Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1(C(=O)OCC)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1

Procedure:
12.1 grams of ethyl 1-n-hexyl-2-hydroxy-cyclopentane carboxylate obtained in Example 17 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 18.16 g of yellow liquid. MS: 346(M+′), 345(M+−1), 301 (M+—OCH2CH3), 273(M+—CO2CH2CH3), 262, 241 (M+−C6H5CO), 225(M+—C6H5CO2), 195, 185, 151, 140, 105 (base), 77.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([N:16]1[C:25](=[O:26])[C:24]2[NH:23][C:22]([C:27]3[N:31]([CH3:32])[N:30]=[C:29]([O:33][CH2:34][C:35](O)=[O:36])[CH:28]=3)=[N:21][C:20]=2[N:19]([CH2:38][CH2:39][CH3:40])[C:17]1=[O:18])[CH2:14][CH3:15]>>[CH3:40][CH2:39][CH2:38][N:19]1[C:17](=[O:18])[N:16]([CH2:13][CH2:14][CH3:15])[C:25](=[O:26])[C:24]2[C:20]1=[N:21][C:22]([N:23]=2)=[C:27]1[N:31]([CH3:32])[NH:30][C:29]([O:33][CH2:34][C:35]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[O:36])=[CH:28]1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)N3CCN(c4ccccc4)CC3)NN1C)N=2

