Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[H-].[Na+].[F:8][C:9]1[C:17]2[NH:16][C:15]([CH3:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[F:19][C:20]([F:41])([F:40])[S:21]([O:24][C:25]1[CH:39]=[CH:38][C:28]([O:29][C:30]2[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=2)=[CH:27][CH:26]=1)(=[O:23])=[O:22]>O>[F:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[CH:26][C:25]([O:24][S:21]([C:20]([F:41])([F:19])[F:40])(=[O:23])=[O:22])=[CH:39][CH:38]=4)=[CH:37][CH:36]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Oc1ccc(Oc2ccc(CBr)cc2)cc1)C(F)(F)F
Reactant: Cc1nc2cccc(F)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(F)cccc2n1Cc1ccc(Oc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a mixture of anhydrous N,N-dimethylformamide (10 ml) and sodium hydride (60% oil suspension; 29 mg), 4-fluoro-2-methylbenzimidazole (110 mg) was added while stirring, and stirring was continued at room temperature for 1 hour. To the reaction mixture, a solution of 4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl bromide (300 mg) in anhydrous N,N-dimethylformaide (3 ml) was dropwise added, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene extract was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to eliminate toluene The residue was purified by silica gel column chromatography to give 4-fluoro-2-methyl-1-[4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl]benzimidazole (164 mg) as a colorless liquid nD26 1.5615.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=O)=[O:9])[C:2]#[CH:3].[Na+].S(Cl)([Cl:15])=O>ClCCl>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([Cl:15])(=[O:11])=[O:9])[C:2]#[CH:3]
Reactant: O=S(Cl)Cl
Reactant: C#CCOCCCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOCCCS(=O)(=O)Cl
Yield: 95.6 %

Procedure:
Referring to FIG. 16, a slurry of sodium 3-(propargyloxy)propyl sulfonate (5.0 g, 25.0 mmol, 1.0 equiv.) and thionyl chloride (25 mL, 344 mmol, 13.8 equiv.) was heated to 100° C. under N2 for three hours. The mixture was concentrated to a thick oil, diluted with 50 mL benzene, and concentrated again by rotavap to obtain a waxy solid. The material was slurried in 50 mL dichloromethane and filtered. The solids were discarded and the mother liquor concentrated on rotavap to obtain product as an orange oil (4.7 g, 95%). 1H NMR (300 MHz. CDCl3) δ 4.17 (d, 2H), 3.82 (t, 2H), 3.70 (t, 2H). 2.47 (t, 1H), 2.34 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][C:9]=1[CH3:18])[CH2:3][CH3:4].N>O1CCCC1.[Zn]>[CH2:2]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([CH3:18])=[CH:10][C:11]([NH2:15])=[CH:12][C:13]=1[CH3:14])[CH2:3][CH3:4]
Reactant: CCCOC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Agent: Cl
Agent: N
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCOC(=O)Nc1c(C)cc(N)cc1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
Aqueous hydrochloric acid (6 M, 8.3 mL) was added slowly to a mixture of zinc dust (4.9 g) and (2,6-dimethyl-4-nitro-phenyl)-carbamic acid propyl ester (1.26 g) in tetrahydrofuran (50 mL) cooled to 0° C. The reaction mixture was then stirred for 5 hours at 25° C., and the pH adjusted to 10 with 25% aqueous ammonia. The product was extracted with ethyl acetate (3×50 mL), the combined organic phases were dried over magnesium sulfate and concentrated in vacuo to furnish 1.1 g (99% yield) of the title compound as a dark oil. The crude product was used without further purification. 1H NMR (500 MHz, DMSO-d6): 0.91 (t, 3H), 1.60 (m, 2H), 1.99 (s, 6H), 3.95 (t, 2H), 4.82 (s, 2H), 6.23 (s, 2H), 8.14 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][C:14]2[C:17]3[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=3[S:24][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C:31]1[C:40]([O:41][CH3:42])=[CH:39][C:34]2[NH:35][C:36](=[O:38])[S:37][C:33]=2[CH:32]=1>>[CH2:1]([N:8]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][C:14]2[C:17]3[C:22]([NH:30][C:31]4[C:40]([O:41][CH3:42])=[CH:39][C:34]5[NH:35][C:36](=[O:38])[S:37][C:33]=5[CH:32]=4)=[N:21][CH:20]=[N:19][C:18]=3[S:24][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN(Cc1ccccc1)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2sc3c(c12)CCC(C(=O)N(CCN(C)C)Cc1ccccc1)C3

