Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:11][O:12][CH2:13][C:14]([O:16][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:15]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COCC(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)COC(=O)COC

Procedure:
71 ml of ethyl 4-chloro-3-oxo-butyrate are reacted with 89.5 g of methoxyacetic acid and 132 ml of triethylamine in 1 l of toluene by the procedure described in Example 4. The product is purified by bulb tube distillation.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[C@@H:10]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[Pd]>[CH2:24]([C@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[CH3:22])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)c1cccc(C)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H]1CNCCN1C(=O)c1cccc(C)c1C
Yield: 116.9 %

Procedure:
4-Benzyl-2(S)-n-butyl-1-(2,3-dimethylbenzoyl)piperazine (0.93 g, 2.55 mmol) was dissolved in methanol and hydrogenated in a Parr apparatus under 60 psi hydrogen in the presence of 10% Pd/C (0.186 g) for 24 h. The catalyst was removed by filtration through Celite, and the solvent removed in vacuo to obtain the title compound (0.818 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4]C.[F:6][C:7]1[CH:8]=[C:9]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([C:31]2[CH:32]=[N:33][N:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:35]=2)[CH:27]=[N:26]3)[CH:10]=[C:11]([F:20])[C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:6][C:7]1[CH:8]=[C:9]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([C:31]2[CH:32]=[N:33][N:34]([CH:36]4[CH2:41][CH2:40][N:39]([C:3](=[O:4])[CH3:2])[CH2:38][CH2:37]4)[CH:35]=2)[CH:27]=[N:26]3)[CH:10]=[C:11]([F:20])[C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Fc1cc(-c2cccc3ncc(-c4cnn(C5CCNCC5)c4)nc23)cc(F)c1CN1CCOCC1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(n2cc(-c3cnc4cccc(-c5cc(F)c(CN6CCOCC6)c(F)c5)c4n3)cn2)CC1
Temperature: 95 °C

Procedure:
2-chloroethylmethyl ether (13.5 μl, 0.143 mmol) is added dropwise to a solution of 8-(3,5-Difluoro-4-morpholin-4-ylmethyl-phenyl)-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)-quinoxaline (as obtained in example 98, 67 mg, 0.137 mmol), Cs2CO3 (24 mg, 0.075 mmol) in DMF (0.5 ml). The resulting mixture is heated under Ar at 95° C. for 17 h. Two products are formed in a ratio 1:1, as identified by example 122 and example 123. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 40 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient CH2Cl2/(CH2Cl2:EtOH:NH3 90:9:1) from 1:0=>0:1) to afford example 122 and example 123.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[CH3:10][C:11]1[CH:12]=[C:13]2[C:18](=O)[O:17][C:15](=[O:16])[C:14]2=[CH:20][CH:21]=1>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:18](=[O:17])[C:13]3=[CH:12][C:11]([CH3:10])=[CH:21][CH:20]=[C:14]3[C:15]2=[O:16])[CH2:3]1)[CH3:9]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: CCN1CCCC(N)C1
Product: CCN1CCCC(N2C(=O)c3ccc(C)cc3C2=O)C1

