Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]=[C:29]4[C:35]5[CH:36]=[CH:37][CH:38]=[N:39][C:34]=5[CH2:33][O:32][C:31]5[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]4=5)[CH2:13]3)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: O=C1CN([C@@H]2CCNC2)Cc2ccc(Cl)cc2N1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CC[C@@H](N3CC(=O)Nc4cc(Cl)ccc4C3)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of (R)-8-chloro-4-pyrrolidin-3-yl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.198 g, 0.58 mmol) in acetonitrile/water (8:2) (5.8 mL) was added K2CO3 (0.655 g, 4.6 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.183 g, 0.48 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.077 g, 28%). 1H-NMR (CDCl3): δ1.55 (s, 6H), 1.74 (septet, 1H), 2.01 (sextet, 1H), 2.32-2.60 (m, 6H), 2.76 (t, 1H), 3.26 (pentet, 1H), 3.43 (d, 1H), 3.46 (s, 2H), 3.74 (s, 2H), 5.27 (bs, 2H), 6.12 (t, 1H), 6.78 (d, 1H), 6.96 (s, 1H), 7.06 (dd, 1H), 7.13 (d, 1H), 7.19-7.27 (m, 2H), 7.44 (d, 1H), 7.55 (dd, 1H), 8.47 (dd, 1H), 8.49 (s, 1H). ESI-MS m/z: 559 (M+1), retention time 1.24.
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][C:13]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]3=[O:33])[C:18]([F:34])=[CH:17][C:16]=2[N+:35]([O-])=O)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][C:13]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[N:23]([CH3:32])[C:22]3=[O:33])[C:18]([F:34])=[CH:17][C:16]=2[NH2:35])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(N)cc2F)c1=O
Temperature: 35 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a mixture of 2.0 g of an iron powder, 6 ml of acetic acid and 0.6 ml of water was added dropwise a solution of 1.9 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 5.0 ml of acetic acid, while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 2 hours, then, the reaction solution was filtrated through Celite and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel column chromatography to obtain 1.0 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]=[CH:16][C:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1)=[CH:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4].Cl>O1CCOCC1.[OH-].[Na+]>[N+:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:15]1[CH:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[N:12][C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:5]=2[C:3]([OH:4])=[O:2])([O-:29])=[O:28]
Reactant: COC(=O)c1c2ccccc2nc2cc(OCc3cccc([N+](=O)[O-])c3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1c2ccccc2nc2cc(OCc3cccc([N+](=O)[O-])c3)ccc12

Procedure:
3-(m-Nitrobenzyloxy)acridine-9-carboxylic acid methylester (6.5 g; 16.7 mmol) was refluxed in 400 ml dioxane and 300 ml NaOH 1N. After 2 hours the solution was cooled and acidified to pH 1 with HCl conc., then evaporated in vacuo. The precipitate was collected on a Buchner funnel, washed with water and dried in vacuo at 50° C. Yield 5.9 g (95%), Fp.>250° C. 1H-NMR(DMSO-d6): 8.44(1H, s, ar.); 8.23(1H, d, ar.); 8.10(2H, t, ar.); 8.03(1H, d, ar.); 7.95(1H, d, ar.); 7.72(2H. m, ar.); 7.42(2H, m, ar.); 7.27(1H, d, ar.); and 5.50 ppm (2H, s, CH2). MS: M+ =374.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:25](=[O:26])[CH2:24][C:22](=[O:23])[O:21]1>O>[N:11]1([CH2:10][C:9]2[CH:8]=[C:7]([O:17][CH3:18])[CH:6]=[C:3]3[C:2]=2[O:1][C:25](=[O:26])[C:24]([C:22]([OH:23])=[O:21])=[CH:4]3)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1cc(C=O)c(O)c(CN2CCOCC2)c1
Solvent: O
Product: COc1cc(CN2CCOCC2)c2oc(=O)c(C(=O)O)cc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
2-hydroxy-5-methoxy-3-(4-morpholinylmethyl)benzaldehyde (0.349 g, 1.39 mmol) and Meldrum's acid (0.200 g, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 0.381 g of 8-(4-morpholinylmethyl)-3-carboxy-6-methoxy-coumarin in an 85% yield: LCMS (ESI) m/z 320 (MH+).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>>[N+:12]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][C:1]([OH:11])=[O:10])=[CH:9][CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCc1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
In a 2-liter, 3-necked, round-bottomed flask equipped with mechanical stirrer, thermometer, and addition funnel was placed 361 g (2.41 mol) of hydrocinnamic acid which was warmed to 50° to maintain it in a liquid state. To the warm liquid was added slowly dropwise over a 4 hour period with good stirring a mixture of 241 g of nitric acid and 546 g of sulfuric acid. The reaction is very exothermic so that a water cooling bath was required to which ice was added occasionally to keep the temperature at 50° C. The very thick reaction mixture was stirred for an additional 2 hours and poured onto 3 liters of ice. The solid was collected by filtration and washed repeatedly with a total of 6 liters of water. After air drying, the entire sample was recrystallized from 800 ml of acetone, giving a first crop of 150.4 g mp. 162°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1.N1C=CN=C1.[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Si:38]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 110.5 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 15h (1.0 g, 2.09 mmol) in dichloromethane (15 mL) were added imidazole (0.57 g, 8.39 mmol), tert-butyldimethylsilyl chloride (0.63 g, 4.19 mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in turn at 0° C. The mixture was warmed up to room temperature and stirred for 1.5 hours. The reaction mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7 and partitioned. The aqueous layer was extracted with dichloromethane (20 mL×2). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 15i as yellow oil (1.37 g, 100%). This material was not further purified.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu](I)I.CCOC(C)=O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: Brc1ncccn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2ncccn2)c1