Procedure:
146 mg (340 μmol) (RS)—N-benzyl-4-chloro-N-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 92a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 8.4 mg (4%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:18][CH3:19])[CH:14]=[C:15]([O:16][CH3:17])[C:10]3=[N:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.Cl.[OH-].[Na+]>CO>[CH3:19][O:18][C:13]1[CH:14]=[C:15]([O:16][CH3:17])[C:10]2[N:11]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4([NH2:30])[CH2:27][CH2:28][CH2:29]4)=[CH:24][CH:25]=3)[N:9]=2)[N:12]=1
Reactant: COc1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79 %

Procedure:
To a solution of tert-butyl (1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.18 g, 0.37 mmol) in methanol (2.2 mL) and DCM (3.5 mL) was added hydrogen chloride (4 M in dioxane, 1.8 mL, 7.3 mmol, 20.0 eq), and the resulting mixture was stirred at room temperature for 20 h. The resulting mixture was added to ice water, made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (3×25 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; 10 g SNAP cartridge: 100% DCM 6.0 min., gradient to 95% DCM/5% MeOH 4 min., 95% DCM/5% MeOH 5 min., gradient to 90% DCM/10% MeOH 3.5 min.) to give 1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.11 g, 79%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[C:31]1=[O:38].Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:35]([CH:32]5[CH2:33][CH2:34][N:30]([CH3:29])[C:31]5=[O:38])=[O:36])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:27][CH:28]=1
Reactant: CN1CCC(C(=O)O)C1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (15.0 mg, 0.040 mmol; obtained from Example 5, Step D), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (28.4 mg, 0.20 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (38.0 mg, 0.20 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (26.8 mg, 0.20 mmol), N-ethyl-N-isopropylpropan-2-amine (0.035 mL, 0.20 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material was consumed. Water (10 mL) was added, and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated, and the resulting residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford the desired product (14.8 mg, 74.1%). LRMS (APCI neg) m/e 502 (M−1). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.78 (dd, J=12.4, 2.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 2H), 7.25-7.34 (m, 1H), 7.18 (m, 1H), 6.82 (d, J=8.8 Hz, 2H), 6.14 (m, 1H), 5.56 (s, 2H), 3.78 (s, 3H), 3.38-3.49 (m, 3H), 2.88 (s, 3H), 2.71 (s, 3H), 2.36-2.48 (m, 1H), 2.22-2.31 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][CH2:8][CH2:7]2
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Solvent: c1ccncc1
Product: CCOC(=O)N1CCCc2cc3c(c(C)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 201 mg of t-butyl 11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2 ml of pyridine was added 0.1 ml of ethyl chloroformate, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 261 mg of 8-t-butyl 1-ethyl 11-methyl-3,4,6,7,9,10-hexahydro-1H-azepino[4,5-g]quinoline-1,8(2H)-dicarboxylate as a colorless viscous substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][C:4]=1[OH:15].CCCCCC>CC(C)=O.[O-2].[O-2].[Mn+4]>[OH:15][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[CH:2]=[O:1])=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2
Reactant: COc1ccc2ncc(O)c(CO)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1ccc2ncc(O)c(C=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
Manganese dioxide (650 mg, 7.5 mmol, 10.0 eq) is added at room temperature to a stirred solution of 4-hydroxymethyl-6-methoxy-quinoline-3-ol (220 mg, 0.75 mmol, 1.0 eq) in acetone (30 mL). After 2 hours stirring at room temperature, the reaction mixture is filtered through decalite and the filtrate is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: hexane:acetone, 1:1, v/v) to afford 3-hydroxy-6-methoxy-quinoline-4-carbaldehyde as a yellow solid (85 mg, 34% yield).
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:24]=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](OC=O)(=[O:31])C>ClCCl>[CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([CH:29]=[O:31])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CC(=O)OC=O
Solvent: ClCCl
Product: O=Cc1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10-(4-Cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine of Example 4 (1.065 g) in dichloromethane (50 mL) was reacted with formic acetic anhydride. After stirring at room temperature overnight, the reaction mixture was washed with water and saturated aqueous sodium bicabonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was filtered through a short column of Magnesol® to provide the desired title compound which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2=[O:15].C(=O)([O-])[O-].[K+].[K+].I[CH:23]([CH3:25])[CH3:24]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:23]([CH3:25])[CH3:24])[O:8][C:7]([CH3:13])([CH3:14])[CH2:6][C:5]2=[O:15]
Reactant: CC1(C)CC(=O)c2cc(Br)c(O)cc2O1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc2c(cc1Br)C(=O)CC(C)(C)O2

