Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[OH-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>O1CCOCC1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:2][N:3]2[CH2:4][CH:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][CH2:8]2)=[S:26])=[CH:20][CH:19]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: NN1CC=C(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(NC(=S)NN2CC=C(c3ccccc3)CC2)cc1
Reaction time: 5 h
Yield: 64.4 %

Procedure:
To a stirred solution of N-amino-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.05 g) in a mixture of dioxane (10 ml) and water (5 ml) was added 1N sodium hydroxide solution (5 ml) under ice-bath cooling, and then a solution of 4-fluorophenyl isothiocyanate (1.15 g) in dioxane (5 ml) was added thereto. The mixture was stirred for 5 hours under ice-bath cooling. The reaction mixture was evaporated in vacuo and the residue was extracted several times with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give a crude product, which was recrystallized from ethyl acetate to give N-[[(4-fluorophenyl)thiocarbamoyl]amino]-4-phenyl-1,2,3,6-tetrahydropyridine (1.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])OC(=O)[CH:4]=1.[C:11]([O:19][CH3:20])(=[O:18])[C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]([C:11]([O:19][CH3:20])=[O:18])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)oc(=O)c1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)c1cc(OC)cc(C)c1C(=O)OC
Temperature: 180 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of compound K (41.4 g, 295 mmol) and dimethyl but-2-ynedioate (47.2 mL, 384 mmol) was stirred at 180° C. for 1 hour, then at 210° C. for 30 minutes. The mixture was cooled to room temperature and purified by silica gel chromatography (ethyl acetate:hexane=20:1-4:1) to give compound L (53.4 g, 76%) as a pale-yellow oil. 1H NMR (CDCl3, 400 MHz): δ 2.34 (3H, s), 3.84 (3H, s), 3.88 (3H, s), 3.90 (3H, s), 6.91 (1H, d, J=2.4 Hz), 7.29 (1H, d, J=2.4 Hz). EIMS (+): 238 [M]+
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](OC(C)(C)C)=[O:11])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].Cl.[CH:29](N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](=[O:11])[CH3:29])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (465 mg, 1.2 mmol) was dissolved in dichloromethane (1 mL) and HCl (4M dioxane, 3 mL) was added. The resultant suspension was stirred at room temperature for 30 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF and diisopropyl ethylamine (154 mg, 1.2 mmol) was added, followed by acetic anhydride (122 mg, 1.2 mmol). The reaction was stirred at room temperature. After 30 minutes, all volatiles were removed in vacuo. The crude material was purified by silica gel chromatography (eluent: DCM/MeOH) to yield the product 1-Acetyl-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-4-carboxylic acid methyl ester (273 mg, 0.829 mmol): LCMS-ESI+: calc'd for C14H23N3O6: 329.4 (M+); Found: 330.4 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[C:15]([CH:21]2[CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([Cl:20])[N:19]=1.[C:24](=[O:26])=[O:25].Cl>O1CCCC1>[Cl:20][C:18]1[C:17]([C:24]([OH:26])=[O:25])=[N:16][C:15]([CH:21]2[CH2:23][CH2:22]2)=[C:14]([Cl:13])[N:19]=1
Reactant: Clc1cnc(C2CC2)c(Cl)n1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1nc(C2CC2)c(Cl)nc1Cl
Temperature: -100 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
Under an argon atmosphere, to a mixture of tetrahydrofuran (6 mL) and diisopropylamine (258 μL) was added dropwise n-butyllithium (1.62 M n-hexane solution, 1.04 mL) under ice-cooling. After cooling to −100° C., a mixture of 3,5-dichloro-2-cyclopropylpyrazine (290 mg) and tetrahydrofuran (2 mL) was added dropwise thereto, followed by stirring for 10 minutes. The obtained reactant was added to dry ice (10 g) and tetrahydrofuran (5 mL), followed by stirring for 30 minutes in a water bath. To the reactant were added 1 M hydrochloric acid and a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3,5-dichloro-6-cyclopropylpyrazine-2-carboxylic acid (350 mg) as an oily material.
Reaction SMILES: Cl.[C:2]1([C:7]2([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.O>C(O)C.[OH-].[Na+]>[ClH:18].[C:2]1([C:7]2([CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])[CH2:11][CH2:10]/[C:9](=[CH:23]\[C:22]3[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=3)/[C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CN(C)CCC1(C2=CCCC2)CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)CCC1(C2=CCCC2)CC/C(=C\c2ccc(Cl)cc2)C1=O
Reaction time: 12 h

