Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].O>CN1CCCC1=O>[NH:18]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:19]
Reactant: NN
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCOCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: NNc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5 g of 4-fluorobenzenesulfonic acid morpholide were dissolved in 15 ml of N-methylpyrrolidone and mixed with 2.5 g of hydrazine hydrate, and the mixture was heated at 100° C. for 1 hour. After cooling to room temperature, 75 ml of water were added and the mixture was stirred at room temperature. After 2 hours, the solid was filtered off with suction and recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCNC2)C(=O)O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(Cc3ccccc3)C2)C(=O)O1
Temperature: 80 °C
Yield: 13.2 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (530 mg, 1.67 mmol) in DMF (10 mL) was added benzyl bromide (573 mg, 3.35 mmol) and K2CO3 (924 mg, 6.7 mmol), and the mixture was heated to 80° C. for 5 hours. The reaction was quenched by H2O. The layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-benzylpiperidin-3-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (90 mg, 13%).
Reaction SMILES: C(OC(C[NH:7][C:8](=[O:27])[NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[CH3:21])=O)C.[H-].[Na+].[C:30](OCC)(=[O:32])[CH3:31].Cl>O1CCCC1.O>[O:27]=[C:8]1[NH:7][C:30](=[O:32])[CH2:31][N:9]1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CNC(=O)Nc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=C1C(=O)Nc2ccc(N3CC(=O)NC3=O)cc21)c1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 5-(N′-(ethoxycarbonylmethyl)ureido)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (95 mg, 0.25 mmol) in tetrahydrofuran (2.5 mL) was treated with NaH (16 mg, 0.40 mmol). After stirring overnight, ethyl acetate (15 mL) and water (5 mL) were added and the reaction mixture was neutralized with 6N HCl. The organic layer dried (NaSO4) and concentrated to afford a crude product (90 mg). Purification by reverse phase HPLC (acetonitrile/water) afforded 5-(2,4-dioxoimidazolidin-1-yl)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (8 mg); 1H NMR (400 MHz, DMSO-d6) δ 2.72 (s, 3H), 4.02 (s, 2H), 6.36 (m, 1H), 6.96 (d, 1H), 7.04 (m, 2H), 7.36 (d, 1H), 7.60 (m, 1H), 8.22 (s, 1H), 11.14 (s, 1H) ppm.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([C:11]1[CH:77]=[CH:76][CH:75]=[CH:74][C:12]=1[CH2:13][O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C@@H:21]([NH:66]C(OC(C)(C)C)=O)[C:22]([O:24][C@H:25]1[C@@H:29]([OH:30])[C@H:28]([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][C:36]=3[NH2:40])[O:27][C@H:26]1[CH2:41][O:42][P:43]([O:46][C@H:47]1[CH2:51][C@H:50]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:49][C@@H:48]1[CH2:60][O:61][P:62]([OH:65])([OH:64])=[O:63])([OH:45])=[O:44])=[O:23])=[O:16])=[N+:9]=[N-:10]>ClCCl>[NH2:66][C@H:21]([CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][CH2:13][C:12]1[CH:74]=[CH:75][CH:76]=[CH:77][C:11]=1[N:8]=[N+:9]=[N-:10])=[O:16])[C:22]([O:24][C@H:25]1[C@@H:29]([OH:30])[C@H:28]([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][C:36]=3[NH2:40])[O:27][C@H:26]1[CH2:41][O:42][P:43]([O:46][C@H:47]1[CH2:51][C@H:50]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:49][C@@H:48]1[CH2:60][O:61][P:62]([OH:65])([OH:64])=[O:63])([OH:45])=[O:44])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccccc1COC(=O)NCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.45 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,35,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk63) (51 mg, 0.050 mmol) in dichloromethane (0.45 mL), and the mixture was stirred at room temperature for 45 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-((((2-azidobenzyl)oxy)carbonyl)amino)pentanoate (Orn(oAcbz)-pdCpA) (Compound tk64) (42.6 mg, 93%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].[NH:25]1[CH2:30][CH2:29][CH:28](CN2C3C(=CC=CC=3)C3(C4=CC5OCOC=5C=C4OC3)C2=O)[CH2:27][CH2:26]1.BrC1C=CC=CN=1.BrC1C=CC=CC=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24]
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Brc1ccccn1
Solvent: Brc1ccccc1
