Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)=[C:10]([N+:18]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:16][CH2:17]3)=[C:10]([NH2:18])[CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1
Reactant: [H][H]
Reactant: CC1CC(=O)NN=C1c1ccc(NC2CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NC2CC2)c(N)c1

Procedure:
5.8 gm of 5-methyl-6-(3-nitro-4-cyclopropylamino-phenyl)-3-oxo-4,5-dihydro-2H-pyridazine were hydrogenated in a mixture consisting of 100 ml of ethanol and of 20 ml of glacial acetic acid in the presence of 0.5 gm of 10% palladium charcoal at a hydrogen pressure of 5 bar. 120 ml of glacial acetic acid were added, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was reacted further without further purification.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:32]([CH3:34])[CH3:33])[CH3:15])=[CH:8][C:7]=1[CH3:35].[OH-].[Na+].Cl>CO.C1COCC1>[CH:32]([C:17]1[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:23][CH:22]=2)[O:20][C:16]=1[CH:14]([CH3:15])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]([CH3:35])[CH:8]=1)([CH3:33])[CH3:34]
Reactant: COC(=O)CCc1ccc(OCC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
A solution of 3-(4-{2-[4-isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid methyl ester (239 mg, 0.473) in MeOH (1.0 mL) and THF (0.5 mL) is treated with NaOH (1.5 mL, 2.0 M) and stirred at room temperature for 12 hours. The mixture is neutralized to pH=4 with HCl (5 N) and extracted with EtOAc (20 mL×2), and the combined organics are dried (Na2SO4), concentrated and purified on silica gel chromatography column with EtOAc/Hexanes (50/50) to yield the acid as white solid (202 mg, 87%). MS (ES): 492.2; the structure is also confirmed by proton NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].I[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1
Reactant: CC(C)I
Reactant: Oc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoro-5-hydroxypyridine (6.000 g, 53.05 mmol) in N,N-dimethyl formamide (50 mL) cooled with an ice bath was added NaH (2.80 g, 60%, 70.0 mml) in several potions. After the addition, the mixture was stirred at 0° C. for 10 minutes. 2-iodopropane (6.5 mL, 65.00 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was poured into water, extracted with ether (2×), the combined extracts were washed with 1N NaOH (1×), water (1×), brine (1×), dried over MgSO4 and concentrated to give the product that was used directly without further purification.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Orcinol monohydrate (1.42 g, 10 mmol) and 2-chlorobenzenesulfonyl chloride (2.43 g, 11 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature for 2 days. The reaction mixture was diluted with 50 mL of water and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (2% ethyl acetate in dichloromethane) to give the title compound as a pale yellow liquid (2.15 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 2.22 (s, 3 H), 5.24 (s, 1 H), 6.43 (s, 1 H), 6.52 (s, 2H), 7.38 (m, 1 H), 7.60 (m, 2 H), and 7.96 (dd, 1 H, J =0.6, 3.9 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[Cl:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]>C1(C)C=CC=CC=1>[ClH:8].[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: O=C(CCl)NCCc1ccccc1
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: COC(CNCC(=O)NCCc1ccccc1)OC
Product: Cl
Yield: 31.2 %

Procedure:
Aminoacetaldehyde dimethylacetal (20.05 g, 191 mmol) was added to the solution of 2-chloro-N-phenethyl-acetamide (18.33 g, 92.7 mmol) in toluene (92 ml) and refluxed in 2 hours. After ice-cooling and removal of precipitate by filtration, filtrate was washed with water and dried with magnesium sulfate. The solvents were removed under reduced pressure, and 4N hydrogen chloride in ethyl acetate (18 ml) was added to the residue followed by filtration and wash with ethyl acetate and diethyl ether afforded 2-(2,2-dimethoxy-ethylamino)-N-phenethyl-acetamide hydrochloride (8.77 g, 52%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][CH2:27][NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(NCCCc1ccccc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-phenylpropylamine as the starting materials.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[C:7]([Cl:26])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:11][C:9]1[CH:10]=[C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])[CH:6]=[C:7]([Cl:26])[C:8]=1[O:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1
Reactant: COC(=O)C(=O)c1cc(Cl)c(OCCOc2ccc3ccccc3c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1cc(Cl)c(OCCOc2ccc3ccccc3c2)c(Cl)c1
Yield: 99.2 %