Temperature: 115 °C
Yield: 105.7 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1 g, 4.2 mmol), 2-bromo-pyrimidine (0.58 g, 5.1 mmol), potassium carbonate (powder, 1.4 g, 10.1 mmol), copper iodide (325 mesh powder, 0.6 g, 3.2 mmol) and pyridine (5 mL) was heated at 115° C. for 12 h. CH2Cl2 (100 mL) was added, the reaction mixture was filtered through celite and rinsed with CH2Cl2 (2×50 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title product (1.4 g, quantitative yield).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]#[N:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[Br:16]Br.O>O1CCOCC1>[Br:16][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:2]([Br:1])[NH:6][C:5]=1[C:7]#[N:8]
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(Br)[nH]1
Reactant: BrBr
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1[nH]c(Br)c(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A sample of 5-bromo-4-(p-chlorophenyl)pyrrole-2-carbonitrile (2.2 g., 0.0078 mol) is dissolved in 30 mL of dry dioxane. The solution is heated with bromine (1.3 g., 0.008 mol) in dioxane (20 mL) and then stirred overnight at room temperature. The reaction mixture is poured into water precipitating a tan solid (2.6 g., 92%). A portion (1.6 g) is purified by flash chromatography using 75/25 hexane/ethyl acetate to give 0.8 g of grey solid with m.p. 191°-194° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[CH:18]1([C:21]2[C:22]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:28]3[CH2:33][CH2:32][N:31]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:16])=[CH:15][CH:14]=4)=[O:13])[CH2:30][CH2:29]3)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH2:19][CH2:20]1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C2CC2)c1
Yield: 9.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (241 mg) described in Preparation Example 16 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 85 and by the reaction and treatment in the same manner as in Example 86, the title compound (42 mg) was obtained.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[NH:16][C@@H:15]([C@@H:17]([O:19]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH3:18])[CH2:14][O:13][CH2:12]2)=[CH:7][CH:6]=1>CO>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[NH:16][C@@H:15]([C@@H:17]([OH:19])[CH3:18])[CH2:14][O:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: C[C@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Sodium methoxide (1.9 mL, 28% methanol solution) was added to a methanol (40 mL) solution of 4-nitrobenzoic acid (S)-1-[(3R,5R)-5-(4-chlorophenyl)morpholin-3 yl]ethyl ester (1.46 g). Stirring was continued for 1 hour at room temperature. The solvent was removed under a vacuum, and ethyl acetate and water were added, and the organic layer was partitioned. The organic layer was washed with brine, and the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→1/3), and the title compound (833 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][CH:31]=[C:30]([C:34](Cl)=[O:35])[CH:29]=1>>[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)=[O:35])[CH:29]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(Cl)c1cccc(-c2ccccc2)c1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(-c5ccccc5)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available biphenyl-3-carbonyl chloride gave the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH:8][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Dissolve 3,5-di-t-butyl-4-hydroxy-aniline (2.21 g, 10 mmol) in anhydrous pyridine (25 mL) and cool to 5° C. Add, by dropwise addition, p-toluenesulfonyl chloride (2.1 g, 11 mmol) and stir overnight. Partition between water and ethyl acetate and separate the organic phase. Wash the organic phase with cold 1N hydrochloric acid, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:30][CH3:31])[CH:22]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH:2]2[C:8]3=[N:9][C:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][N:15]=4)=[CH:11][C:12](=[O:13])[N:7]3[CH2:6][CH2:5][O:4][CH2:3]2)=[O:26])=[C:23]([O:30][CH3:31])[CH:22]=1
Reactant: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1C(=O)NC1COCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of 0.700 g (2.70 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one dissolved in 54 mL of dimethylformamide was added 0.554 g (2.97 mmol) of 4-chloro-2-methoxy-benzoic acid. To the resulting mixture was added 440 μL (2.97 mmol) of diethyl cyanophosphonate and 450 μL (3.24 mmol) of triethylamine at 0° C. The resulting mixture was stirred at room temperature for 4 hours. Water and ethyl acetate were added and the mixture was stirred. The resulting residue was filtered, washed with water, ethyl acetate and diethyl ether to afford 0.932 g (81%) of the pure product as a white powder.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36]C)=[CH:34][CH:33]=[C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[CH3:44])[CH:31]=3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B(Br)(Br)Br>ClCCl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([OH:36])=[CH:34][CH:33]=[C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[CH3:44])[CH:31]=3)[C@H:14]2[CH3:45])[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:46])[CH:8]=1