Product: O=C1N(CCNc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.87, and making non-critical variations using 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-bromopyridine to replace 2-bromobenzene, 1′-(2-(pyridin-2-ylamino)ethyl)-spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained as the first fraction from the chromatography as a white solid (5%): mp 61-63° C.; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, 1H), 7.50-6.97 (m, 5H), 6.57 (dd, 1H), 6.50 (s, 1H), 6.38 (d, 1H), 6.03 (s, 1H), 5.85 (s, 1H), 5.84 (s, 1H), 4.84 (d, 1H), 4.79 (t, 1H), 4.60 (d, 1H), 4.15-3.94 (m, 2H), 3.81-3.64 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.4, 158.2, 156.0, 149.0, 148.0, 142.4, 142.38, 137.4, 132.3, 129.1, 124.0, 123.5, 119.5, 113.3, 109.0, 108.3, 103.2, 101.6, 93.7, 80.5, 58.3, 40.1, 39.9; MS (ES+) m/z 402 (M+1). 1′-(2-(dipyridin-2-ylamino)ethyl)-spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained as the second fraction from the chromatography (31%): mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.31 (dd, 2H), 7.48 (d, 2H), 7.23 (t, 1H), 7.09-6.83 (m, 7H), 6.47 (s, 1H), 5.95 (s, 1H), 5.88-5.81 (m, 2H), 4.73 (d, 1H), 4.67-4.49 (m, 2H), 4.46 (d, 1H), 4.20 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 177.6, 157.0, 156.0, 148.8, 148.4, 143.1, 142.3, 137.4, 132.3, 128.9, 123.6, 123.1, 119.6, 117.5, 114.5, 109.3, 103.4, 101.6, 93.6, 80.7, 58.2, 45.9, 39.5; MS (ES+) m/z 479 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16]([C:18]1[N:19]=[C:20]([C:37]#[N:38])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:22]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:16]([C:18]1[N:19]=[C:20]([C:37]#[N:38])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:22]=2)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O)C1CC1
Temperature: 150 °C
Yield: 45.9 %

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (20 mg), 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (15 mg) and DBU (10 mg) in DMA (0.3 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (10 mg). LC-MS ESI+: 492 (M+1)+.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][C:9]([OH:12])([CH3:11])[CH3:10].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([NH:20][S:2]([NH:5][C:6]([O:12][C:9]([CH3:11])([CH3:10])[CH3:8])=[O:7])(=[O:4])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NCc1ccccc1
Reactant: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chlorosulfonylisocyanate (14.14 g) was dissolved in DCM (50 mL) and cooled to 0° C. A solution of t-BuOH (9.6 mL) in DCM (50 mL) was added within 30 min. Stirring was continued for additional 30 min at rt. The solution thus obtained was then added at 0° C. within 1 h to a solution of benzylamine (10.7 g) and TEA (15.32 mL) in DCM (200 mL). Stirring is continued for 10 h at rt. The mixture was concentrated in vacuo, taken up in EA (500 mL) and washed with water (2×40 mL) and brine (30 mL), dried over MgSO4, filtered. The filtrate was concentrated in vacuo and the crude material was crystallized from EA and dried under HV to give N-benzyl-N′-tert-butoxycarbonyl sulfamide (13.68 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18]O)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Br:27]P(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][Br:27])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CO)cc2C1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CBr)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of 0.380 mmol of tert-butyl-7-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 2.5 ml CH2Cl2 were added at 0° C. 1.139 mmol Et3N and 0.456 mmol tribromophosphine. The mixture was allowed to warm to room temperature and stirred for 1 h. To the reaction mixture were added saturated NaHCO3 solution and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed, dried over MgSO4 and filtered. Evaporation of the solvent gave 105 mg of crude material that was purified by flash chromatography to yield 76 mg of colorless oil (61.3%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][O-:12].[Na+].CO>CO.O>[NH2:1][C:2]1[N:3]=[C:4]([O:12][CH3:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(N)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(N)cnc1C#N
Temperature: 80 °C
Yield: 58 %

Procedure:
5-Amino-3-chloropyrazine-2-carbonitrile (52 mg, 0.34 mmol) was suspended in NaOMe/MeOH (2M, 2 mL). The reaction mixture was heated at 80° C. for 30 min using microwave irradiation. After cooling, the mixture was diluted with MeOH (3 mL) and water (2 mL). The solvents were concentrated and the resulting precipitate was filtered off, washed with water (3 mL) and dried in vacuo to give the title compound as a yellow solid (33 mg, 58%).