Procedure:
As described in General Procedure A, 6-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one, (Compound 3, 1.0 g, 3.8 mmol) in acetone (50 mL) was treated with anhydrous potassium carbonate (2.1 g, 14.9 mmol) and 2-iodopropane (0.7 mL, 7.5 mmol) to give the title compound as a white solid after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:21][C:22]([Cl:29])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:19][C:20]1[S:21][C:22]([Cl:29])=[CH:23][C:24]=1[S:25]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:27])=[O:26]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1cc(Cl)sc1Cl

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with 2,5-dichlorothiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J=1.5 & 10.5 Hz, 1H), 7.28-7.20 (m, 2H), 7.08 (dd, J=9.0 & 17.4 Hz, 2H), 6.99 (s, 1H), 6.03 (dt, J=2.1, 8.7 & 17.4 Hz, 1H), 5.56 (br s, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[B:23](OCC)([O:27]CC)[O:24]CC>CCCCCC>[CH3:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([B:23]([OH:27])[OH:24])=[CH:3][CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: Cc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(B(O)O)c2ccccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 125 mL round-bottomed flask equipped with N2 inlet were added 1.78 g (11.4 mmol) 1-bromo-4-methylnaphthalene and 20 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 5.49 mL (13.7 mmol) of a 2.5M solution of n-butyl lithium in hexane was added over 5 minutes, and the reaction stirred at −70° C. for 10 minutes. The solution was then treated with 2.34 mL (13.7 mmol) triethyl borate, stirred 5 minutes at −70° C., then warmed to room temperature and stirred 40 hours. The reaction was quenched with aqueous ammonium chloride solution, poured into 0.5 N hydrochloric acid, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to a white solid after trituration with hexane, mp 224-228° C., 1.9 g (90%).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][NH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
A mixture of N-aminomorpholine (4 g), t-butyl bromoacetate (7.6 g) and sodium carbonate (2.1 g) in 20 ml of DMF was stirred at room temperature overnight. After concentration in vacuo, the residue was taken up in ethyl acetate. The organic solution was washed with water, dried, filtered and concentrated in vacuo to give 2.5 g of crude N-(morpholino)glycine t-butyl ester (compound III-A). This crude compound was used without further purification. To a solution of 5 g of the product (I-D) in 10 ml of methylene chloride was added a solution of 2.5 g of compound (III-A) and 5 ml of pyridine in 5 ml of methylene chloride over a period of 10 minutes. After 16 hours the reaction mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and once with brine. The organic solution was dried, filtered, concentrated in vacuo, and purified by dry column chromatography to give 3.5 g of oily product (III-B), N-(morpholino)-N-[N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]-N-(2,2,2-trichloroethoxycarbonyl)-L-alanyl]glycine t-butyl ester: ##STR21## To a solution of 0.6 g of product (III-B) in 10 ml of glacial acetic acid was added 2 g of zinc dust. After three hours the mixture was filtered through celite and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water. The organic solution was dried, filtered, concentrated in vacuo, and chromatographed to give 0.4 g of product (III-C), N-(morpholine)-N-[N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]L-alanyl]glycine t-butyl ester: ##STR22## The dihydrochloric acid salt of the free acid was formed by bubbling dry hydrogen chloride gas into an ethereal solution containing 0.5 g of product (III-C) at 0° C. for 2.5 hours. Concentration in vacuo gave 0.4 g of solid product.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C@H:16]([C:17](O)=[O:18])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([OH:23])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.[CH3:25][O:26][C:27](=[O:45])[C@@H:28]([NH2:44])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>>[CH:1]([O:4][C:5]([N:7]1[C@H:16]([C:17](=[O:18])[NH:44][C@H:28]([C:27]([O:26][CH3:25])=[O:45])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:34][CH:35]=2)[CH2:15][C:14]2[C:9](=[CH:10][C:11]([OH:23])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=2)[CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1Cc2cc(O)c([N+](=O)[O-])cc2C[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)C
Yield: 79.7 %

