Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:23]([O:25][CH3:26])=[O:24])[C:11]3[NH:12][C:13]4[CH:14]=[C:15]([CH:21]=O)[CH:16]=[CH:17][C:18]=4[C:19]=3[N:20]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C.C(Cl)Cl>[C:27]([N:31]1[CH2:36][CH2:35][N:34]([CH2:21][C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[N:20]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)[CH:9]=[C:10]([C:23]([O:25][CH3:26])=[O:24])[C:11]=4[NH:12][C:13]=3[CH:14]=2)[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N1CCNCC1
Reactant: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1cc(C=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1cc(CN3CCN(C(C)(C)C)CC3)ccc12
Reaction time: 0.08 h
Yield: 41.8 %

Procedure:
A suspension of methyl 2-(3-chlorophenyl)-7-formyl-5H-pyrido[3,2-b]indole-4-carboxylate (80 mg, 0.22 mmol) in DMF (1 mL) was stirred for 5 min and then diluted with DCM (10 mL). 1-tert-butylpiperazine (38 mg, 0.26 mmol) was added and the suspension was cooled in an ice bath. Sodium triacetoxyborohydride (125 mg, 0.592 mmol) was added and the suspension was left stirring for 0.5 hr. Acetic acid (0.025 mL, 0.44 mmol) was then added and the bath removed. The reaction was left stirring at RT overnight, diluted with DCM, and washed with sat. aq. NaHCO3 solution followed by water (2×). After drying with sodium sulfate, the solvent was removed and radial chromatography (step gradient elution with DCM containing 0 to 3% MeOH) afforded methyl 7-((4-tert-butylpiperazin-1-yl)methyl)-2-(3-chlorophenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (45 mg, 0.092 mmol, 42% yield) as a yellow solid. MS (ESI) m/z 491.19 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.49 (1H, s), 8.36 (1H, d, J=7.94 Hz), 8.24 (1H, s), 8.20 (1H, s), 8.04 (1H, d, J=7.63 Hz), 7.53 (1H, t, J=7.78 Hz), 7.35-7.39 (1H, m), 7.33 (1H, d, J=7.93 Hz), 4.09 (3H, s), 3.70 (2H, s), 2.63 (8H, br. s.), 1.07 (9H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([CH2:15][CH2:16]C)[C:7]=1O.[OH:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].[C:31](=[O:34])([O-])[O-].[K+].[K+]>>[CH2:26]([O:25][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][CH:30]=[C:20]([O:19][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:31]([OH:34])[C:7]=2[CH2:8][CH2:15][CH3:16])[CH:21]=1)[CH3:27]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CCCc1c(C(C)=O)ccc(OCCCBr)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1c(OCCCOc2cccc(C(=O)OCC)c2)ccc(C(C)=O)c1O
Yield: 84 %

Procedure:
A mixture of 1.5 g of 1-[4-(3-bromopropoxy)-3-hydroxy-2-propylphenyl]ethanone, 0.79 g of ethyl 3-hydroxybenzoate and 1.0 g of potassium carbonate was allowed to react according to Example 79 to give 1.6 g (83% yield) of 3-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzoic acid ethyl ester, the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12]C)=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+]([O-])=O.C[CH2:18][O:19]C(C)=O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][O:19][CH3:18]
Reactant: CCOC(C)=O
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Product: COCCOc1cc(C=O)ccc1O
Yield: 97 %

