Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH2:4][CH2:3]1
Reactant: CN1CCC(C(=O)c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of 1-methylpiperidin-4-yl phenyl methanone 1.02 g (5 mmol) in 30 ml methanol was added in small portions sodium borohydride 0.378 g (10 mmol). The reaction mixture was stirred at room temperature for two hours, concentrated, added water and extracted with methylene chloride 2×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 1 g of the title compound in 98% yield.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[N:28]=3)[C:23](=[O:31])[C:22]([C:32]([O:34]CC)=[O:33])=[CH:21]2)[C:15]([F:19])=[CH:16][C:17]=1[F:18])=O)C1C=CC=CC=1.Cl>C(O)(=O)C>[NH2:11][C:12]1[CH:13]=[C:14]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[N:28]=3)[C:23](=[O:31])[C:22]([C:32]([OH:34])=[O:33])=[CH:21]2)[C:15]([F:19])=[CH:16][C:17]=1[F:18]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OCc3ccccc3)c(F)cc2F)c2nc(Cl)ccc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3ccc(Cl)nc32)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To 1.0 g of ethyl 1-(3-benzyloxycarbonylamino-4,6-difluorophenyl)-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate were added 4 ml of 12N hydrochloric acid and 8 ml of acetic acid. The solution was heated at reflux for 3 hours and stirred at room temperature overnight. The solid precipitated in the reaction solution was collected by filtration and successively washed with ethanol, chloroform and diethyl ether to give 550 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:9][O:10][C:11](=[O:29])[CH:12]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.N1C=CN=C1>ClCCl>[CH3:9][O:10][C:11]([C@@H:12]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([O:20][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[CH2:16][CH2:15]1)=[O:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(CC1CCC(O)CC1)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a solution of TBSCl (12.7 g, 85 mmol) in dichloromethane (20 mL) was added dropwise a mixture of 2-tert-butoxycarbonylamino-3-(4-hydroxy-cyclohexyl)-propionic acid methyl ester (17 g, 56 mmol) and imidazole (7.68 g, 113 mmol) in dichloromethane (200 mL) at 0° C. After stirring at rt for 5 h, the reaction mixture was washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to give tert-butyl (S)-1-(methoxycarbonyl)-2-(4-(t-butyldimethylsilyloxy)cyclohexyl)ethylcarbamate (21 g, 91%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 0.08 (d, 6 H), 0.89 (d, 9H), 1.45 (s, 9 H), 1.51 (m, 4 H), 1.58 (m, 1 H), 1.68 (t, 4 H), 1.85 (d, 1 H) 3.71 (d, 3 H), 3.91 (m, 1H), 4.34 (m, 1H), 4.86 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].S([O-])([O-])(=O)=O.[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19][S:20][CH2:21][CH2:22][NH+:23]=[C:24]([NH2:26])S.[CH3:27][C:28]1[NH:32][CH:31]=[N:30][C:29]=1[CH2:33][S:34][CH2:35][CH2:36][NH+:37]=[C:38]([NH2:40])S>>[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19][S:20][CH2:21][CH2:22][N:23]=[C:24]([NH2:26])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:38]([NH2:40])=[N:37][CH2:36][CH2:35][S:34][CH2:33][C:29]1[N:30]=[CH:31][NH:32][C:28]=1[CH3:27]
Reactant: NCCCCCN
Reactant: Cc1[nH]cnc1CSCC[NH+]=C(N)S
Agent: O=S(=O)([O-])[O-]
Product: Cc1[nH]cnc1CSCCN=C(N)NCCCCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
The reaction of 1,5-diaminopentane (0.43 g) with S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethylthiouronium sulphate (2.52 g) by the method described in Example 5 afforded the title compound which was isolated as the dipicrate (1.8 g) m.p. 115-120°.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1>>[CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1

Procedure:
2-n-Butyl-3-(4-methoxyphenylsulfonyl)benzofuran was demethylated with pyridine hydrochloride at 185° according to the procedure described in Example 1 to give 2-n-butyl-3-(4-hydroxyphenylsulfonyl)benzofuran, m.p. 163°-165°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:12]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(c1ccc([N+](=O)[O-])cc1)CN2c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(c1ccc(N)cc1)CN2c1ccccc1
Yield: 96.8 %

