene (75 mL). After 10 hr of reflux, the solution was cooled and filtered, and the solvent was evaporated from the filtrate to afford the crude product (3.29 g, 74% yield). A portion was purified by column chromatography on silica gel with dichloromethane-ethyl acetate. 1H N NMR (CDCl3) δ 1.7 (1H, s, NH), 3.02 (1H, dd, CHSO2), 3.65 (1H, dd, CHSO2), 4.4 (4H, m, CH2Ph), 4.95, (1H, m, CHN), 6.57 (2H, m, CH=CH), 7.23 (10H, s, arom).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>COCCOC.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:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1cccnc1
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: COCCOC
Solvent: O
Product: O=Cc1cc2cccc(Cl)c2nc1-c1cccnc1
Temperature: 90 °C
Yield: 90.5 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (5.0 g, 22.2 mmol), Na2CO3 (3.51 g, 33.2 mmol) and 3-pyridylboronic acid (2.72 g, 22.2 mmol) in DME (60 mL) and water (30 mL) was degassed by bubbling N2 through it for 5 minutes. Pd(PPh3)4 (1.28 g, 1.11 mmol) was added and the mixture heated at 90° C. for 7 h. The mixture was allowed to cool to room temperature. The resultant precipitate was filtered off and washed with water (5×50 mL) and diethyl ether (5×50 mL) to give the title compound (5.4 g, 91%) as a tan solid. δH (DMSO-d6) 10.15 (s, 1H), 9.15 (s, 1H), 8.94 (dd, J 2.3, 0.8 Hz, 1H), 8.77 (dd, J 4.9, 1.7 Hz, 1H), 8.31 (dd, J 8.3, 1.3 Hz, 1H), 8.20-8.19 (m, 1H), 8.18-8.16 (m, 1H), 7.75 (dd, J 7.9, 7.5 Hz, 1H), 7.62 (ddd, J 7.7, 4.9, 0.8 Hz, 1H). LCMS (ES+) 269 (M+H)+, RT 1.82 minutes.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:11][C:12]1[N:13]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][Cl:27])=[CH:19][CH:18]=2)[O:15][CH:16]=1>CN(C)C=O>[Cl:27][CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[O:15][CH:16]=[C:12]([CH2:11][N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][C:1]3=[O:7])[N:13]=2)=[CH:22][CH:21]=1
Reactant: O=C1CCCCN1
Reactant: ClCCCOc1ccc(-c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1Cc1coc(-c2ccc(OCCCCl)cc2)n1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A suspension of delta-valerolactam (0.14 g, 1.4 mmol, 1 eq) and sodium hydride (60% dispersion in mineral oil, 0.056 g, 1.4 mmol, 1 eq) in N,N-dimethylformamide (10 ml) is cooled to 0° C. and treated with 4-(chloromethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole ax57 (0.4 g, 1.4 mmol, 1 eq). The mixture is then stirred at room temperature. After 20 h, the solvent is evaporated, the residue is taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 0.58 g of 1-({2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}methyl)piperidin-2-one i55 immediately engaged in the next step without any further purification.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH:13]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CCOCC>[N:13]1([C:1]([O:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:10])[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Benzyl carbonochloridate (3.57 mL, 25.36 mmol) at 0° C. was added to methyl pyrrolidine-3-carboxylate hydrochloride (4.00 g, 24.15 mmol) and K2CO3 (6.68 g, 48.3 mmol) in THF:water (100 mL, 1:1). The reaction mixture was stirred at room temperature for 2 hours. Ether (50 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 54% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](C(F)(F)F)=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](I)[CH:8]=2)[N:3]=1.[Li]CCCC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1>O1CCCC1>[CH2:12]([C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[Cl:23])=[CH:8][C:7]([C:37]([C:34]1[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=1)([C:39]1[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=1)[OH:38])=[CH:6][CH:5]=2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)cc1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(Cc3ccccc3)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-benzyl-6-bromo-2,4-dichloroquinoline (500 mg, 1.36 mmol, Intermediate 2: step c) in tetrahydrofuran (10 mL). n-BuLi (0.6 mL, 2.5 M in hexanes) was then added at −78° C. The resulting solution was stirred for 1 hour at −78° C. (4-Chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (301 mg, 1.36 mmol, Intermediate 1: step b) was added to this solution. The resulting solution was allowed to react, with stirring, for an additional 8 hours at room temperature. The reaction was then quenched by the addition of 10 mL of water/ice. The resulting solution was extracted with 3×20 mL of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with dichloromethane/methanol to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.20 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.69-7.79 (m, 2H), 7.44 (d, J=7.5 Hz, 2H), 7.25-7.37 (m, 4H), 7.14-7.25 (m, 4H), 6.20 (s, 1H), 4.47 (s, 2H), 3.31 (s, 3H); MS m/e 508 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH2:9][CH3:10])[CH:7]=[N:6][C:5]=1[CH3:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([N:8]1[C:4]([CH2:3][S:19][C:17]2[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=2)=[C:5]([CH3:11])[N:6]=[CH:7]1)[CH3:10]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCn1cnc(C)c1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1cnc(C)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
A mixture of 5-(chloromethyl)-1-ethyl-4-methyl-1H-imidazole hydrochloride (1.0 g, 5.1 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (500 mg, 3.5 mmol), and potassium carbonate (1.2 g, 9.0 mmol) in acetone (25 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-6% MeOH/DCM), affording 2-{[(1-ethyl-4-methyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methyl-pyrimidin-4-ol (428 mg, 46% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3H, J=6.7 Hz), 2.11 (s, 3H), 2.22 (s, 3H), 3.95 (m, 2H), 4.48 (s, 2H), 6.02 (s, 1H), 7.54 (s, 1H); M+ 266. The product was used without further purification.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[CH3:29])[C:20](=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)C1C=CC=CC=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:21]1[C:20](=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]1[CH2:11][NH:10][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(-n2c(CNC(=O)OCc3ccccc3)nc3ccccc3c2=O)c(C)c1
Product: Cc1ccc(-n2c(CNS(=O)(=O)c3ccccc3)nc3ccccc3c2=O)c(C)c1

Procedure:
[3-(2,4-Dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]carbamic acid benzyl ester, as prepared above in Example 4, was hydrogenated in a similar manner as described above in Example 6, and then condensed, as described above in Paragraph A, with benzenesulfonyl chloride to yield N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide; MS (ESI) 420 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:14][CH:15]1[CH2:20]CNC[CH2:16]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:13][CH2:16][CH:15]([CH3:20])[CH2:14][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Reactant: CC1CCNCC1
Product: CC1CCN(c2ccc(N)c(C(N)=O)c2)CC1

Procedure:
According to the preparation of 25, 4-methylpiperidine was used to afford 28 (0.8 g) as brown liquid;