Procedure:
(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (2.4 mmol) was hydrolyzed according to general procedure B to provide the acid (0.704 g). (S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester (2.16 mmol) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester-hydrochloride (2.38 mmol) according to general procedure A to provide the amide (1.01 g) LC/MS: m/z 588.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C:19](=[O:21])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]([O:24][CH3:25])=[O:23])[NH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C:19](=[O:21])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]([O:24][CH3:25])=[O:23])[N:11]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(Cc1ccccc1)C3
Reactant: ICc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Yield: 49.1 %

Procedure:
To a solution of 2-benzyl-4-oxo-5-carbomethoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (0.928 g, 2.78 mmol) in dry tetrahydrofuran (5 mL) was added 60% sodium hydride in oil (111 mg). The resulting mixture was stirred at room temperature until gas evolution ceased. A solution of benzyl iodide (0.606. g, 2.78 mmol) in dry tetrahydrofuran (5 mL) was added to the reaction mixture and the resulting solution stirred at room temperature for 60 h. The mixture was diluted with methylene chloride and washed twice with saturated sodium chloride solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate resulting in a yellow precipitate (163 mg). The filtrate was concentrated in vacuo and chromatographed (silica gel, 5% methanol/95% methylene chloride) to provide an additional 580 mg of the title compound (743 mg total, 63%) as a crystalline solid: mp 198-199° C. 1H NMR (CDCl3) d 7.43 (d, J=7 Hz, 1 H), 7.36 (d, J=8 Hz, 1 H), 7.25 (m, 9 H), 6.95 (m, 2 H), 5.24 (s, 2 H), 4.01 (s, 3 H), 3.78 (m, 4 H), 3.40 (bs, 2 H); MS EI+ m/e 425 (p+1); IR (KBr, cm−1) 1726, 1648, 1449, 1291, 1134, 1107.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[O:15][C:14]2=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.O[C:22]1[CH:26]=[CH:25][O:24][N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][O:19][C:22]3[CH:26]=[CH:25][O:24][N:23]=3)[O:15][C:14]2=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-n2ccnc2)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(-n2ccnc2)c(F)c1
Reaction time: 2 h
Yield: 59.8 %

Procedure:
3-(3-Fluoro-4-(imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (WO 96/23788; 280 mg, 1 mmol), 3-hydroxyisoxazole (94 mg, 1.1 mmol), and triphenylphosphine (330 mg, 1.25 mmol) were suspended by stirring in dry tetrahydrofuran (10 ml) under nitrogen at ambient temperature. Diisopropylazodicarboxylate (308 mg, 1.5 mmol) was added dropwise over 10 minutes. The suspension dissolved, and stirring was continued at the same temperature for 2 hours. The mixture was evaporated to dryness, and the residue purified by chromatography on a 20 g silica Mega Bond Elut® columns, eluting with a gradient increasing in polarity from 50 to 100% EtOAc in isohexane. Relevant fractions were combined and evaporated to give the desired product (206 mg). MS (ESP): 345 (MH+) for C16H13FN4O4.