Procedure:
To a refluxing solution of tert-butyl 3-(4-nitrophenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.0 g, 2.2 mmol) and ammonium chloride (1.18 g, 22.0 mmol) in 2:1 mixture of ethanol/water (21 mL), was added iron powder (0.37 g, 6.6 mmol) over a period of 45 minutes. After refluxing for another hour, the reaction mixture was extracted with dichloromethane, washed the organic extracts with water and brine. The organic phase was dried over MgSO4 and concentrated to obtain tert-butyl 3-(4-aminophenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.9 g, 97%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][C:18]([CH3:24])([CH2:22][CH3:23])[C:19](O)=[O:20]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:19](=[O:20])[C:18]([CH3:24])([CH3:17])[CH2:22][CH3:23])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(C)(C)C(=O)O
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C(C)(C)CC)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 58A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 78 mg (0.67 mmol) 2,2-dimethylbutanoic acid and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: O[CH2:2][C:3]1[C-:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16].[Na+].[I-].Cl[Si](C)(C)C.[NH:24]([CH2:27][CH3:28])[CH2:25][CH3:26]>CC#N.C(Cl)Cl>[CH2:25]([N:24]([CH2:2][C:3]1[C-:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH2:27][CH3:28])[CH3:26].[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16]
Reactant: CN(C)[c-]1cccc1CO
Reactant: CCNCC
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Agent: [I-]
Solvent: CC#N
Solvent: ClCCl
Product: CCN(CC)Cc1ccc[c-]1N(C)C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
A stirred solution of alcohol 61 (90 mg, 0.35 mmol) and NaI (104 mg, 0.69 mmol) in MeCN (3 mL) under argon at room temperature was treated with ClSiMe3 (0.11 mL, 0.87 mmol), resulting in the formation of fine precipitate. After stirring for 10 minutes, Et2NH (0.14 mL, 1.39 mmol) was added and the reaction mixture was left to stir for a further 15 h. CH2Cl2 (10 mL) was added and the mixture washed with H2O (3×5 mL), brine (1×5 mL), dried over Na2SO4, filtered, and all volatiles were removed in vacuo. The crude product was dissolved in EtOAc and filtered through a pad of silica gel, eluting with 95:3:2 EtOAc/i-PrOH/Et3N. Evaporation of the filtrate afforded amine 64 (103 mg, 95%) as an orange oil: Rf=0.25 (silica, 95:3:2 EtOAc/i-PrOH/Et3N); IR (KBr, neat) vmax 3093, 2968, 2937, 2819, 2780, 1487, 1452, 1421 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.13 (s, 5H), 3.97 (t, 1H, J=1.8 Hz), 3.89 (t, 1H, J=2.0 Hz), 3.86 (t, 1H, J=2.4 Hz), 3.75 (AB d, 1H, J=13.2 Hz), 3.12 (AB d, 1H, J=12.9 Hz), 2.68 (s, 6H), 2.61 (dq, 2H, J=13.8, 6.9 Hz), 2.41 (dq, 2H, J=13.0, 7.1 Hz), 0.98 (t, 6H, J=7.2); 13C NMR (75 MHz, CDCl3) δ 113.7, 76.6, 68.5, 68.3, 61.7, 56.9, 52.2, 45.9, 44.9, 11.2; EIMS [m/z (%)] 314 (M+, 100), 241 (39), 121 (38); HRMS (EI) calcd for C17H26N256Fe: 314.1445. Found 314.1445.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2o1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2o1

Procedure:
This material was prepared according to the method described in Example 66 using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzooxazol-2-ylamine, (Example 70(c)), (0.27 g, 0.72 mmol) and acetic anhydride (82 uL, 0.87 mmol) in pyridine (3 mL). Purification by silica gel chromatography (1:1.5 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 415 (M+1). Mp: 205.1–205.2° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Br[C:48]1[CH:55]=[CH:54][C:51]([CH:52]=[O:53])=[C:50]([F:56])[C:49]=1[F:57]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[F:57][C:49]1[C:50]([F:56])=[C:51]([CH:52]=[O:53])[CH:54]=[CH:55][C:48]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=Cc1ccc(Br)c(F)c1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1F
Reaction time: 16 h
Yield: 94.9 %

