Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:37][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.C(O)C.S(=O)(=O)(O)O>O>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 5 °C
Yield: 146.8 %

Procedure:
A mixture of 3β-benzoyloxy-14α,15α-epoxy-5α-cholest-7-ene (26, 12.0 g, 23.8 mmol), 95% ethanol (300 mL), and water (35 mL) was cooled to 5° C. in an ice water bath. To this solution was added, in portions of 5 mL, concentrated sulfuric acid (65.0 mL). After the addition (~5 min) the reaction mixture was heated under reflux for 22 h. Stirring must be effective to prevent clumping of the starting material. The clear reaction mixture was cooled to ambient temperature, then poured into ice (700 g). A sticky precipitate was formed (could not be filtered). The water phase was extracted three times with ethyl acetate (400, 200, and 200 mL). The combined ethyl acetate phase was washed with water, 5% sodium bicarbonate, and sodium chloride solution, and dried over sodium sulfate. Evaporation of the solvent gave a semisolid yellowish compound (14 g). The crude compound 27 was purified by flash chromatography (4.0×35 cm column) and eluted with ethyl acetate/hexane (1:3). Fractions containing product were combined and evaporated to give after crystallization from methanol/water pure product as fine needles 4.5 (47%). Mp, NMR, and IR data were in agreement with published data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH2:13][Si](C)(C)C)[CH:12]=2)=[CH:4][CH:3]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cn1cc(-c2ccc(F)cc2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(F)cc2)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1-trimethylsilanylmethyl-1H-[1,2,3]triazole (5.80 g, 23 mmol) in THF (85 mL) was added water (840 μL, 47 mmol) and then tetrabutylammonium fluoride (1 M in THF, 27.9 mL, 28 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was poured into water and then the THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (4.0 g, 98%) as an off white solid. MS: m/e=178.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]([S:10]([NH:13][C:14]1[CH:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[CH:32][C:33]=2[NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:25][CH:24]=1)(=[O:12])=[O:11])[CH3:9].[CH3:41][N:42](C=O)C.CN>ClCCl>[CH3:41][NH:42][C:20]([C:18]1[CH:17]=[CH:16][C:15]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:30][CH:31]=[CH:32][C:33]=3[NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])=[CH:25][CH:24]=2)=[C:14]([NH:13][S:10]([CH:8]([CH3:7])[CH3:9])(=[O:12])=[O:11])[CH:19]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: CC(C)S(=O)(=O)Nc1cc(C(=O)O)ccc1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c(NS(=O)(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add oxalyl chloride (0.12 mmol) to a suspension of 2-(Propane-2-sulfonylamino)-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.1 mmol) and DMF (0.05 mmol) in dichloromethane at 0° C. Stir 1 h at RT. Concentrate to dryness under reduced pressure. Dissolve resultant residue in 3 ml CH2Cl2 and add (2.8 mmol) of MeNH2 (2M in THF). Concentrate the reaction to dryness and purify by flash chromatography (Silica gel- eluting with 5%MeOH/CH2Cl2). Concentrate the desired fractions to provide the title compound. MS (ES−): 534(M−1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(OCc3ccccc3)cccc21
Reaction time: 16 h
Yield: 40.6 %

Procedure:
4′-Hydroxy-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.25 g, 0.77 mmol), benzyl bromide (0.13 mL, 1.1 mmol), and cesium carbonate (0.751 g, 2.30 mmol) were combined in anhydrous N,N-dimethylformamide (10 mL) at ambient temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was taken up in water (25 mL) and extracted with dichloromethane (3×25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane, followed by recrystallization from methanol/dichloromethane to afford 4′-(benzyloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.130 g, 41%) as a colorless solid: mp 198-200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-7.23 (m, 4H), 7.03-7.01 (m, 2H), 6.81 (d, J=8.5 Hz, 1H) 6.74 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.20 (s, 1H), 5.06 (s, 2H), 4.70 (ABq, 2H), 4.19-4.11 (m, 4H), 3.16 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.8, 154.4, 145.0, 144.3, 137.8, 137.3, 130.6, 128.5, 127.9, 127.0, 120.5, 117.6, 111.5, 108.1, 102.8, 98.8, 77.5, 69.1, 64.7, 64.1, 57.7, 27.1; MS (ES+) m/z 416.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.[C:23](OCCC)(=[O:26])[C:24]#[CH:25]>C(O)CC>[F:21][C:19]([F:22])([F:20])[C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[CH:25]=[CH:24][C:23](=[O:26])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:5]=2[CH:15]=1
Reactant: NC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Reactant: C#CC(=O)OCCC
Solvent: CCCO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-trifluromethyl-5-phenyl-3H-1,4-benzodiazepine, propyl propiolate and propanol were refluxed. The mixture was chromatographed to give 9-trifluoromethyl-7-phenylpyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:25])[N:10]=[CH:11][C:12]=2[CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[C:4]([C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[CH:3]=1.N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH3:25])[N:10]=[CH:11][C:12]=3[CH2:13][N:14]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:4]=2[CH:3]=1
Reactant: Cn1ncc(CN2C(=O)c3ccccc3C2=O)c1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: N
Solvent: CO
Product: Cn1ncc2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 48 h

