Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)=[C:14]([F:28])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)=[C:14]([F:28])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(-n2cc(C(=O)O)cn2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
Ethyl 1-(4-{[benzyloxycarbonyl]amino}-2-fluorophenyl)-1H-pyrazole-4-carboxylate (J. Med. Chem, 2000, 43, 5, p 953) (1.33 g, 3.45 mmol) was taken up in ethanol/water (1/1, 80 ml), tetrahydrofuran (10 ml) was added, followed by aqueous sodium hydroxide solution (1M, 155 ml) and it was stirred at room temperature for 5 hours. The organic solvents were removed and the aqueous solution was acidified with 1M aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate, dried over magnesium sulfate and the solvent removed under reduced pressure to give the title product (1.1 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[CH2:21][OH:22].Cl>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[CH:21]=[O:22]
Reactant: COc1cc(CO)c(Br)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(C=O)c(Br)cc1Cl
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
To a solution of oxalyl chloride (0.58 mL, 6.9 mmol) in DCM (20 mL) was added dropwise a solution of dimethylsulfoxide (1.11 mL, 15.6 mmol) in DCM (10 mL), at temperature lower than −65° C. The resulting mixture was stirred for about 20 min at about −70° C. Then a solution of (2-bromo-4-chloro-5-methoxy-phenyl)methanol (1.56 g, 6.2 mmol) in DCM (20 mL) was added dropwise at temperatures lower than −65° C., and the resulting mixture was stirred for about another 20 min. Subsequently, TEA (3.52 mL, 25.2 mmol) was added dropwise at temperatures lower than −70° C., and the mixture was stirred for about 10 min at about −70° C. The mixture was allowed to warm to rt and stirred for about 16 h, treated with 1 M aqueous HCl (100 mL) and DCM (50 mL). The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with water (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 5:95) to give 2-bromo-4-chloro-5-methoxybenzaldehyde (1.48 g, 5.9 mmol, 95%) as a white solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 3.96 (3 H, s), 7.46 (1 H, s), 7.68 (1 H, s), 10.3 (1 H, s).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:41](=[O:42])[N:6]2[C:7]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[F:43][C:44]([F:51])([F:50])[S:45]([O:48]C)(=[O:47])=[O:46]>ClCCl>[F:43][C:44]([F:51])([F:50])[S:45]([O-:48])(=[O:47])=[O:46].[CH3:44][N+:23]1[C:24]([CH3:27])=[CH:25][CH:26]=[C:21]([C:19]([C:16]2[N:17]=[CH:18][N:13]3[CH:12]=[C:11]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:41](=[O:42])[N:6]5[C:7]=4[C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=4)=[O:29])[S:15][C:14]=23)=[O:20])[CH:22]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(C(=O)c2ncn3cc(C4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)sc23)cn1
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ncn3cc(C4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)sc23)c[n+]1C
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 0.5 h

Procedure:
Under ice cooling, 92 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was dissolved in 4 ml of dichloromethane to prepare a solution, and 0.018 ml of methyl trifluoromethanesulfonate was added to the solution. The mixture was stirred at that temperature for 30 min. The reaction solution was then concentrated under the reduced pressure to give 110 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(1,6-dimethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate trifluoromethanesulfonate.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1(=O)[O:11][CH2:10][CH2:9][CH2:8]1>>[CH3:5][C:2]([N:1]1[CH2:7][CH2:8][CH2:9][C:10]1=[O:11])([CH3:6])[CH2:3][OH:4]
Reactant: CC(C)(N)CO
Reactant: O=C1CCCO1
Product: CC(C)(CO)N1CCCC1=O
Yield: 59 %

Procedure:
In a procedure similar to that of Example 1, 2-amino-2-methylpropanol was reacted with γ-butyrolactone resulting in a 59% yield of N-(1,1-dimethyl-2-hydroxyethyl)-2-pyrrolidinone, b.p. 175°/21 torr, after two cycles. The material melted at 56°-58° with 13CNMR peaks shifted 176.1, 69.7, 58.7, 46.3, 32.9, 23.2 and 18.2 ppm from TMS. The elemental analyses agreed with the theoretical values for the expected compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].[CH2:8]([I:11])[CH2:9][CH3:10]>C1(C)C=CC=CC=1>[I-:11].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:8][CH2:9][CH3:10])[C:3]=1[CH3:7]
Reactant: Cc1nccn1C
Reactant: CCCI
Solvent: Cc1ccccc1
Product: CCCn1cc[n+](C)c1C
Product: [I-]
Temperature: 25 °C
Yield: 92 %