Procedure:
To a solution of 1.0 g (3.9 mmole) of 2-(1-cyclopenten-1-yl)-2-dimethylaminoethyl cyclopentanone hydrochloride and 8.1 mmole of 4-chloro-benzaldehyde in 40 ml of ethanol, 3.2 ml of 5N NaOH was added dropwise. The resulting mixture was stirred at about room temperature for about 12 hours and then mixed with 60 ml of water and extracted with ether. The ether extract was extracted with 6N HCl. The HCl extract was basified and extracted with ether, and then dried over anhydrous MgSO4. The ether solution was treated with ethanolic hydrogen chloride to give a precipitate, which was recrystallized from ethanol to give the 2-(1-Cyclopenten-1-yl)-2-dimethylaminoethyl-5-(E)-[(4-chloro) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 234°-236° C.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[C:22]([CH2:29][CH3:30])=[N:23][CH:24]=[CH:25][C:26]=1[CH2:27][CH3:28]>CN(C=O)C>[CH2:29]([C:22]1[C:21]([CH2:20][S:1][C:2]2[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=2)=[C:26]([CH2:27][CH3:28])[CH:25]=[CH:24][N:23]=1)[CH3:30]
Reactant: CCc1ccnc(CC)c1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccnc(CC)c1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (592 mg, 3.0 mmol) was dissolved in anhydrous DMF (25 mL), and then potassium carbonate (1.25 g, 9.0 mmol) and 3-(bromomethyl)-2,4-diethylpyridine (3.6 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-12% DCM/MeOH to afford 2-{[(2,4-diethylpyridin-3-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (860 mg, 69% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.13-1.20 (m, 6H), 2.67 (q, J=7.5 Hz, 2H), 2.81 (q, J=7.5 Hz, 2H), 4.54 (s, 2H), 6.67 (s, 1H), 7.10 (d, J=5.1 Hz, 1H), 8.34 (d, J=5.1 Hz, 1H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (Example Ac, 1.24 g, 5.0 mmol) in POCl3 was refluxed under nitrogen for 3 hrs. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as a pale-yellow solid (1.29 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d, J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].C([NH:13][C:14]1[C:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:18]=2[C:17]([Cl:26])=[CH:16][CH:15]=1)(=O)C.[OH-].[Na+]>>[NH2:13][C:14]1[C:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:18]=2[C:17]([Cl:26])=[CH:16][C:15]=1[N+:6]([O-:9])=[O:7]
Reactant: CC(=O)Nc1ccc(Cl)c2c1CCN(C)CC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCc2c(Cl)cc([N+](=O)[O-])c(N)c2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 200 g. of concentrated sulfuric acid and 50 g. of concentrated nitric acid at 0°-5° C. is added, in portions, 12.6 g. (0.05 mole) of 9-acetamido-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. The solution is stirred at 0°-5° C. for 2 hours and then it is poured cautiously into 500 ml. of ice/water. The solution is made alkaline with sodium hydroxide. After being stirred at 25° C. for 16 hours, the mixture is filtered to give 9-amino-6-chloro-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10])(=[O:19])=[O:18]
Reactant: COc1ccccc1N
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: COc1ccccc1NS(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of o-anisidine with 2-methyl-benzenesulfonyl chloride
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[C:27](Cl)(=[O:30])[CH2:28][CH3:29].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of compound 24 (0.102 g, 0.27 mmol) in CH2Cl2 (2 mL) was added propionyl chloride (0.035 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). The reaction mixture was stirred at room temperature for 20 hrs, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with CH2Cl2/diisopropyl ether and vacuum filtered to yield the desired product as a powder. The powder was redissolved in CH2Cl2 and chromatographed for a second time over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder. The powder was triturated with diisopropyl ether and vacuum filtered to yield compound 57 (0.061 g, 52.1% yield, 96.6% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.27 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J=9 Hz, 1H), 6.68 (s, 2H), 3.71 (m, 2H), 3.54 (m, 2H), 3.35 (m, 4H), 2.34 (s, 6H), 2.32 (m, 2H), 1.13 (t, J=7 Hz, 3H); MS (ESI, EI+): m/z=428 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:17][C:18]1([CH3:51])[O:22][C@H:21]([C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:31]3[C:36]([F:37])=[CH:35][C:34]([N:38]4[CH2:42][C@H:41]([CH2:43]OS(C)(=O)=O)[O:40][C:39]4=[O:49])=[CH:33][C:32]=3[F:50])=[CH:27][CH2:26]2)=[O:24])[CH2:20][O:19]1.O>CN(C)C=O>[CH3:51][C:18]1([CH3:17])[O:22][C@H:21]([C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:31]3[C:36]([F:37])=[CH:35][C:34]([N:38]4[CH2:42][C@H:41]([CH2:43][N:10]([C:11]5[O:15][N:14]=[C:13]([CH3:16])[CH:12]=5)[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[O:40][C:39]4=[O:49])=[CH:33][C:32]=3[F:50])=[CH:27][CH2:26]2)=[O:24])[CH2:20][O:19]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)on1
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)CC2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)C(=O)OC(C)(C)C)on1
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Sodium hydride (60% in oil, 72 mg, 1.8 mM) was suspended in dry N,N-dimethylformamide (3 ml), cooled to 0° under nitrogen, and a solution of 5-(t-butoxycarbonylamino)-3-methylisoxazole (356 mg, 1.8 mM) in N,N-dimethylformamide (3 ml) added. After stirring for 10 minutes, a solution of 3-(4(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one (516 mg, 1.5 mM) in N,N-dimethylformamide (3 ml) was added, and the mixture heated to 40° for 5 hours. After cooling, the mixture was poured into water (50 ml), extracted with dichloromethane (4×20 ml). The organic phase was dried (magnesium sulfate), evaporated and crude product purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 50% to 75% ethyl acetate in isohexane. Relevant fractions were combined to give the desired product (420 mg).
Reaction SMILES: [F:1][CH:2]([CH3:13])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9](Br)[CH2:8][CH2:7]1.Cl[SiH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.Cl[SiH]1CCC(C2C=CC(F)=C(F)C=2)CC1>>[F:1][CH:2]([CH3:13])[CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([Si@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:8][CH2:7]1
Reactant: CC(F)CCCC1CCC(Br)CC1
Reactant: FC(F)(F)Oc1ccc(C2CC[SiH](Cl)CC2)cc1
Agent: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Product: CC(F)CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](c3ccc(OC(F)(F)F)cc3)CC2)CC1