Procedure:
A solution of 0.33 g of 3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-4-phthalimidomethyl-2-methyl-pyrazole in 20 ml of methanol is saturated with ammonia and allowed to stand at room temperature for 2 days. The residue obtained after removal of solvent is treated with water and then extracted with diethyl ether. The ether extract is washed with a diluted aqueous sodium hydroxide solution, water and a saturated solution of sodium chloride in water and dried over sodium sulfate. Removal of ether yields an oil which is then chromatographed on a column of silica gel, the material being eluted with ethyl acetate. The solid residue obtained after removal of ethyl acetate is crystallized from a mixture of ethyl acetate and petroleum ether to yield the 8-chloro-6-(2-fluorophenyl)-1-methyl-1H,4H-pyrazolo [4,3-d](2) benzazepine m.p. 127°-129°, which is identical with the compound prepared according to the process of example 2.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([CH3:14])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)c(F)c(F)c1C(=O)Cl
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of 8.2 g (39.4 mmol) of 2,3,4,5-tetrafluoro-6-methylbenzoic acid, 6.0 g (47.2 mmol) of oxalyl chloride, and 100 mL of dichloromethane was treated with three drops of DMF. The solution was stirred for 3 hours, then concentrated to give 8.8 g of the title compound as a yellow liquid. The product was used as is in the next step.
Reaction SMILES: [C:1]1([C:7]2[O:13][C@H:12]3[C@H:9]([C:10](=[O:34])[N:11]3[C:14]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:15]([CH3:17])[CH3:16])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+].[CH2:48]([O:50][C:51](=[O:55])[C@H:52]([CH3:54])[OH:53])[CH3:49]>>[CH2:48]([O:50][C:51]([C@H:52]([O:53][C@H:12]1[N:11]([C:14]([C:18]([O:20][CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])=[C:15]([CH3:16])[CH3:17])[C:10](=[O:34])[C@@H:9]1[NH:8][C:7](=[O:13])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:54])=[O:55])[CH3:49]
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Reactant: CCOC(=O)[C@H](C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: CCOC(=O)[C@@H](C)O[C@@H]1[C@@H](NC(=O)c2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10 Grams of (1R,5S)-3-phenyl-6-(1-diphenylmethoxycarbonyl-2-methylprop-1-enyl)-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-ene as used in Example 9(1) was dissolved in 35 ml of L-(+)-lactic acid ethyl ester instead of the DL-α-lactic acid ethyl ester employed in Reference Example 1(1). To the resultant solution was added 0.5 ml of trifluoromethanesulfonic acid, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction solution thus obtained was poured into 200 ml of aqueous sodium bicarbonate and allowed to stand under ice-cooling for 30 minutes.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>COC(C)(C)C>[CH3:22][S:23]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
To a solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.00 mmol) and triethylamine (0.21 mL, 1.5 mmol) in tert-butyl methyl ether (4 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). After 90 min., the mixture was filtered, washing the white solid with tert-butyl methyl ether (3×2 mL). The filtrate was concentrated in vacuo to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3,): δ 4.40-3.95 (m, 3H), 3.49-3.32 (m, 2H), 3.02 (s, 3H), 2.11-1.80 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[F:26])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:27]I>ClCCl.C(Cl)(Cl)Cl>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[CH:2]([CH2:3][I:27])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])=[C:20]([F:26])[CH:21]=1
Reactant: II
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine (0.236 g, 0.564 mmol) (from Example 19, Step E, supra) in dichloromethane (30 mL) was added I2 (1.43 g, 5.64 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with chloroform (100 mL), and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated to give the desired 4-(4-bromo-2-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as an off white oil. (Yield 0.034 g, 11%).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:44]=N[C:46]([CH3:49])=[CH:47][CH:48]=1)[CH2:4][CH2:3]2.BrC1C=CC=[C:53]([S:57]C)N=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:49]([S:57][CH3:53])[N:44]=1)[CH2:4][CH2:3]2
Reactant: CSc1cccc(Br)n1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccc(SC)n3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 12 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromo-6-(methylthio)pyridine (0.020 g, 0.100 mmol) was used in place of 3-bromo-6-methylpyridazine. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound as a white glassy solid (10.3 mg, 12% yield) bis TFA salt. LCMS: m/e 696.5 (M+H)+, 2.34 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.95-7.85 (m, J=8.2 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.20-7.12 (m, J=8.2 Hz, 2H), 6.53 (d, J=7.6 Hz, 1H), 6.37 (d, J=7.9 Hz, 1H), 5.25 (d, J=4.6 Hz, 1H), 4.85 (s, 1H), 4.72 (br. s., 1H), 3.96 (s, 1H), 3.78-3.59 (m, 2H), 3.28-3.13 (m, 2H), 2.95-2.83 (m, 1H), 2.49 (s, 3H), 2.08-1.86 (m, 6H), 1.78-1.69 (m, 4H), 1.69-1.52 (m, 5H), 1.52-1.31 (m, 6H), 1.31-1.07 (m, 7H), 1.01 (s, 3H), 0.95-0.83 (m, 9H), 0.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][Cl:34]>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH2:31][CH2:32][CH2:33][Cl:34])[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCCBr
Reactant: O=c1[nH]c(Cl)c(Cc2ccccc2)c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Cc2ccccc2)c(Cl)n(CCCCl)c(=O)n1Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a suspension of 24.51 g (75 mmol) of 6-chloro-3,5-dibenzylpyrimidine-2,4(1H,3H)-dione and 16.58 g (120 mmol) of potassium carbonate in 120 ml of N,N-dimethylformamide, 14.8 ml (150 mmol) of 1-bromo-3-chloropropane was added at room temperature. This mixture was stirred at 90° C. for 2 hours. After cooling, the reaction mixture was concentrated to dryness; the resulting residue was dissolved in chloroform-water. After the organic layer was washed with water and dried, the solvent was distilled off to yield an oily substance, which was then purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→3/1) to yield 22.68 g (74.9%, yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[NH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]1=[O:20])[CH3:27]
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]cc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O