Procedure:
A solution of 3,5-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from benzene-hexane provided 0.575 g of purified 3,5-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid (6:1) molar benzene solvate as a colorless solid, mp 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[C:6]([Cl:13])[N:5]=[C:4]([N:14]=CN(C)C)[N:3]=1.Cl.CO.C(Cl)(Cl)Cl.[OH-].[NH4+]>C(O)C>[NH2:14][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([N:8]=[CH:9][N:10]([CH3:11])[CH3:12])=[C:6]([Cl:13])[N:5]=1
Reactant: CN(C)C=Nc1nc(Cl)c(N=CN(C)C)c(Cl)n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Yield: 94.7 %

Procedure:
4,6-Dichloro-2,5-bis-{[(dimethylamino)methylene]amino}pyrimidine (Example 1, 5.87 g, 20.3 mmol) was dissolved in 95% ethanol (200 mL) and 6 N aqueous hydrochloric acid (13.5 mL) added. The solution was heated in an oil bath at 55° C. under nitrogen for 30 minutes, at which point TLC (silica gel, 5% methanol-chloroform) showed that starting material had been cleanly converted to a lower-Rf product. The cooled (ice bath) solution was adjusted to pH ˜8 with concentrated ammonium hydroxide and the resulting mixture (white precipitate formed) concentrated on a rotary evaporator to ˜5 mL to remove ethanol. Additional water (20 mL) was added and the cooled mixture was filtered. The white precipitate was washed with additional water (2×20 mL) and dried to give the title compound as a white powder (4.50 g, 95%), m.p. >dec 250° C.; mass spectrum (CI/CH4): 236, 234 (M+1); 1H-NMR (DMSO-d6) δ: 7.59 (s, 1, CH), 6.90 (s, 2, NH2), 3.00 and 2.94 (both s, 3 each, 2CH3); UV (pH 7 phosphate buffer) λmax: 328 nM (ε 4500), 255 (15,800).
Reaction SMILES: C(C1C=CC(COC2C=CC(CO)=CC=2)=CC=1)(C)(C)C.C[O:22][C:23](=[O:53])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=3)=[CH:36][CH:35]=2)=[CH:28][C:27]=1[CH3:52]>>[C:48]([C:45]1[CH:46]=[CH:47][C:42]([CH2:41][O:40][C:37]2[CH:38]=[CH:39][C:34]([CH2:33][S:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:23]([OH:53])=[O:22])=[C:27]([CH3:52])[CH:28]=3)=[CH:35][CH:36]=2)=[CH:43][CH:44]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(C(C)(C)C)cc3)cc2)cc1C
Agent: CC(C)(C)c1ccc(COc2ccc(CO)cc2)cc1
Product: Cc1cc(SCc2ccc(OCc3ccc(C(C)(C)C)cc3)cc2)ccc1OCC(=O)O

Procedure:
Preparation of [4-(4-tert-Butyl-benzyloxy)-phenyl]-methanol (compound 34A) The title compound was prepared in the manner analogous to Example 14A using 1-bromomethyl-4-tert-butyl-benzene and 4-hydroxymethyl-phenol. MS m/z 253 (M-OH). Step 2. Preparation of 4-tert-Butyl-1-(4-chloromethyl-phenoxymethyl)-benzene (compound 34B) The title compound was prepared in the manner analogous to Example 3B using 34A. MS m/z 253 (M-Cl). Step 3. Preparation of {4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (compound 34C) The title compound was prepared in the manner analogous to Example 1F using 34B and 2C. MS m/z 465 (M+1). Step 4. Preparation of {4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid (compound 34) The title compound was prepared in the manner analogous to Example 1 using 34C. mp 135-137° C.; IR (KBr) cm−1: 2961, 2908, 1751, 1495, 1233, 1194; 400 MHz 1H NMR (DMSO-d6): δ 13.00 (br(s), 1H), 7.27-7.38 (m, 4H), 7.02-7.17 (m, 4H), 6.82-6.88 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 4.96 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 2.08 (s, 3H), 1.22 (s, 9H); MS m/z 451 (M+1). Anal. Calc'd for C27H30O4S: C, 71.97; H, 6.71; found: C, 71.66; H, 6.52.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[OH:20].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(F)cc1)C2