Procedure:
The above compound was obtained in the same manner as Example 6, using 4-(4-fluoropentyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-trifluoromethoxybenzene instead of 4-(4-fluorobutyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1,2-difluorobenzene, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:42])[CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCNc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCN(C)c1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product from Example 290 and sodium triacetoxyborohydride in 9/1 dichloromethane/methanol was added excess formaldehyde (37% in water). The mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by reverse phase preparative HPLC with the AA method to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.88 (t, J=7.35 Hz, 3 H) 1.34 (d, J=6.99 Hz, 6 H) 1.54 (m, 2 H) 2.93 (s, 3 H) 3.25 (m, 3 H) 6.75 (d, J=9.19 Hz, 2 H) 6.85 (d, J=7.72 Hz, 1 H) 7.27 (d, J=8.82 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.87 (d, J=8.46 Hz, 1 H) 8.04 (d, J=2.57 Hz, 1 H) 8.07 (d, J=2.21 Hz, 1 H) 8.17 (m, 1 H) 8.49 (d, J=2.21 Hz, 1 H) 8.58 (s, 1 H) 8.88 (d, J=8.82 Hz, 1 H) 10.13 (s, 1 H) 10.91 (s, 1 H); MS (ESI+) m/z 642/644 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[CH:11](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: ClC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1cnn(C(c2ccccc2)c2ccccc2)c1
Temperature: 100 °C