Reactant: COc1ccc(-c2ccccc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(O)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C

Procedure:
To a cold solution (−78° C. bath) of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6′-methoxy-2″-methyl-4-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (75 mg, 0.11 mmol) in dichloromethane (1 mL) was added boron tribromide (106.6 mg, 0.426 mmol). The resulting mixture was aged cold (−78° C. bath) for 1 hour then allowed to warm to ambient temperature overnight. Reaction was quenched with ice followed by extraction with dichloromethane. The combined extracts were washed with brine and then over Na2SO4. The resulting mixture was filtered and concentrated. The residue was purified by preparative TLC on SiO2 (eluted with 30% ethyl acetate in hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6′-hydroxy-2″-methyl-4-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=653.16; found=654.19 (M+1)+. 1H NMR signals are doubled because of atropoisomerism 1H NMR (CDCl3, 500 MHz) δ 7.87-7.84 (m, 1H), 7.76 (s, 0.5H), 7.72-7.65 (m, 2.5H), 7.63 (s, 1H), 7.53-7.47 (m, 1H), 7.33-7.23 (m, 3H), 7.23-7.16 (m, 2H), 7.12 (dd, J=10.5, 2.5 Hz, 1H), 7.04 (d, J=8.0 Hz, 0.5H), 7.02 (d, J=8.5 Hz, 0.5H), 5.64 (d, J=8.0 Hz, 0.5H), 5.32 (d, J=7.5 Hz, 0.5H), 4.98, 4.92 (d, J=16 Hz, 1H), 4.23 (d, J=15.5 Hz, 0.5H), 4.07 (d, J=15.5 Hz, 0.5H), 3.89-3.82 (m, 0.5H), 3.74-3.67 (m, 0.5H), 2.32, 2.28 (s, 3H), 0.58 (d, J=7 Hz, 1.5H), 0.49 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:7].[NH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(CC)CC)C>CO>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:10][C@H:9]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:7]
Reactant: CS(=O)(=O)OCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: NN1CCOCC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCNN2CCOCC2)C[C@H]1Cc1c[nH]c2ccccc12
Yield: 27.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-methylsulfonyloxyethyl)piperazine (200 mg), 4-aminomorpholine (36 mg) and triethylamine (52 mg) in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) as an eluent to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[2-(morpholinoamino)ethyl]piperazine (55 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([O:14]CC)(=O)[C:8]([O:10]CC)=O>C(OCC)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH3:6])[C:7](=[O:14])[C:8]1=[O:10]
Reactant: CNCCNC
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: CN1CCN(C)C(=O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a stirred solution of N,N′-dimethylethylenediamine (25.0 g, 0.28 mol) in 150 mL of dry diethyl ether was added diethyl oxalate (38.5 mL, 0.28 mol) in one portion. After a few minutes white crystals started to precipitate. The reaction mixture was stirred at room temperature overnight. The product was filtered and washed with dry diethyl ether. The product was dried under vacuum at 47° C. overnight to give colorless crystals (38.64 g, 96%). 1H NMR (200 MHz, CDCl3, δ): 3.50 (s, 4H), 2.99 (s, 6H). 13C{1H} NMR (200 MHz, CDCl3, δ): 157.35, 45.91, 34.74.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:17][CH:18](O)[CH3:19]>>[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH:18]([CH3:19])[CH3:17])=[O:13]
Reactant: CC(C)O
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)O
Product: CC(C)OC(=O)c1cc(N)ccc1Cl
Reaction time: 6 h
Yield: 75 %

Procedure:
Methanesulfonic acid (99%, 318 g, 3.3 mole) was added slowly to a stirred mixture of 5-amino-2-chloro-benzoic acid (85%, 215 g, 1.1 mole) in 2-propanol (about 1100 ml). The mixture was heated under reflux with stirring for 6 hours, then the excess 2-propanol was evaporated under reduced pressure. Water (about 1000 ml) was added to the residue and the mixture was neutralized with solid sodium bicarbonate and extracted with methylene chloride (about 1200 ml). The extract was washed twice with water, dried over magnesium sulfate and evaporated to give a purple oil, which crystallized on seeding. The product was reprecipitated from dilute hydrochloric acid solution by slowly basifying with concentrated ammonium hydroxide and seeding. The resulting crystals after drying melted at 50.5°-52° C. (170 g, 75% yield).
Reaction SMILES: [OH:1][CH:2]([CH:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=O.B.O1CCCC1.[ClH:30]>>[ClH:30].[CH3:8][CH:6]([NH:5][CH2:3][CH:2]([OH:1])[CH:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7]
Reactant: Cc1ccccc1OC(c1ccccc1)C(O)C(=O)NC(C)C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccccc1OC(c1ccccc1)C(O)CNC(C)C

Procedure:
This compound was prepared by reduction of α-hydroxy-N-(1-methylethyl)-β-(2-methylphenoxy)benzenepropanamide (1.8 g.) with borane-tetrahydrofuran complex (1 M solution in tetrahydrofuran, 13 ml.) and subsequent treatment with hydrochloric acid as described in Example 24. The crude product was purified by recrystallization from tetrahydrofuran. The product melted at 193°-195°, and weighed 0.75 g.