Procedure:
1,2-dimethylimidazole (7.2 g, made by Aldrich) and propyl iodide (12.7 g, made by Kanto Chemical) were stirred in toluene at 75° C. for 15 hours. After the end of the reaction, the reaction mixture was cooled to room temperature and the crude crystals formed were recovered. A mixed solvent of toluene and isopropanol was used for recrystallization. The crystals were dried in vacuo to obtain 1,2-dimethyl-3-propylimidazolium iodide (18.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.C[CH2:18][N:19](C(C)C)C(C)C.CS(OS(C)(=O)=O)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:18]#[N:19])[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Cl)cc(CC#N)c21

Procedure:
To a solution of compound 17 (1 g, 4.2 mmol), at room temperature and under nitrogen atmosphere, in dry dichloromethane (10 mL) were added DIPEA (0.8 mL, 4.62 mmol) and methane sulfonic anhydride. (0.8 g, 4.62 mmol) The resulting mixture was stirred for 2 h. Then, the reaction mixture was quenched with water and the mixture was extracted with more dichloromethane. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent evaporated to give the desired product as yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:6]1.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([NH:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:14]=1)[NH:11][C:10]([C:7]1[S:8][CH2:9][C@@H:5]([CH2:4][C:3]([OH:26])=[O:2])[N:6]=1)=[CH:18]2
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 905.1 %

Procedure:
The compound (1.5 g, 3.83 mmol) prepared in Example 26 was dissolved in tetrahydrofuran (100 ml) and methanol (50 ml). Lithium hydroxide monohydrate (640 mg, 15.3 mmol) was dissolved in water (50 ml) and added to the reaction solution, which was then stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran and methanol. 1N hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (13.1 g, Yield 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>CCOCC>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: OC1(c2ccc(F)nc2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-fluoro-pyridine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:15][CH3:16])=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH:20]=[CH:19]1>>[Cl:2][C:3]1[C:4]([CH2:15][CH3:16])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]3[N:25]=[C:26]4[C:21]([CH:20]=[CH:19][C:18](=[O:17])[NH:27]4)=[CH:22][CH:23]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: CCc1c(Cl)cccc1N1CCNCC1
Agent: Cl
Product: CCc1c(Cl)cccc1N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1

Procedure:
In a manner similar to that of other examples above, 1-(3-chloro-2-ethyl-phenyl)-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 441.2 (Exact Mass: 440.20).
Reaction SMILES: ClC[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[CH2:34]1COCC1>>[CH:18]1([C:17]2[C:11]3[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:4]=[CH:3][N:28]=[C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[C:26]=4[CH3:34])=[N:13][C:12]=3[C:14]([O:24][CH3:25])=[CH:15][CH:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNC1
Reactant: C1CCOC1
Reactant: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Product: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccnc(N4CCCC4)c3C)nc12
Temperature: 70 °C
Yield: 18 %

Procedure:
To a solution of 0.13 g (0.31 mMol) 2-chloromethyl-N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-isonicotinamide in 1 ml THF were added 0.1 ml (1.3 mMol) pyrrolidine. The reaction mixture was heated to 70° C. for 3 h. The solvent was evaporated to dryness, the residue taken up in dichloro methane and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (dichloro methane/methanol 19:1->9:1) and subsequent crystallization from methanol/ethyl acetate/diethyl ether afforded 0.026 g (18%) of N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-2-pyrrolidin-1-yl-methyl-isonicotinamide as a yellow solid. ES-MS m/e (%): 451 ([M+H]+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15]C(NC)=[N:13][C:12]=2[CH:18]=1.[H-].[Na+].O.[CH3:22][N:23](C)[CH:24]=O>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:1]([N:2]([CH3:6])[C:3](=[O:4])[N:23]([CH3:24])[CH3:22])=[N:13][C:12]=2[CH:18]=1
Reactant: CN(C)C=O
Reactant: CN(C)C(=O)Cl
Reactant: CNc1nc2cc(Cl)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=O)N(C)c1nc2cc(Cl)ccc2s1