Procedure:
Reaction of 6,7-dichloro-5-hydroxy-2-(p-fluorophenyl)-1-indanone with ethyl bromoacetate according to the procedure of Example 1, STEP (a), affords the title compound. Crystallization from ethanol provides analytically pure material, m.p. 143°-144°.
Reaction SMILES: O[CH2:2][C:3]1([NH2:10])[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[ClH:13].[NH2:10][C:3]1([CH2:2][Cl:13])[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9]
Reactant: O=S(Cl)Cl
Reactant: NC1(CO)CCCNC1=O
Solvent: ClC(Cl)Cl
Product: Cl
Product: NC1(CCl)CCCNC1=O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 3-hydroxymethyl-3-amino-2-piperidone (7 g or 0.049 mol) in anhydrous dimethylforamamide (50 ml) is added one equivalent of thionyl chloride (3.6 ml). The reaction mixture is stirred at 80° C. under nitrogen. After 24 hours, another equivalent of thionyl chloride (3.6 ml) is added and stirring is continued for 2 hour. Then the solvent is stripped off under reduced pressure. Trituration of the semi-solid residue with chloroform (2×30 ml) leaves 2.1 g of crystalline analytically pure 3-amino-3-chloromethyl-2-piperidone hydrochloride: m.p. 230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[N:17]=[C:16]([CH2:18][CH2:19][CH:20]4[NH:26][C:25](=O)[CH2:24][CH2:23][CH2:22][CH2:21]4)[NH:15][C:12]3=[N:13][CH:14]=2)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[N:17]=[C:16]([CH2:18][CH2:19][CH:20]4[NH:26][C:25](=[S:37])[CH2:24][CH2:23][CH2:22][CH2:21]4)[NH:15][C:12]3=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Yield: 83 %

Procedure:
The title compound is synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 120 mg of 7-{2-[6-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-azepan-2-one (compound B3) and 222 mg of Lawesson's reagent. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 104 mg of the title compound as a light yellow, waxy solid. ESI-MS: 381.2 (MH+). TLC: Rf=0.64 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH3:18])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=[CH:20][CH2:21][C@@H:22]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][C:33]=1[S:42]([C:45]([F:48])([F:47])[F:46])(=[O:44])=[O:43])[CH2:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)Cl>[P:1]([O:13][CH2:14][CH2:15][N:16]([CH2:17][CH3:18])[CH2:20][CH2:21][C@@H:22]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:39])(=[O:40])[NH2:41])=[CH:34][C:33]=1[S:42]([C:45]([F:48])([F:46])[F:47])(=[O:43])=[O:44])[CH2:23][S:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:2]
Reactant: NS(=O)(=O)c1ccc(N[C@H](CC=O)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CCNCCOP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reaction time: 4 h
Yield: 50.4 %

Procedure:
A solution of di-tert-butyl 2-(ethylamino)ethyl phosphate (INTERMEDIATE 49, 455 mg, 1.62 mmol) in 1,2-dichloroethane (0.5 ml) at r.t was added to a solution (R)-4-(4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 45, 0.78 g, 1.62 mmol) and 1,2-dichloroethane (10.0 ml). The resulting reaction mixture was stirred for 15 minutes at r.t and solid sodium triacetoxyborohydride (0.514 g, 2.42 mmol) was added. The resulting mixture was stirred at r.t for 4 hours. A solution of NaOH (aq., 0.5 N, 40 ml) and DCM (20 ml) were added to the reaction mixture. After stirring for 15 min at r.t, the layers were separated. After separation, the organic layer was washed with saturated NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. The concentrate was purified by column chromatography (ISCO, silica gel, eluting with 0→100% EtOAc/hexanes) to give the title compound (610 mg, yield: 50%).
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:2].Cl[C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1.[CH3:24]COC(C)=O>>[CH2:8]([O:7][C:5](=[O:6])[C@@H:4]([N:3]([CH2:1][CH3:2])[C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1)[CH3:9])[CH3:24]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCN[C@@H](C)C(=O)OC
Reactant: CCOC(C)=O
Product: CCOC(=O)[C@H](C)N(CC)c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
(S)-methyl 2-(ethylamino)propanoate (1.83 g, 14.0 mmol) was added to methyl 6-chloro-5-nitronicotinate (1.30 g, 6.00 mmol) and the reaction mixture was stirred in a closed vial at 90° C. for 1 h. It was cooled and diluted with EtOAc (25 mL). The resulting precipitate was filtered off, the filtrate was concentrated in vacuo and purified using flash column chromatography on silica gel (220 g SiO2, ethyl acetate in hexanes 0-50%) to afford the title compound as a yellow oil (1.23 g, 66%). [M+H] calc'd for C14H19N3O6, 326; found, 326.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][Si:10]([C:13]#[C:14][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)([CH3:12])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1cc(Br)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1csc(C=O)c1
Yield: 100 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxaldehyde (3.0 g, 16 mmol) in N,N-dimethylformamide (30 ml) were added successively (trimethylsilyl)acetylene (11 ml, 79 mmol), triethylamine (13 ml, 94 mmol), and dichlorobis(triphenylphosphine)palladium (1.1 g, 1.6 mmol) under a nitrogen atmosphere with stirring, and the resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere. After stirring, the reaction mixture was diluted with ethyl acetate, poured into a saturated aqueous solution of ammonium chloride (250 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:1 to 1:19) as the eluent to afford the title compound (3.3 g) in a yield of 100% as a brown oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][NH:15][CH3:16]>C1COCC1>[CH3:14][N:15]([CH3:16])[S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrobenzenesulfonyl chloride (22.8 mmol, 5.05 g) was dissolved in dry THF (50 mL). Dimethylamine in THF (2M, 34 mL) was added and the mixture was refluxed for 2 hours. Upon cooling, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate (250 mL), washed with water (3×50 mL) and dried over MgSO4. Evaporation of the solvent afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11])([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:11][C:30]1=[O:32])([O-:3])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1CNCCC(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OC(c2ccccc2)CCN1Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.9 %