Procedure:
3-Amino-1-ethylpiperidine and 4-methylphthalic anhydride are reacted in a similar manner to that described in Example 3 to give the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[S:12])[C:6]=2[CH:5]=[CH:4]1.CI.[C:15]([O-])(O)=O.[Na+].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH3:15][S:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3]2
Reactant: S=C1CCCc2[nH]ccc21
Reactant: O=C([O-])O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1cccc2[nH]ccc12
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
NaH (637 mg, 15.87 mmol, 60% dispersion) was added in portions to a solution of 1,5,6,7-tetrahydro-indole-4-thione (2 g, 13.23 mmol) in THF (100 mL) at −20° C. under N2 and stirred for 20 min. MeI (1.3 mL, 19.84 mmol) was added in dry THF (10 mL), and the reaction mixture stirred at −20° C. for 1 h. The reaction mixture was then poured into NaHCO3 (sat'd aq), and the crude product extracted into benzene (˜250 mL). The organic layer was washed with brine, and dried over Na2SO4. To this was added DDQ (3 g, 13.23 mmol), and the mixture stirred at RT for 1 h. The solvent was removed under vacuum, the residue taken up in CHCl3, and the insoluble solid filtered off. The solvent was removed by evaporation to dryness and the solid immobilized on silica gel. The product was purified by column chromatography (0 to 25% EtOAc/hexane) to provide 4-methylsulfanyl-1H-indole (1.2568 g, 58.2% yield).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Li+].[CH2:11](Br)[CH2:12][C@H:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:14]>C(OCC)C.C1COCC1.[Cu](Cl)Cl>[CH3:14][C@@H:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:12][CH2:11][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CC(C)=CCC[C@H](C)CCBr
Agent: Cl[Cu]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=CCC[C@H](C)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A flask was charged with 100 mL of dry THF and cooled to 0° C. To this flask was added 103 mL (205 mmol) of 2 M cyclohexylmagnesium chloride in diethylether. Then 2.30 g (17 mmol) copper (II) chloride was taken up in 60 mL of THF and added as a slurry to the Grignard reagent. To this mixture was added 0.73 g (17.1 mmol) lithium chloride, and the mixture was stirred at 0° C. for 30 minutes. Then 13.5 mL (68.4 mmol) of (S)-citronellyl bromide was added, and the mixture was stirred 2 hours at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of sat. aq. NH4Cl until bubbling ceased. The THF was removed under reduced pressure. The residue was taken up in water and extracted with diethyl ether. The combined ether layers were dried over MgSO4. The drying agent was removed by filtration. The solvent was removed under reduced pressure to yield 11.48 g (76% yield) of a clear oil. The crude long-chain alkyl was not readily characterized, and was carried on without further purification.
Reaction SMILES: [C:1]([C:5](O)=O)([F:4])([F:3])[F:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[CH:34]1([C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][C:38]=2[NH2:46])[CH2:36][CH2:35]1.C(Cl)(Cl)(Cl)[Cl:48]>>[Cl:48]/[C:5](=[N:46]\[C:38]1[CH:39]=[C:40]([N+:43]([O-:45])=[O:44])[CH:41]=[CH:42][C:37]=1[CH:34]1[CH2:36][CH2:35]1)/[C:1]([F:4])([F:3])[F:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1C1CC1
Reactant: O=C(O)C(F)(F)F
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C2CC2)c(/N=C(\Cl)C(F)(F)F)c1

Procedure:
A mixture of CF3CO2H (0.98 mL, 12.65 mmol, 0.9 eq), PPh3 (9.21 g, 35.13 mmol, 2.5 eq) and Et3N (1.96 mL, 14.05 mmol, 1.0 eq), in 25 mL CCl4 was stirred at 0° C. for 10 minutes. 2-Cyclopropyl-5-nitrobenzeneamine (2.50 g, 14.05 mmol, 1.0 eq) was then added to the reaction mixture and the mixture was heated to reflux for 12 hours. Solvent was removed under reduced pressure and the residue was purified by column chromatography, eluting with n-hexane: ethyl acetate (10:1), giving the (Z)—N-(1-chloro-2,2,2-trifluoroethylidene)-2-cyclopropyl-5-nitrobenzenamine intermediate in semi pure form as a light yellow solid. This compound was taken to the next step with out further purification.
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.[F:40][C:41]([F:56])([F:55])[C:42]([NH:44][S:45]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH2:54])[CH:49]=1)(=[O:47])=[O:46])=[O:43]>CN(C)C=O>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:54][C:50]3[CH:51]=[CH:52][CH:53]=[C:48]([S:45]([NH:44][C:42]([C:41]([F:40])([F:55])[F:56])=[O:43])(=[O:46])=[O:47])[CH:49]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: CCN(CC)CC
Reactant: Nc1cccc(S(=O)(=O)NC(=O)C(F)(F)F)c1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)Nc2cccc(S(=O)(=O)NC(=O)C(F)(F)F)c2)(C2CCCCC2)N=Cc2ccccc21
Yield: 17.7 %