Procedure:
(2,4-Difluorophenyl)boronic acid (5.39 g), a 2 M aqueous sodium carbonate solution (34.1 mL), tris(dibenzylideneacetone)dipalladium(0) (1.46 g), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.40 g) were added at room temperature to a toluene (150 mL) solution of 4-bromo-2,3-difluorobenzaldehyde (5.03 g), and the mixture was stirred at 100 C for 16 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The organic layer was separated, washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.49 g).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8](=[CH:14]N(C)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)=[C:4]([Cl:20])[CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:46]=[C:44]([NH:43][C:33]3[CH:34]=[CH:35][C:36]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:31]([O:30][CH3:29])[CH:32]=3)[N:45]=2)=[C:4]([Cl:20])[CH:3]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Br)cc1Cl
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1ccc(Br)cc1Cl
Yield: 28 %

Procedure:
The title compound was prepared from crude ethyl 2-(4-bromo-2-chloro-benzoyl)-3-dimethylamino-acrylate (50 mg, 0.14 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (43 mg, 0.12 mmol) using in analogous manner the procedure described in example 28b). Obtained as a yellow solid (50 mg) in 28% yield.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC)=[NH:17])=[NH:14].[CH3:36][C:37]([CH3:39])=O>>[ClH:3].[CH3:36][C:37]1([CH3:39])[N:14]=[C:13]([NH:12][CH2:11][C:10]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:8]([O:7][CH3:6])[CH:9]=2)[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:17]1
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCCNC(=N)NC(=N)NCc1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(OC)c(OC)c2)N1

Procedure:
75 ml of methanol, 120 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 3.5 g (7.5 mmol) of N1-(3,4-dimethoxybenzyl)-N5-dodecyl-biguanide dihydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.2)), and dissolved in 70% aqueous acetonitrile. The solution was concentrated under reduced pressure to remove the solvent, and the residue was sufficiently dried under reduced pressure to obtain 2.2 g of a colorless resinous solid.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.[OH:25][C@@H:26]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39](O)[CH:38]=1)[CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CCOC(C)=O>[OH:25][C@@H:26]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH:42]=1)[CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCO2)cc1
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCO2)c1

Procedure:
tert-Butyl ((3R)-3-hydroxy-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propyl)-carbamate was prepared by the reaction between rac-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate and phenol (7, Intermediate I) at +100° C. following the method used in Example 12 with the following exception. After the reaction was complete (as judged by TLC), the reaction mixture was diluted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:hexane 10-40% gradient) gave the product as an off-white semi-solid. Yield (0.36 g, 66%); 1H NMR (400 MHz, CDCl3): δ 7.23 (t, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.82 (d, 1H), 4.88 (bs, 1H), 4.71 (bs, 1H), 4.28-4.25 (m, 1H), 3.96-3.90 (m, 3H), 3.85-3.82 (m, 1H), 3.49 (bs, 1H), 3.19-3.13 (m, 2H), 1.97-1.92 (m, 2H), 1.83-1.74 (m, 3H), 1.60 (s, 1H), 1.45 (s, 9H); MS: m/z 352.8 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH:8]([C:13]([O:15]C)=[O:14])[CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1
Reactant: COC(=O)C1CC(=O)Nc2cc(OC)ccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)NC(=O)CC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 89.5 %

Procedure:
To a solution of methyl 2,3,4,5-tetrahydro-8-methoxy-2-oxo-1H-1-benzazepine-4-carboxylate (5.035 g) in methanol (60 ml) was added 1 N aqueous sodium hydroxide (40 ml). The reaction mixture was stirred at room temperature for 6.5 hr, made acidic by adding 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The resulting crude crystals were washed with diethyl ether to obtain the titled compound (4.253 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[N+:22]([O-])([OH:24])=[O:23]>>[CH3:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(CCc2ncccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(CCc2ncccc2C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of fuming nitric acid (d.l.50) (80 ml) was portionwise added 3-methyl-2-[2-(4-acetamidophenyl)ethyl]pyridine (16.2 g) at -15° to 15° C. and the mixture was stirred at the same condition for 30 minutes. The resultant solution was poured into an ice-water and the solution was adjusted to pH 8.0 with 20% aqueous sodium hydroxide. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran, and the extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 3-methyl-2-[2-(4-acetamido-3-nitrophenyl)ethyl]pyridine (16.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(Cl)c1
Reaction time: 0.05 h
Yield: 95.7 %