Procedure:
Followed the procedure described in Step 3 of Intermediate 65, where the reaction was refluxed for 2 days. Isolated 900 mg, yield 97% after column chromatography (PE:EtOAc=10:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](O)=[O:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH2:27][CH2:28][C:29](=[O:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([NH:27][CH2:28][C:29](=[O:31])[CH3:30])=[O:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)CN
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(=O)O)(c2ccccc2)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)CNC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (200 mg, 0.5 mmol) in anhydrous CH2Cl2 (10 mL) was added 1-aminopropan-2-one (119 mg, 0.7 mmol), HOBt (195 mg, 1.44 mmol), EDCl (283 mg, 1.44 mmol) and DIEA (620 mg, 4.8 mol) at 0° C. The formed mixture was stirred overnight at ambient temperature under nitrogen. Then the reaction mixture was washed with 1N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by prep TLC to give 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-N-(2-oxopropyl)acetamide (118 mg, 50%). 1H NMR (400 MHz, CDCl3): δ=1.43 (d, 3H), 2.06 (s, 3H), 2.20 (m, 1H), 2.43 (m, 2H), 2.68 (m, 1H), 2.86 (m, 2H), 3.90 (m, 1H), 4.12 (m, 1H), 5.51 (m, 1H), 6.53 (m, 1H), 6.78 (m, 2H), 7.14 (m, 2H), 7.30 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13].CC1C=CN=C(N)C=1C.C1C[O:31][CH2:30][CH2:29]1>>[C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[O:1][C:30](=[O:31])[CH3:29])(=[O:14])[CH3:13]
Reactant: C1CCOC1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccnc(N)c1C
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
2-Amino-5-nitro-phenol (46) (20 g, 97.3 mmol) was suspended in THF (125 mL) and Acetic-anhydride (75 mL) was added. Di-methyl-amino-pyridine (DMAP) (300 mg, 2.45 mmol) was added and the mixture was stirred for 16 h at room temperature. A solid precipitated and was collected by filtration followed by rinsing with 3:1 hexane/EtOAc (3×100 mL). The solid was dried under high vacuum for 8 h to give the desired product (416) as a yellow powder (21 g, 88.2 mmol, 90.7% yield). LC-MS (ESI): (exact mass: 238.06) m/e=239.2 [M+1]+ (15%), 477.1 [2M+1]+ (100%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:13]([O-])[CH:14]=1)C1C=CC=CC=1.OC1C=CC(C(NC(C)(C)C)C)=NC=1>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:13][CH:14]=1
Reactant: CC(C)(C)NCC(O)c1ccc(OCc2ccccc2)c[n+]1[O-]
Agent: [Pd]
Agent: CC(NC(C)(C)C)c1ccc(O)cn1
Product: CC(C)(C)NCC(O)c1ccc(O)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Into a 250 ml. Parr bottle there were introduced 250 mg. (0.79 mmole) of 5-benzyloxy-2-(1-hydroxy-2-tert-butylaminoethyl)pyridine N-oxide and 125 mg. of 5% palladium on carbon of 45 psi. The mixture was shaken at room temperature for 6 hours. The catalyst was removed by filtration under a nitrogen atmosphere followed by removel of the solvent in vacuo to give the product which was triturated with isopropanol and filtered. In this manner, there was obtained 175 mg. (75%) of 5-hydroxy-2-(1-tert-butylaminoethyl)pyridine as white crystals, m.p. 165°-168° C. (decomp).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].C(N(CC)C(C)C)(C)C.Cl[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]3[S:6][C:5]([NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[CH:9]=4)=[N:4][C:3]=3[C:18]([NH2:20])=[O:19])=[O:37])=[CH:34][CH:33]=2)[CH2:44][CH2:43]1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc(C(=O)Nc3sc(Nc4ccc5ccccc5c4)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.1 %

Procedure:
To a mixture of 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.50 g, 1.76 mmol) and. N,N-diisopropylethylamine (0.3 mL, 1.94 mmol) in DMA (30 mL) was added 4-chloromethylbenzoyl chloride (0.37g, 1.94 mmol) at 0° C. The mixture was stirred for 3 hrs at rt. Then 1-methylpiperazine (0.1 mL, 0.95 mmol) was added to the mixture (0.083 g in 5 mL DMA), and the mixture was stirred for 16 hrs at rt. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the crude residue was purified by silica gel column chromatograph eluted with 5% MeOH in DCM to give 0.010 g (11% yield) of the titled compound.
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2]C1C=CC=CC=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[S:31]([NH2:35])([NH2:34])(=[O:33])=[O:32]>ClC1C=CC=CC=1>[NH2:34][S:31]([NH:35][CH:23]([P:1](=[O:2])([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:33])=[O:32]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: NS(N)(=O)=O
Reactant: O=Cc1ccccc1
Solvent: Clc1ccccc1
Product: NS(=O)(=O)NC(c1ccccc1)P(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
A mixture of equimolar quantities of triphenyl phosphite, benzaldehyde, and sulfamide in chlorobenzene is warmed at 95°-100° C. for 2.5 hrs, and then the reaction mixture is stripped to 120°/0.2mm. The residue is recrystallized from acetonitrile and then from chlorobenzene, giving a white solid: mp 171°-174°; 31P nmr(DMSO-d6) -14.4(d, J = 25Hz); 1H nmr δ8.2(d of d, 1, J = 2 and 10Hz, NH), 6.9-7.6(m, 15, aryl), 6.7 (s, 2, NH2), 5.2(d of d, 1, J = 10 and 26, CH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:14][CH2:13][CH:12]([NH:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH2:11][CH2:10]1.Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[N:35][OH:36])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:14][CH2:13][CH:12]([NH:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH2:11][CH2:10]1
Reactant: O=Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(C=NO)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 32 h
Yield: 85.5 %