Procedure:
Using N-phenyl-piperazine and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1>O1CCCC1.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([NH:2][OH:3])=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1
Reactant: NO
Reactant: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.18 g, 2.5 mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO3 (0.30 g, 3.5 mmol) in water (5 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a solution of (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in tetrahydrofuran (5 mL) and the obtained mixture was stirred at ambient temperature for 0.5 hours. The mixture was poured into water (25 mL), extracted with ethyl acetate, the extract was washed with water, brine, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform—isopropanol (9:1) as eluent to give the title compound (0.087 g, 34%). M.p. 125-126° C. 1H NMR (DMSO-de, HMDSO), δ: 2.26-2.42 (4H, m); 2.81-3.00 (4H, m); 4.39 (1H, s); 6.64 (1H, d, J=15.8 Hz); 7.07 (4H, t, J=8.6 Hz); 7.37 (4H, dd, J8.4 and 5.6 Hz); 7.57 (1H, d, J=15.8 Hz); 7.74 (2H, d, J=8.0 Hz); 7.83 (2H, d, J=8.0 Hz); 9.19 (1H, s); 10.93 (1H, s). HPLC analysis on Alltima C18 column: impurities 2% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 70:30; sample concentration 1.0 mg/ml; flow rate 1.0 ml/min; detector: UV 215 nm). Anal. Calcd for C26H25F2N3O4S*0.3 Et20*0.2 iso-PrOH*0.1 CHCl3 (an exhaustively dried material contains all the indicated traces of solvents (PMR)), %: C, 59.87; H, 5.35; N, 7.51; S, 5.73. Found, %: C, 59.85; H, 5.36; N, 7.29; S, 5.60.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][N:3]=1
Reactant: Cc1ccc(C#C[Si](C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C)nc1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A mixture of 654 mg (3.45 mmol) of 2-methyl-5-trimethylsilanylethynyl-pyridine and 8 mL of 1 M TBAF in THF was stirred for 2 h. The mixture was concentrated and chromatographed (10-50% EtOAc in hexanes) to provide 301 mg of 2-methyl-5-ethynyl pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C1COCC1>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([B:24]([OH:29])[OH:25])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(B(O)O)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirring solution of 4-(triisopropyl)silyloxy-1-bromobenzene (6) (540 mg, 1.64 mmol) in THF (15 ml) at −78° C. was added n-butyl lithium (0.9 ml, 2.18 M in hexanes, 1.96 mmol) dropwise. The reaction mixture was stirred for 30 minutes then triisopropyl borate (0.5 ml, 2.17 mmol) was added in one portion. The reaction was stirred at −78° C. for 1 hour, allowed to warm to ambient temperature over 4 hours, quenched with 3 N HCl (5 ml) and stirred for 30 minutes at 0° C. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were dried over MgSO4. Purification by flash SiO2 chromatography (loaded with DCM, eluted with hexanes/ethyl acetate (10:1) to (3:1) to (1:1)) gave 7 as a white solid (328 mg, 68% yield): 1H-NMR (400 MHz, chloroform-d) δ 8.10 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 1.30 (septet, J=7.6 Hz, 3H), 1.13 (d, J=7.6 Hz, 18H); 13C-NMR (100 MHz, chloroform-d) δ 160.1, 137.4, 119.6, 17.9, 12.7.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
(5R)-5-(Azidomethyl)-3-(4-Iodophenyl)-1,3-oxazolidin-2-one (8.0 g, 23.2 mmol) was dissolved in acetonitrile (160 ml) and water (16 ml). Triphenylphosphine (7.3 g, 27.9 mmol) was added and the mixture stirred at room temperature overnight. The volatiles were removed by concentration in vacuo, and the resulting residue partitioned between water (200 ml) and dichloromethane (200 ml). The aqueous layer was extracted with dichloromethane (2×200 ml) and dried over sodium sulfate. The crude material was purified by flash chromatography on silica gel with 0-10% methanol in dichloromethane as the eluent giving the desired product (6.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[F:22])[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[F:22])[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1F
Reactant: Ic1ccc(I)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared from rac-[(4-chloro-2-fluoro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 3) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISP): 489.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[C:7]([CH3:21])=[N:8][C:9]2[N:10]([N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=2)[C:11]=1O)[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:11]1[N:10]2[N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=[C:9]2[N:8]=[C:7]([CH3:21])[C:6]=1[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1O
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
A mixture of ethyl 6-(2-ethoxy-2-oxoethyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (25 g, 81 mmol), and N,N-dimethylaniline (20.6 mL, 163 mmol) in POCl3 (100 mL) was heated at 120° C. for 3 h. Then the reaction was cooled to rt and concentrated in vacuo to half the volume. It was poured into a large quantity of ice water and stirred for 20 min. Precipitates formed and were collected by filtration. This solid was dissolved in ethyl acetate (1 L) and washed with water. The aqueous phase was back-extracted with ethyl acetate and the combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude was then triturated with EtOAc/hexane to afford ethyl 7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (22 g, 67.5 mmol, 83% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.21 (s, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.94 (s, 2H), 2.66 (s, 3H), 1.48 (t, J=7.0 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H). LCMS (M+1)=326.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[C:6]=1[CH2:21][Br:22])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n([C@H](C)c2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n([C@H](C)c2ccccc2)c1CBr
Yield: 85.4 %

Procedure:
A mixture of (R)-5-bromo-2-methyl-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (3.32 g, 9.5 mmol), N-bromosuccinimide (1.86 g, 10.4 mmol), and benzoyl peroxide (0.23 g, 0.95 mmol) in CCl4 (100 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-25% EtOAc/hexanes) to give 3.48 g of the title compound as a white solid. MS: (+) m/z 452.06 (M+Na).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1>O1CCOCC1>[ClH:1].[CH3:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1(C)CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
4M HCl in dioxane (25 mL) was added to 1-tert-butyl 4-methyl 4-methylpiperidine-1,4-dicarboxylate (5.28 g, 20.55 mmol) at ambient temperature. The reaction mixture was allowed to stir at ambient temperature for 5 hrs. The solvent was removed under reduced pressure and ether was added to the residue and the suspension was filtered and dried to give the title compound as a white solid (3.82 g, 19.72 mmol, 96%); 1H NMR δ 1.12 (s, 3H), 1.53-1.60 (m, 2H), 1.99-2.04 (m, 2H), 2.76-2.82 (m, 2H), 3.07-3.12 (m, 2H), 3.61 (s, 3H), 8.72 (s, 1H); MS m/e MH+-157
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6](=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)[CH3:3].[Cl:27][C:28]1[N:33]=[C:32](Cl)[C:31]([I:35])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:27][C:28]1[N:33]=[C:32]([NH:1][C@H:2]([C:4]2[N:5]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:6](=[O:20])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[CH3:3])[C:31]([I:35])=[CH:30][N:29]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[C@H](N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(S)-3-(1-Aminoethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (63) (570 mg, 1.66 mmol), 2,4-dichloro-5-iodopyrimidine (455 mg, 1.66 mmol) and DIEA (0.27 mL, 1.66 mmol) were dissolved in n-butanol (12 mL) in a sealed tube, and the resulting mixture was stirred at 100° C. for 16 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate (150 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (64) as an oil. The product obtained was used in the next step without purification. ESI-MS m/z: 583.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][N:23]=1)=[O:20].C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1[C:6]2[CH2:7][N:8]([C:28]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:17]=4[CH3:16])=[N:23][CH:24]=3)=[O:29])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)cn1