Reaction SMILES: CC1C2N=C(C3C=NC(OCCCC4CCN(C)CC4)=CC=3)NC=2C=CC=1.[CH3:28][C:29]1[CH:34]=[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)[N:32]=[CH:31][C:30]=1[CH:46]=O.[Cl:48][C:49]1[CH:54]=[C:53]([NH2:55])[C:52]([NH2:56])=[C:51]([CH3:57])[CH:50]=1>>[Cl:48][C:49]1[CH:50]=[C:51]([CH3:57])[C:52]2[N:56]=[C:46]([C:30]3[CH:31]=[N:32][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[CH:34][C:29]=3[CH3:28])[NH:55][C:53]=2[CH:54]=1
Reactant: Cc1cc(OCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1cc(Cl)cc(N)c1N
Agent: Cc1cccc2[nH]c(-c3ccc(OCCCC4CCN(C)CC4)nc3)nc12
Product: Cc1cc(OCCCC2CCN(C)CC2)ncc1-c1nc2c(C)cc(Cl)cc2[nH]1
Yield: 29.7 %

Procedure:
4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole. This compound was prepared by the method described in General Procedure 3 using 4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde (60 mg, 0.22 mmol, 1.0 equiv), 5-chloro-3-methyl-benzene-1,2-diamine (34 mg, 0.22 mmol, 1.0 equiv) and Na2S2O5 (54 mg, 0.29 mmol, 1.3 equiv). Purification by Method 2 afforded 27 mg (30%) of the title compound. MS (electrospray): mass calculated for C23H29ClN4O, 412.20. m/z found, 413.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.77 (s, 1H), 8.23 (dd, J=8.7, 2.3 Hz, 1H), 7.25 (m, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.04-6.98 (m, 1H), 6.74 (d, J=8.7 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.84-2.76 (m, 2H), 2.73-2.34 (br s, 3H), 2.23 (s, 3H), 1.92-1.83 (m, 2H), 1.81-1.62 (m, 4H), 1.39-1.17 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([O-:10])=[O:9])=O.[CH2:14](N)CCC.[N+:19]([CH3:22])([O-:21])=[O:20].O>C(O)(=O)C>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:22][N+:19]([O-:21])=[O:20])=[CH:11][C:7]=1[C:8]([O:10][CH3:14])=[O:9]
Reactant: CCCCN
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1C(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C=C[N+](=O)[O-])ccc1OC
Temperature: 22 °C

Procedure:
To a solution of 1.01 g (6.09 mmol) of 5-formyl-2-hydroxybenzoic acid in 25 mL of acetone was added 4.25 g (30.5 mmol) of potassium carbonate and 1.15 mL (18.3 mmol) of iodomethane. The mixture was heated to reflux for about 16 h, cooled to 22° C. and filtered. The collected solid was washed with acetone. The filtrates were combined, evaporated and the residue purified by flash chromatography on silica gel eluting with a mixture of hexane and ethyl acetate to give methyl 5-formyl-2-methoxybenzoate as an off-white solid. To a solution of 0.609 g (3.66 mmol) of 5-formyl-2-methoxybenzoate in 10 mL of acetic acid at 22° C. was added 2.2 mL (22 mmol) of n-butylamine followed by 0.337 mL (5.50 mmol) of nitromethane. The mixture was heated to reflux for 3 h, cooled to 22° C. and poured into 250 mL of water. A yellow precipitate resulted which dissolved when the mixture was extracted with 200 mL of ethyl acetate. The organic layer was washed with saturated NaHCO3 (2×100 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel eluting with a mixture of hexane and ethyl acetate to give methyl 2-methoxy-5-(2-nitrovinyl)benzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S@:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:2]=1.[BH4-].[Na+].O.C(OCC)(=O)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][S@:12]2=[O:13])[CH:2]=1
Reactant: O=[S@@]1CCCC=C1c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=[S@@]1CCCC[C@@H]1c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
A stirred solution of (R)-6-(3-pyridyl)-3,4-dihydro-2H-thiopyran 1-oxide (22.43 g;88.2%ee) in ethanol (227 ml) is treated, portionwise, with sodium borohydride powder (3.52 g) under nitrogen at room temperature, and the mixture is stirred for 2.5 hours. It is then treated with a further quantity of sodium borohydride (0.43 g), and the mixture is stirred for a further period of 15 minutes. The mixture is treated with water (454 ml) and extracted with dichloromethane (2×340 ml). The combined extracts are washed with water 340 ml), dried over magnesium sulphate and the solvent is removed by evaporation under reduced pressure, to give an oily paste (18.1 g). This paste is treated with ethyl acetate (72 ml) and the mixture is heated at reflux, with stirring. The solution is allowed to cool to room temperature, and stirred for 3 hours. The resulting suspension is cooled to 0° C. for 1 hour, and then filtered. The pale yellow solid is washed with a little cold