Procedure:
A solution of the product of Example 80 (0.40 g, 0.80 mmol), hydroxylamine hydrochloride (0.16 g, 2.4 mmol) and sodium acetate (0.19 g, 2.4 mmol) in ethanol (60 ml) was heated at reflux for 16 hours and stirred at room temperature for 32 hours. The mixture was evaporated in vacuo and extracted with ethyl acetate (50 ml). The organic phase was washed with brine (sat. 40 ml), dried (magnesium sulfate) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with 20-28% ethyl acetate/isohexane to give the oxime (0.36 g, 87%). 1H NMR (DMSO, 360 MHz): 1.49 (2H, bt, J=12.3), 1.82 (2H, bd, J=14.0), 2.40 (2H, bt, J=13.8), 2.50-2.60 (2H, m), 3.64 (1H, bs), 7.08-7.20 (2H, m), 7.28-7.34 (1H, m), 7.37 (2H, d, J=8.3), 7.72 (2H, d, J=8.3), 8.24 (1H, s), 9.76 (0.5H, d, J=5.9), 11.74 (0.5H, s)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]#[C:23][CH3:24]>>[C:1]([O:5][C:6](=[O:19])[C:7]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)(=[O:9])=[O:10])([CH2:16][C:11]#[C:12][CH3:13])[CH2:21][C:22]#[C:23][CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)CC(=O)OC(C)(C)C)cc1
Reactant: CC#CCBr
Product: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Yield: 90 %

Procedure:
2-(4Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-butyne (2.68 g, 20 mmol), 3.50 g of the product was isolated. Yield 90%; white solid; mp 85-87° C.; MS: 391.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([NH:15][NH2:16])[C:9]([Cl:17])=[N:8]2)=[O:4].[CH3:18][O:19][C:20](OC)(OC)OC>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:18]([O:19][CH3:20])=[N:16][N:15]=[C:10]1[C:9]([Cl:17])=[N:8]2)=[O:4]
Reactant: COC(=O)c1ccc2nc(NN)c(Cl)nc2c1
Reactant: COC(OC)(OC)OC
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1nnc(OC)n12
Temperature: 23 °C

Procedure:
A solution of 3-chloro-2-hydrazino-quinoxaline-6-carboxylic acid methyl ester (890 mg) in tetramethylorthocarbonate (10 mL) was heated at 100° C. for three hrs. After cooling to 23° C., the precipitated solid was isolated by filtration and rinsed with EtOAc, providing 4-chloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester as an orange solid. MS (M+H)+=293.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[C:12]1([C:18]2[N:19]=[C:20]([CH2:29][O:30][C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)[O:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[N:19]=[C:20]([CH2:29][O:30][C:31]3[CH:32]=[CH:33][C:34]([CH:35]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:37][CH:38]=3)[O:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reactant: COC(=O)CP(=O)(OC)OC
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1