Procedure:
3-(2-Nitrobenzylamino)-1-phenylpropanol (3.00 g, 10.5 mmol), triethylamine (4.24 g, 42.0 mmol) were dissolved in toluene (50 ml). Under ice cooled condition, a solution in which triphosgene (1.24 g, 4.19 mmol) was dissolved in toluene (5 ml) was slowly added dropwise thereto and heated to reflux for six hours after stirred at room temperature for one hour. The reaction mixture was poured into water and, after standing to cool, extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid water and then dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was washed with a mixture of ether-ethyl acetate (1:2) to obtain 3-(2-nitrobenzyl)-6-phenyl-[1,3]-oxazinan-2-one (1.70 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:7]([CH2:8][CH:9]([C:11]([OH:13])=[O:12])N)=[CH:6][NH:5]2.C(N(CC)CC)C.N12CCCN=C1CCCCC2.Cl.C[OH:37]>[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14]([C:7]([CH2:8][C:9](=[O:37])[C:11]([OH:13])=[O:12])=[CH:6][NH:5]2)=[CH:15][CH:16]=1
Reactant: NC(Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Reactant: CO
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: O=C(O)C(=O)Cc1c[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To 600 mg of 6-chloro-DL-tryptophan, suspended in 5 ml of methanol, are added, at room temperature, 0,230 ml of triethylamine and the mixture is stirred for approximately 10 minutes. Then, rapidly and under stirring, pyridine-4-carboxyaldehyde (0,240 ml) is added. After approximately 5 minutes, total dissolution of the suspension is obtained. Stirring is continued for 10 minutes. 122 mg of anhydrous ZnCl2 are then added, stirred for 10 minutes, followed by 0,490 ml of 1,8-diazabicyclo-(5,4,0)-undec-7-ene. The solution becomes orange-red in colour. It is left under stirring for approximately 80-90 minutes at room temperature. The limpid red solution is then quickly added dropwise and under rapid stirring to 100 ml of HCl 1N preheated to 50° C. After approximately 10 minutes from completion of the addition a spontaneous precipitation occurs, increasing in time, of a yellowish solid. The mixture is left for a further 20 minutes at 55° C., then for approximately 3 hours it is cooled to room temperature. The abundant precipitate is filtered, washed with acidic water and dried. 195 mg are recovered, with a yield of 54%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3C=CC=[CH:19][C:14]=3[N:13](C)[C:12]2=[O:21])=[O:10])[CH2:3][CH2:2]1.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][CH:28]=1)[CH:23]1[O:25][CH2:24]1>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:13]([CH:14]([CH3:15])[CH3:19])[C:12]2=[O:21])=[O:10])[CH2:3][CH2:2]1.[O:25]1[CH:23]([CH2:22][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24]1
Reactant: Cn1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: Fc1ccc(OCC2CO2)cc1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: c1ccc(OCC2CO2)cc1

Procedure:
The procedure given in Example 104 was followed using 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 4-fluorophenyl glycidyl ether as a reactant, instead of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give the title compound.