Procedure:
40% Methanolic Triton B (0.053 mL, 0.12 mM) was added to a solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (33.2 mg, 0.12 mM) in 2 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (53.8 mg, 0.27 mM) was added and the resultant mixture stirred at room temperature for 20 h. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 42.1 mg (95%) of the {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (CHCl3, cm−1) 3450, 3400, 1744, 1676, 1591, 1457, 1369, and 1150. MS (FD) m/e 464, 466.
Reaction SMILES: C([N:4]1[CH2:9][C@@H:8]([CH3:10])[N:7]([CH2:11][CH2:12][CH2:13][Cl:14])[CH2:6][C@@H:5]1[CH3:15])C=C.C(O)(=O)C1C(=CC=CC=1)S>C1COCC1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][CH2:13][CH2:12][CH2:11][N:7]1[C@H:8]([CH3:10])[CH2:9][NH:4][C@@H:5]([CH3:15])[CH2:6]1
Reactant: C=CCN1C[C@@H](C)N(CCCCl)C[C@@H]1C
Agent: O=C(O)c1ccccc1S
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CN[C@@H](C)CN1CCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of (2S,5R)-1-allyl-4-(3-chloro-propyl)-2,5-dimethyl-piperazine (14.05 g, 61 mmol) in anhydrous THF (78 mL) under argon was added thiosalicylic acid (10.33 g, 67 mmol, 1.1 eq) followed by the addition of a solution of tris(dibenzylidenacetone)-dipalladium (Pd2(dba)3, 2.8 g, 3.1 mmol, 5 mol %) and 1,4-bis(diphenylphosphino)butane (DPPB, 1.33 g, 3.1 mmol, 5 mol %) in anhydrous THF (26 mL, pre-mixed for 15 minutes). After stirring at room temperature for 2 hours, the mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was partitioned between 1N aqueous HCl (70 mL) and Et2O (70 mL). The aqueous layer was separated and extracted with Et2O (50 mL×2), and treated with NaOH (solid) to bring its pH to 13. The aqueous phase was extracted with CHCl3 (50 mL×4). The combined organic phase was dried (Na2SO4) and concentrated in vacuo to give 11.6 g (100%) of (2S,5R)-4-(3-chloro-propyl)-2,5-dimethyl-piperazine as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O[C@H:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:24][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:10]3[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C@@H:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=2)=[N:23][N:22]=1
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Reactant: O=C1NCC[C@@H]1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@@H]2CCNC2=O)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a stirring mixture of Methyl 3-hydroxy-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (2.5 g) (Intermediate 7) and (S)-(−)-3-hydroxy-2-pyrrolidinone (Intermediate 17) (0.8 g) in dry THF (70 mL) taken in round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (3.77 g) was added. Diisopropyl azodicarboxylate (DIAD) (2.1 mL) in dry THF (2 mL) was added drop wise to the above reaction mixture. The reaction was stirred at room temperature. Reaction was monitored by TLC for completion. After completion, reaction mixture was concentrated under vacuum to remove the solvents. Diluted with DCM and coated over silica gel and chromatographed to furnish the product as white solid (2 g).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:10]1
Reactant: COCCCOC(c1ccccc1)C1CCCNC1
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCOC(c1ccccc1)C1CCCN(CC(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
3-((3-Methoxypropoxy)(phenyl)methyl)piperidine HCl salt (63 mg, 0.212 mmol) was mixed with methyl bromoacetate (20 μL), K2CO3 (75 mg, 2.5 equiv.), and anhydrous DMF (3 mL). The mixture was stirred overnight at rt. LC-MS indicated the reaction was complete. The mixture was diluted with EtOAc and washed with water. The water layer was extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over Na2SO4. After concentration, the residue was purified by flash chromatography on a 4-g silica gel cartridge eluted with a 0-10% methanol in dichloromethane gradient to afford methyl 2-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)acetate (19 mg, 27% yield). LC-MS (3 min) tR=1.07 min, m/z 336 (M+1).