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 4, using 5-cyclohexyl-1,3-dihydro-1-methyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.5 g, 1.2 mmol), triethylamine (0.16 ml, 1.2 mmol), dimethylformamide (10 ml) and 1-(trifiuoromethyl carbonylaminosulphonyl)-3-aminobenzene (0.32 g, 1.2 mmol). The product was purified by chromatography on silica gel eluting with dichloromethane-methanol (9:1). This afforded the title compound (60 mg, 9%) as a pale beige solid. mp 190° C. (dec.). 1H NMR (360 MHz, D6 -DMSO) δ 0.86-1.00 (1H, m), 1.10-1.67 (7H,m), 1.76 (1H, m), 1.89-1.98 (1H, m), 2.95 (1H, m), 3.33 (3H, s) 5.08 (1H, m), 7.28 (3H, m), 7.38 (1H, m), 7.52 ( 2H, m), 7.64 (1H, m), 7.77 (2H, m), 9.21 (1H,s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([OH:9])=O.S(Cl)([Cl:12])=O>CN(C=O)C>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCOCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCOCCCl

Procedure:
Prepared analogously to Example 90c from 3-(2-chloro-ethoxy)-propionic acid and thionyl chloride with DMF.
Reaction SMILES: ClC1N=C(N[C@H]2C3C(=C(F)C=CC=3)OCC2)C([N+:20]([O-:22])=[O:21])=CN=1.ClC1[C:32](Cl)=[CH:31][C:27]2[N:28]=[CH:29][NH:30]C=2C=1.C(=O)([O-])[O-].[K+].[K+].C(#[N:42])C>CCOC(C)=O>[N+:20]([C:32]1[CH:31]=[CH:27][N:28]=[C:29]([NH2:30])[N:42]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Reactant: CC#N
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Nc1nccc([N+](=O)[O-])n1
Temperature: 25 °C

Procedure:
A solution of (R)-2-chloro-N-(8-fluorochroman-4-yl)-5-nitropyrimidin-4-amine in acetonitrile was treated with 5,6-dichlorobenzimidazole and potassium carbonate. The mixture was stirred at reflux for 6 hours, cooled to room temperature, diluted with 150 mL of EtOAc, and washed twice with 30 mL portions of water. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (2% MeOH/DCM) gave the intermediate nitropyrimidinamine. The title compound was synthesized from the intermediate nitropyrimidinamine via the procedures described in Example 24. 1H-NMR (300 MHz, CDCl3) δ 8.7 (s, 1H), 8.3 (s, 1H), 8.2 (s, 1H), 7.8 (t, 1H), 7.0 (t, 1H), 6.6 (m, 2H), 5.9 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.0 (m, 1H), 2.3 (m, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:10][C:8]1[CH:9]=[C:4]([Br:3])[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:11][CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(Br)cc(O)c1OC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(OCc2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (60% in mineral oil, 300 mg) was added in 3 equal portions to a cooled 0° C. solution of 5-bromo-2,3-dimethoxyphenol (1.16 g) in DMF (10 mL) After 20 minutes, benzyl bromide (0.9 ml) was added, and the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was then poured into 100 mL of water and extracted with ethyl acetate (4×50 mL). The combined organic layer was then washed with water (4×75 mL) followed by brine (75 mL) and then dried over sodium sulfate and concentrated under vacuum. Chromatography on silica with 5% ethyl acetate/hexane provided 3-benzyloxy-4,5-dimethoxybromobenzene as a colorless oil (1.4 g). 1H NMR (400 MHz) (CDCl3) δ 3.87 (s, 6H), 5.12 (s, 2H), 6.75 (s, 1H), 6.80 (s, 1H), 7.34-7.47 (m, 5H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: COc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3c(Cl)cc(O)cc23)cc1
Yield: 97 %