Procedure:
Reaction of trimethyl phosphonacetate and 4-[(4,5-diphenyl-2-oxazolyl)methoxy]benzaldehyde according to the procedure of Example 21 provided the title compound, m.p. 159°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:22][CH2:23][CH2:24][N:25]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=4)[CH:28]=[CH:27][C:26]3=[O:37])([C:17]([O:19]CC)=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:22][CH2:23][CH2:24][N:25]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=4)[CH:28]=[CH:27][C:26]3=[O:37])([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2cccc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(CCSc4cccc(F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
To 1.5 mL of an ethanol solution containing 90 mg of ethyl 1-(2-((3-fluorophenyl)thio)ethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 0.50 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 3.5 hours. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, water was added, and adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to give 64 mg of 1-(2-((3-fluorophenyl)thio)ethyl)-4-(3-(7-methoxyl-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylic acid as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:19][CH:18]3[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH:12]2[C:20]([NH:22][C@H:23]([C:42]([O:44]C)=[O:43])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:41])[C:33]3[C:38]([Cl:39])=[CH:37][N:36]=[CH:35][C:34]=3[Cl:40])=[CH:27][CH:26]=2)=[O:21])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:19][CH:18]3[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH:12]2[C:20]([NH:22][C@H:23]([C:42]([OH:44])=[O:43])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:41])[C:33]3[C:38]([Cl:39])=[CH:37][N:36]=[CH:35][C:34]=3[Cl:40])=[CH:29][CH:30]=2)=[O:21])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC(=O)C1C2CCCCC2CN1S(=O)(=O)c1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(S(=O)(=O)N2CC3CCCCC3C2C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cncc3Cl)cc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
N-(N-(3-Methylbenzenesulfonyl)-octahydroisoindole-1-carbonyl)-4-(N-(3,5-dichloroisonicotinoyl)amino)-(L)-phenylalanine, methyl ester (0.036 mmol, 24 mg) was dissolved 0.089 mL of MeOH and 0.089 mL of a 0.4 N solution of NaOH in MeOH. The resulting mixture was stirred overnight at rt. Volatiles were removed in vacuo and the residue was partitioned between 5% citric acid and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2×). The organic extracts were combined and washed with brine, and dried over anhydrous Na2SO4. The residue obtained after filtration and evaporation of volatiles was purified by flash column chromatography on silica gel eluted with a mixture of CH2Cl2 and MeOH to provide N-(N-(3-methylbenzenesulfonyl)-octahydroisoindole-1-carbonyl)-4-(N-(3,5-dichloroisonicotinoyl)-amino)-(L)-phenylalanine (18 mg, 67%) as a white foam (homogeneous by TLC (9:1 dichloromethane: methanol)).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26](OCC)(OCC)OCC.[N-:36]=[N+:37]=[N-:38].[Na+]>C(O)(=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[CH:26]=[N:38][N:37]=[N:36]5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-n4cnnn4)ccc32)n1)c1ccccc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (EXAMPLE 79) (80 mg) in acetic acid (2 mL) was added triethyl orthoformate (123 μL). The reaction was stirred at room temperature for 1 h, at 75° C. for 2 h, and then at room temperature again overnight (≈14 h). NaN3 (47 mg, 3 eq.) was added; the reaction was stirred at 75° C. for 5 h. The reaction was cooled, quenched with water, extracted with methylene chloride. The organic solution was washed with water and brine; it was dried over Na2SO4. Removal of the solvent and subsequent purification by preparative thin layer chromatography (acetone:hexane=1:1) provided the title compound (20 mg). Mass spectrum (ESI): 384 (M+1). 1H NMR (500 MHz, CDCl3): δ 9.04 (s, 1H); 8.56 (br s, 1H); 8.46 (d, J=5.2 Hz, 1H); 8.08 (s, 1H); 7.82 (br s, 1H); 7.57 (br s, 1H); 7.50-7.25 (m, 5H); 6.79 (d, J=5.3 Hz, 1H); 5.88 (br s, 1H); 5.18 (br s, 1H); 1.67 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:11]=[CH:10]2
Reactant: C1CNCCN1
Reactant: Oc1cccc2ccc(Cl)nc12
Product: Oc1cccc2ccc(N3CCNCC3)nc12

Procedure:
The quinoline from step (a) above (0.18 g, 1 mmol) and piperazine (0.172 g, 2 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>ClCCl>[F:1][C:2]1[C:3]([C:4]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:6])=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cccc(C(=O)O)c1F
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCCCC2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
162 g (1.47 mol, 1.05 eq) of N-methylmorphorine was added to the mixed solution of 278 g (1.4 mol, 1.0 eq) of 2-fluoro-3-(methoxycarbonyl)benzoic acid obtained from the Step 2 and 2.7 l of dichloromethane, and then stirred for 30 minutes at 0° C. 191 ml (1.47 mol, 1.05 eq) of isobutyl chloromate was slowly added, and then stirred for 1 hour at 0° C. 139 ml (1.4 mol, 1.0 eq) of piperidine was slowly added, and then stirred for 1 hour at a room temperature. After completing the reaction, the reaction solution was washed with 560 ml of a saturated sodium bicarbonate aqueous solution, 560 ml of a saturated ammonium chloride aqueous solution, and 1 l of distilled water in order. A obtained organic layer was dehydrated with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure to obtain 371 g of methyl 2-fluoro-3-(piperidine-1-carbonyl)benzoate in a red-yellow oil phase
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][C:15]=2[CH:22]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:15]([CH2:22][NH:35][CH2:34][CH2:33][CH2:32][NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH:16]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=Cc1ccc(OCCCCCCc2ccccc2)c(C=O)c1
Product: CC(C)(C)OC(=O)NCCCNCc1ccc(OCCCCCCc2ccccc2)c(CNCCCNC(=O)OC(C)(C)C)c1

Procedure:
N,N'-bis(N-tert.butoxycarbonyl-3-amino propyl)-4-(6-phenylhexyloxy)-1,3-benzenedimethanamine (MS: M+H+ =627) was prepared from 4-(6-phenylhexyloxy)-1,3-benzenedicarboxaldehyde and N-tert.butoxycarbonyl-3-aminopropanamine using the method in Example 2.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[Na+].[Na+].C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 185 °C
Yield: 10 %

Procedure:
p-Acetaminophenol 15 g, and sodium carbonate 60 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 2.0 MPa and heated to 185° C., maintained for 24 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve sodium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the yield is 10%.