Procedure:
As described for Example 46, 10,11-dihydrodibenz[b,f][1,4]oxazepine is reacted in dichloromethane with 2-[(2-methyl-5-fluorobenzoyl)amino]-5-pyridinylcarbonyl chloride in the presence of N,N-diisopropylethylamine to give the product as crystals. m.p. 180° C.-186° C.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20]>O1CCCC1>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:19](=[O:20])[O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To an ice cooled solution, under argon, of 7.3 g of p-nitrophenol and 7.5 ml of triethylamine in 36 ml of dry tetrahydrofuran, is added, dropwise, a solution of 10.78 g of p-nitrobenzyl chloroformate in 18 ml of dry tetrahydrofuran. The reaction mixture, a suspension, is stirred at room temperature overnight. The formed solid is collected, washed with water and dried to give 5.9 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:46])[CH2:42][CH2:43][NH:44][CH3:45]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]([CH2:43][CH2:42][N:41]([CH3:46])[CH3:40])[CH3:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: CNCCN(C)C
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 25.6 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (40 mg, 0.073 mmol) in THF (3 mL) and DMF (0.5 mL) were added N,N,N′-trimethyl-1,2-ethanediamine (0.047 mL, 0.364 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (11 mg, 26%). LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) δ 2.18 (s, 6H), 2.40 (m, 5H), 3.02 (m, 3H), 3.50 (m, 2H), 4.17 (s, 2H), 7.15 (m, 4H), 7.52 (m, 2H), 7.71 (m, 2H), 7.82 (s, 1H), 7.97 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:28])([CH3:27])[CH2:9][N:10]2[CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:6][CH:5]=1)([O-])=O>CO>[CH3:27][C:8]1([CH3:28])[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:10]([CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Solvent: CO
Product: CC1(C)CN(CC2CCNCC2)c2cc(N)ccc21
Reaction time: 8 h

Procedure:
tert-Butyl 4-[(6-nitro-3,3-dimethylindolinyl)-methyl]piperidinecarboxylate (900 mg) was dissolved in 10 mL MeOH, the mixture was bubbled with H2 for 10 min. 10% Pd/C (30 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 Hexane:EtOAc to afford a colorless oil. MS: 360 (M+1). Calc'd. for C21H33N3O2—359.5.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)(=[O:3])[CH3:2].C[OH:25]>O>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[NH:6][C:5]=1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:23])=[O:25])=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CSc1ccc(-c2[nH]c(-c3ccncc3)c(C)c2C(C)=O)cc1
Solvent: O
Product: CC(=O)c1c(-c2ccc(S(C)=O)cc2)[nH]c(-c2ccncc2)c1C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-acetyl-4-methyl-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-pyrrole (0.24 g, 0.74 mmol) in methanol (8 mL) was added a solution of NaIO4 (0.6 g) in water (16 mL) at room temperature. After stirring for 15 hours, the precipitates were collected by filtration. The filtrate was extracted with CH2Cl2—EtOH (10:1, 50 mL×2), dried over MgSO4, and concentrated ini vacuo. The solids were purified by flash chromatography eluting with CH2Cl2—EtOH (10:1) to provide the title compound (0.24 g, quantitative yield).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[C:14]([N:26]2[C:30]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:29][N:28]=[C:27]2[CH2:37][O:38][CH3:39])=[C:15]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17](=[O:25])[NH:16]2>CC(C)=O>[Cl:12][C:13]1[C:14]([N:26]2[C:30]([C:31]3[CH:32]=[N+:33]([O-:6])[CH:34]=[CH:35][CH:36]=3)=[N:29][N:28]=[C:27]2[CH2:37][O:38][CH3:39])=[C:15]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17](=[O:25])[NH:16]2
Reactant: COCc1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: COCc1nnc(-c2ccc[n+]([O-])c2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 16.4 %