Procedure:
A suspension of 1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g), benzhydryl chloride (1.9 ml) and potassium carbonate (1.48 g) in anhydrous 1-methyl-2-pyrrolidinone (10 ml) was heated at 100° C. under nitrogen for 6 h. It was diluted with water and extracted with ethyl acetate, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/ethyl acetate (4:1) followed by i-hexane/ethyl acetate (2:1) to give the sub-title compound (2.18 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6](=[O:18])[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2.COC(=O)C.[C:25]([O:29][C:30](=[O:37])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)([CH3:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6](=[O:18])[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:37])[CH:9]=2
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(O)cc21
Solvent: COC(C)=O
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc21

Procedure:
The title compound is prepared using the procedure of Example 75 and (1-ethyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and (4-bromobutyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of (5)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 0.36 mmol), 2,4,5-trichloropyrimidine (66 mg, 0.36 mmol) and diisopropylethylamine (70 mg, 0.54 mmol) was dissolved in 2-propanol (1.5 ml) and stirred at 80° C. overnight. For work-up most of the solvent was evaporated, then aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, 10 to 30% ethyl acetate in heptane) to yield a white solid (141 mg, 92%). MS (ISP): 425.1 ([{35Cl}M+H]+), 427.1 ([{37Cl}M+H]+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[Br:31]C1C=C(C=CC=1)C=O>>[Br:31][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: O=Cc1cccc(Br)c1
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2cccc(Br)c2)Oc2ccc(O)cc21

Procedure:
2-(3-Bromophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.3 ml of 3-bromobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (300 MHz, d6-DMSO) δ: 9.41 (s, 1H), 7.50 (m, 1H), 7.59-7.53 (m, 2H), 7.39 (m, 1H), 7.12 (d, 1H, J 2.9 Hz), 7.05 (dd, 1H, J 8.8, 2.9 Hz), 6.98 (d, 1H, J 8.8 Hz), 5.57 (dd, 1H, J 13.0, 2.9 Hz), 3.12 (dd, 1H, J −16.9, 13.0 Hz), 2.81 (dd, 1H, J −16.9, 2.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[N+:25]([CH:28]([CH3:31])[CH2:29]O)([O-:27])=[O:26].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:29][CH:28]([N+:25]([O-:27])=[O:26])[CH3:31])=[O:11]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(CO)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 41 %

Procedure:
A stirred mixture of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid (50 g, 0.139 mole), 2-nitropropanol (13.2 g, 0.126 mole) and conc. sulfuric acid (1 ml) in benzene (500 ml) was heated to reflux for 24 hours, during which time water (1.9 g) was removed via a Dean Stark trap. The solvent was stripped under reduced pressure and the residue poured into water (700 ml). The product was extracted into ether, which was washed with water and then with 5% sodium bicarbonate. The dried ether solution was concentrated to give 23.2 g of an amber oil which slowly solidified to a tacky semi-solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2 g of conc. H2SO4 in 470 ml of ethanol was refluxed for 16 hours. The reaction mixture was cooled to ambient temperature, stirred with 6 g of solid KCO3 for 30 minutes and then filtered. The filtrate was concentrated in vacuo diluted with Et2O (200 ml), washed with 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless oil. PMR (CDCl3): δ1.25 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.15 (2H, q, J=7.0 Hz), 7.16 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).