Procedure:
650 mg (2.15 mmol) of 5-(5-chloro-2-thienyl)-1-(2-fluorobenzyl)-1,3-dihydro-2H-imidazol-2-one from Example 236A, 516 mg (4.21 mmol) of ethyl chloroacetate and 582 mg (4.21 mmol) of potassium carbonate are stirred in 12 ml acetonitrile for 7 hrs at 80° C. The reaction solution is diluted with ethyl acetate and washed three times with saturated sodium chloride solution. The organic phase is dried over sodium sulphate. After filtration from the drying agent, the filtrate is concentrated in vacuo. After purification by flash chromatography over silica gel (eluent: cyclohexane/ethyl acetate first 5:1, then 1:1), 610 mg (74% of theory) of the target compound are obtained.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:36]([F:39])([F:38])[F:37])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[CH3:34])=[O:21])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:36]([F:39])([F:37])[F:38])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][C:32]=2[CH3:33])=[O:21])[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc2C(F)(F)F)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O)CC3)ccc2C(F)(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
To a solution of methyl 4-[[5-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-2-(trifluoromethyl)benzoyl]amino]-3,5-dimethyl-benzoate (0.10 g, 177.08 moles) in THF (4 ml) is added Bu4NF 1.0 M in THF (1.0 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 6 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 40-60% ethyl acetate in hexanes to afford the title compound as a light yellow solid (0.06 g, 81.5%). Mass spectrum (m/z): 451.2 (M+1).
Reaction SMILES: C([CH2:4][C:5]1[C:6]([F:19])=[C:7]([C:16]([OH:18])=[O:17])[C:8](=[C:12]([F:15])[C:13]=1[F:14])C(O)=O)(O)=O.C(N(CC)CC)C>CS(C)=O>[F:19][C:6]1[C:5]([CH3:4])=[C:13]([F:14])[C:12]([F:15])=[CH:8][C:7]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 140 °C
Reaction time: 64 h
Yield: 58.5 %

Procedure:
To 304.35 g of 4-carboxymethyl-3,5,6-trifluorophthalic acid dissolved in 1.5 liters of dimethyl sulfoxide was added 0.5 liter of triethylamine, followed by 64 hours of stirring at 140° C. After cooling to room temperature, dimethyl sulfoxide was evaporated. The resulting residue was mixed with 1 liter of 1N hydrochloric acid and extracted with ether (1 liter×3). The organic layer was washed with 1 liter of water and 1 liter of saturated brine, and then dried over sodium sulfate. By evaporating the solvent, 177.94 g (0.64 mol, 60%) of the title compound was obtained as a partially purified product.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]([N:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([C:44]2[CH:49]=[C:48]([Cl:50])[CH:47]=[CH:46][C:45]=2[C:51]#[N:52])=[CH:38][C:37]1=[O:53])[C:22]([NH:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=1)=[O:23])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:50][C:48]1[CH:47]=[CH:46][C:45]([C:51]#[N:52])=[C:44]([C:39]2[C:40]([O:42][CH3:43])=[CH:41][N:36]([CH:21]([CH2:20][CH2:19][OH:18])[C:22]([NH:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:23])[C:37](=[O:53])[CH:38]=2)[CH:49]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1cn(C(CCO)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
266 mg (355 μmol) of ethyl 4-[(4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl)amino]benzoate (racemate) in 7 ml of methanol/water (4/1) were reacted with 232 mg (711 μmol) of caesium carbonate according to General Method 4. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 16.5 mg (9% of theory)