Procedure:
A solution of 3-chloroperoxybenzoic acid (0.85 g, 4.93 mmol) in acetone (20 ml) was added in one portion to a suspension of (−)-6,7-dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione (see Example 111) (1.0 g, 2.24 mmol) in acetone (40 ml) which caused all the solid to dissolve. The reaction was stirred at room temperature for 40 minutes after which time a white solid began to form. The reaction mixture was allowed to stir at room temperature for 3 days. The white solid was collected by filtration and purified by flash chromatography on silica gel using dichloromethane:methanol:glacial acetic acid (90:10:1, by volume) as eluent, to give after combination and concentration of the appropriate fractions, the title compound (0.16 g, 17%) as a white solid, m.p. >310° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:29])[NH:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2)c1
Yield: 42.6 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with tert-butyl 2-(2-amino-N-phenylacetamido)acetate (1.25 g) and 3-methylphenyl isocyanate (0.63 g), and after recrystallization in acetonitrile, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (0.8 g), m.p. 180° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11]C(=O)[C@H:9]2[C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.Cl>ClC1C=CC=CC=1Cl>[ClH:1].[NH2:11][CH2:12][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:14]([OH:16])=[O:15]
Reactant: COC(=O)[C@@H]1C(=O)NC[C@H]1c1ccc(Cl)cc1
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 162.4 %

Procedure:
Under a nitrogen atmosphere, methyl (3S,4R)-4-(4-chlorophenyl)-2-oxopyrrolidine-3-carboxylate (5.00 g, 19.7 mmol) was suspended in 1,2-dichlorobenzene (25 ml), and the suspension was dropped over a period of about 3 hours into 6 mol/L hydrochloric acid (20 g) heated up to 100° C. The mixture was reacted for 10 hours, then, cooled to 80° C., and the organic layer was separated by a liquid-separation operation. The aqueous layer was concentrated under reduced pressure, acetonitrile (15 ml) was added, and the mixture was concentrated again, then, acetonitrile (30 ml) was added, and the mixture was stirred at room temperature for 1 hour. The crystal was filtrated and washed with acetonitrile (5 ml) to obtain 4.00 g (16.0 mmol) of a title compound (yield: 81%). The spectrum data corresponded to the value in Example 4. The optical purity of the resultant title compound was measured by HPLC to find a value of 99.9% ee.
Reaction SMILES: [N:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:13][N:14]=[C:15]=[O:16]>C1C=CC=CC=1>[N:10]1[CH:11]=[CH:12][C:7]([N:6]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[C:15]([NH:14][CH3:13])=[O:16])=[CH:8][CH:9]=1
Reactant: c1ccn(Nc2ccncc2)c1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N(c1ccncc1)n1cccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution containing 4 g of N-(1H-pyrrol-1-yl)-4-pyridinamine and 1.6 g of methyl isocyanate in 125 ml of benzene was stirred at 50° C. for two hours, and thereafter cooled and evaporated to 6 g of a solid. This material was purified by HPLC (silica gel, 50% ethyl acetate in dichloromethane) to give 5 g of a solid, mp 156°-160° C. This material was recrystallized twice from benzene to give 2.6 g of crystals, mp 162°-163° C.