Procedure:
This compound was prepared from 45a using 4-methoxyphenylboronic acid according to method P. Orange solid; Yield: 97%; mp 140-142° C.; 1H-NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.11 (d, J=2.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.51 (d, J=2.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.93 (s, 1H), 8.02 (dd, J=8.5, 1.7 Hz, 1H), 8.14 (dd, J=13.1, 2.1 Hz, 1H), 10.21 (s, 1H), 10.27 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.48 (dd, J=13.0, 9.7 Hz); MS (ESI) m/z 394/396 ([M−H]−), 396/398 ([M+H]+); Anal. Calcd for C22H15ClFNO3: C, 66.76; H, 3.82; N, 3.54. Found: C, 66.05; H, 4.01; N, 3.19.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:29])=[CH:26][CH:25]=1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C2c3c(C)c(NC(=O)c4ccc(F)cc4)c(C)c(C)c3OC2(C)C)cc1
Yield: 43 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 43%. Melting point: 148-120° C. (Ethyl acetate-hexane)
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:31])[C:17]2[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[C:19]([CH3:25])[C:18]=2[O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>C(O)C>[CH:27]1([O:26][C:18]2[C:19]([CH3:25])=[CH:20][C:21]([CH2:23][OH:24])=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:31])[CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)C1(NC(=O)c2cc(CO)cc(C)c2OC2CCC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CO)cc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
2-(2-Cyclobutoxy-5-hydroxymethyl-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (70 mg, 0.16 mmol) is dissolved in ethanol (1.5 mL), and solid KOH (191 mg, 3.3 mmol) and water (1504) are added. The mixture is stirred at room temperature for 30 min then concentrated in vacuo. The residue is dissolved in water (1.5 mL) and acidified with conc. HCl until no more white solid precipitated. The mixture is extracted with ethyl acetate (2×8 mL) and the combined organic layers are concentrated in vacuo to give product (286) as white solid (60 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:12][O:11][C:10](=[O:13])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:12][O:11][C:10](=[O:13])[CH2:9]2)=[O:7])=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C1CC(C(=O)c2ccc(Cl)cc2)CO1
Product: O=C1CC(C(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.37 g (15 mmol) of 4-(4-chlorobenzoyl)-tetrahydrofuran-2-one are added portion wise to 30 ml of nitric acid (100%) at -15° C. The temperature should not exceed -5° C. Stirring is continued for 30 minutes after all the compound has been added and the mixture is then poured out on 300 ml of ice water and the solid which has precipitated is separated by suction filtration and washed with water.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13](Br)(Br)([Br:15])[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:14][C:13]([Br:15])=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([CH3:10])[C:2]=1[CH3:1]
Reactant: COc1ccc(C=O)c(C)c1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C=C(Br)Br)c(C)c1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Under an N2 atmosphere, 2,3-dimethylanisaldehyde (3.0 g, 18.3 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0° C. Carbon tetrabromide (9.10 g, 27.4 mmol) was added followed by a dropwise addition of triphenylphosphine (14.4 g, 54.9 mmol) in dichloromethane (100 mL). The reaction was allowed to stir at 1.5 h at 0° C. The reaction was concentrated in vacuo, and the resulting residue was suspended in a mixture of hexanes and chloroform (4:1). The solid was removed by filtration and discarded. The filtrate was concentrated in vacuo and flash column chromatographed on silica gel eluting with 0% to 40% ethyl acetate in hexanes to yield the desired product. 1H NMR (400 MHz) (CDCl3) δ 7.44 (s, 1H); 7.19 (d, J=8.0 Hz, 1H): 6.72 (d, J=8.0 Hz, 1H), 3.82 (s, 3H); 2.17 (s, 3H); 2.16 (s, 3H).
Reaction SMILES: [C:1](=[O:7])([O:3][CH2:4][CH2:5][OH:6])[NH2:2].C1(=O)O[CH2:11][CH2:10][O:9]1.C(=O)([O-])[O-].[K+].[K+]>>[C:1](=[O:7])([O:3][CH2:4][CH2:5][OH:6])[NH2:2].[O:3]1[CH2:4][CH2:5][NH:2][C:1]1=[O:7].[OH:9][CH2:10][CH2:11][N:2]1[CH2:5][CH2:4][O:3][C:1]1=[O:7]
Reactant: O=C1OCCO1
Agent: NC(=O)OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1NCCO1
Product: O=C1OCCN1CCO