ethyl acetate and sucked dry using vacuum filtration, to give (1R,2R)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1 -oxide (8.03 g;99.7%ee), m.p. 124.5°-126.50° C. [Elemental analysis:- C,61.2;H,6.67; N,7.1 ;S,16.7%. Calculated:- C,61.51 ;H,6.71 ;N,7.17; S,16.42%. NMR (CDCl3):- 1.6(m,1H), 8(m,2H),2.0(m,1H),2.4(m,1H),2.7(m,2H),3.2(m,1H), 3.5(dd,1H),7.3(m,1H),7.7(dt,1H),8.6(m,2H)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:52]1[C:57](=[O:58])[CH2:56][NH:55][CH2:54][C:53]1=[O:59]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:28])([F:29])[F:30])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:55]4[CH2:56][C:57](=[O:58])[NH:52][C:53](=[O:59])[CH2:54]4)=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: O=C1CNCC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)NC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (452 mg, 1.00 mmol, 1.00 equiv), dichloromethane (50 mL), TEA (202 mg, 2.00 mmol, 2.00 equiv), EDCI (384 mg, 2.00 mmol, 2.00 equiv), HOBt (270 mg, 2.00 mmol, 2.00 equiv). The mixture was stirred for 0.5 h at room temperature. This was followed by the addition of piperazine-2,6-dione (125 mg, 1.10 mmol, 1.10 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of DCM. The resulting mixture was washed with 3×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 210 mg (38%) of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]piperazine-2,6-dione as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([OH:30])[CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:26][NH:25][C:23](=[O:24])[C:22]3[CH:21]=[C:20]([OH:19])[CH:29]=[C:28]([OH:30])[CH:27]=3)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Reactant: NNC(=O)c1cc(O)cc(O)c1
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=C(C)NNC(=O)c1cc(O)cc(O)c1

Procedure:
From 1-(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 3,5-dihydroxybenzoic hydrazide, 57.0 mg of the desired product was obtained in the same manner as in Synthetic Example 1 as a pale red solid (yield 73%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Product: Cl
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
To a suspension of trans-4-hydroxy-L-proline (100 g, 0.76 mol, 1 equivalent) in methanol (850 mL), thionyl chloride (110 mL, 1.53 mol, 2 equivalents) was added drop-wise at 0-5° C. Then the reaction mixture was stirred for 4 hours at 20-25° C. The reaction mixture was concentrated under reduced pressure. The crude material was stirred in a mixture of ethanol-methyl tert-butyl ether (1:4, 500 mL) for 30 minutes and the solid was collected by filtration. The wet cake was dried in a vacuum tray dryer for 8 hours at about 50° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.09-2.24 (m, 2H), 3.07 (d, 1H, J=12.3 Hz), 3.35 (dd, 2H, J=4.2 Hz, J=11.7 Hz), 3.76 (s, 3H), 4.42-4.51 (m, 2H), 5.59 (bs, 1H), 9.3 (bs, 1H), 10.3 (bs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-])=O.[CH2:16]=[CH:17][CH:18]=[CH2:19]>[Pd].COCCO>[NH2:1][C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Agent: [Pd]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
122 Grams of 5-nitro-1,4-naphthoquinone which contained 10% of the 6-nitro compound, 2800 grams of methyl cellosolve and 48 grams of 1,3-butadiene were charged into an autoclave and reacted at 90° C. for 2 hours. The reaction solution was allowed to stand for cooling and 1.2 grams of a 5% palladium on carbon catalyst was added thereto. Thereafter, the procedure of Example 4 was repeated to obtain 104 grams of 1-aminoanthraquinone containing therein 7% of 2-aminoanthraquinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:19]1[C:15](=[O:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18]1=[O:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 114.5 %

Procedure:
Commercially available (S)-(−)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (1.00 g, 4.97 mmol) was dissolved in toluene (10 mL), and the mixture was stirred at room temperature for 1.5 hours after adding phthalimide (877 mg, 5.96 mmol), triphenylphosphine (1.96 g, 7.46 mmol), and diethyl azodicarboxylate (40% toluene solution, 3.4 mL, 7.46 mmol). The mixture was further stirred at 60° C. for 4 hours. Thereafter, water and ethyl acetate were added to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give (S)-2-[(1,3-dioxoisoindolin-2-yl)methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.88 g, quantitative).