Procedure:
In a reactor 30 g of 2-hydroxyethyl carbamate (0.29 mole) are contacted with 25 g of ethylene carbonate (0.29 mole) in the presence of 0.6 g of potassium carbonate (0.0043 mole) at 150° C. for five hours. The reaction results in a conversion of 91 percent of the 2-hydroxyethyl carbamate with a selectivity to 2-oxazolidinone of 53 percent and N-(2-hydroxyethyl)-2-oxazolidinone of 18 percent.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>CO>[NH:13]([C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][N:3]=1)[NH2:14]
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cn1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-5-sulfamoylpyridine (1.0 g, 0.005 mole) was added to methanol (20 ml) and the reaction mixture was cooled to 5° C. before adding hydrazine hydrate (0.50 ml, 0.52 g, 0.01 mole). After stirring for 10 minutes at 5° C., the mixture was refluxed for 45 minutes. Additional hydrazine hydrate (1.0 ml) was added and the mixture was refluxed for approximately 12 hours. The reaction mixture was concentrated in vacuo to an oil which was slurried with 40 ml of boiling ethanol. The ethanol layer was collected by decantation and cooled in an ice bath to produce a white solid which was collected by filtration and air dried; yield, 0.69 g (73 percent).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:3]=1.[CH2:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[CH2:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:29][CH2:30][N:31]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:4]4[N:5]=[C:6]5[C:11]([CH2:10][CH2:9][C:8](=[O:12])[NH:7]5)=[C:2]([CH3:1])[CH:3]=4)[CH2:32][CH2:33]3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(OCCCC=O)nc2c1CCC(=O)N2
Reactant: c1cc2c(c(N3CCNCC3)c1)CCC2
Product: Cc1cc(OCCCCN2CCN(c3cccc4c3CCC4)CC2)nc2c1CCC(=O)N2

Procedure:
The title compound was prepared by reductive amination of 4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-indan-4-yl-piperazine according to the above procedure. MS: APCI: M+1: 435.6 (Exact Mass: 434.27).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15])=[O:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:38]([NH2:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:40])[CH3:39].Cl>CN(C=O)C.O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:47][C:38]([CH3:40])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:39])=[O:9])=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15])=[O:2]
Reactant: CC(C)(N)c1ccccc1
Reactant: COCOc1cc(C(=O)O)ccc1C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
4-Formyl-3-methoxymethoxybenzoic acid (2.57 g, 12.2 mmol) was dissolved in DMF (50 mL), and the solution was added with EDCI (4.68 g, 24.4 mmol), HOBT monohydrate (1.65 g, 12.2 mmol) and cumylamine (4.03 mL, 24.4 mmol), followed by stirring at room temperature for 4 hours. The reaction mixture was added with water (10 mL) and 1 mol/L hydrochloric acid (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20 to 70/30) to obtain 4-formyl-3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (3.12 g, yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Br:16][C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([N:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[Br:16])=[O:6]
Reactant: Brc1ccc[nH]1
Reactant: COc1cc(OC)c(C(=O)Cl)cc1OC
Product: COc1cc(OC)c(C(=O)n2cccc2Br)cc1OC
Yield: 55.1 %

Procedure:
Following the procedure for Example B, 2,4,5-trimethoxybenzoyl chloride (1.38 g, 6 mmol) and 2-bromopyrrole (4 mmol) gave 0.75 g of the title compound: mp 120-121° C.; 1H NMR (CDCl3) δ: 7.05-6.95 (2 H, m), 6.52 (1 H, s), 6.35 (1 H, dd, J=3.3, 1.8), 6.18 (1 H, t, J=3.5), 3.96 (3 H, s), 3.86 (3 H, s), 3.76 (3 H, s).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:16][CH:17]=1>>[O:4]=[C:2]([CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Product: CCOC(=O)C(=O)C(C(=O)OCC)c1cccc(Cl)c1

Procedure:
This compound is prepared according to the method of Klioze and Ehrgott (U.S. Pat. No. 4,216,218) from diethyl oxalate and ethyl (3-chlorophenyl)acetate.