Procedure:
N,N-dimethylcarbamoylchloride (1.1g) and 5-chloro-2-methylaminobenzothiazole (2g) were dissolved in dimethylformamide (25ml) and the mixture was stirred while adding slowly sodiumhydride (0.44g, 55% oily) in a stream of nitrogen for an hour and maintaining the temperature below -5°C. After stirring 3 additional hours at the room temperature, the mixture was poured into water (100ml) and the precipitate was filtrated, washed and dried.
Reaction SMILES: Cl[C:2]1[C:3]2[C:13](=[O:14])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C(N(CC)CC)C.O.[NH2:34][NH2:35]>O1CCOCC1>[NH:34]([C:2]1[C:3]2[C:13](=[O:14])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[NH2:35]
Reactant: NN
Reactant: CCOC(=O)C1CN(c2ccccc2)c2nc(SC)nc(Cl)c2C1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CN(c2ccccc2)c2nc(SC)nc(NN)c2C1=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 96.4 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)-5-oxo-8-phenyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (21 g, 55.57 mmol) in 1,4-dioxane (400 mL) was added triethylamine (8.52 mL, 61.13 mmol) followed by hydrazine hydrate (3.06 g, 61.13 mmol). The reaction mixture was stirred at room temperature for 5-6 h. Upon completion of the reaction, dioxane was removed under reduced pressure and water (250 mL) was added to the reaction mixture. The reaction mixture was then extracted with dichloromethane (200 mL×3). The combined organic layers was washed with water (500 mL) followed by brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude ethyl 4-hydrazinyl-2-(methylthio)-5-oxo-8-phenyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (20 g) which was used in the next step without purification. LCMS [M+H]: 374
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3]>C(OCC)C>[Cl-:1].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: Cl
Solvent: CCOCC
Product: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Product: [Cl-]
Temperature: 0 °C

Procedure:
Under argon and at 0° C., a 2-molar solution of hydrogen chloride in diethyl ether (370 ml) is added dropwise to a solution of tert-butyl 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (25.0 g) in diethyl ether (200 ml). The reaction mixture is stirred at 0° C. and then slowly warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride are removed. This gives 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (20.0 g, 98%)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@H:10]([CH2:19][CH2:20]O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[C@H](CCO)[NH:29][C:30](OC(C)(C)C)=[O:31])C=C.[CH2:41]([O:48][CH2:49][N:50]1[CH:55]=[CH:54][C:53](=[O:56])[NH:52][C:51]1=[O:57])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:30]1(=[O:31])[NH:29][C:1](=[O:8])[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=[C:7]12.[CH2:1]([O:8][C:9](=[O:22])[CH:10]([CH2:19][CH2:20][N:52]1[C:53](=[O:56])[CH:54]=[CH:55][N:50]([CH2:49][O:48][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:51]1=[O:57])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Reactant: O=c1ccn(COCc2ccccc2)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)NC(CCn1c(=O)ccn(COCc2ccccc2)c1=O)C(=O)OCc1ccccc1
Product: O=C1NC(=O)c2ccccc21
Yield: 74 %

Procedure:
In a similar manner to that described in Example 1(1), a reaction was carried out using (±)-N-(tert-butoxycarbonyl)homoserine benzyl ester, instead of (±)-N-(tert-butoxycarbonyl)homoserine allyl ester, and using 1-benzyloxymethylpyrimidine-2,4-dione, instead of phthalimide, to afford the desired compound (yield 74%) as a pale yellow oil.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:23]
Reactant: CCCCN
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 76.4 %

Procedure:
3.6 g of D-galactose, 1.8 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.2 g of 1-(2-chloroethyl)-3-n-butyl-3-D-galactopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14].[OH-].[K+]>Cl.C1(C)C=CC=CC=1>[CH3:14][C:13]1[CH:12]=[CH:11][C:9]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=2)[N:8]=1
Reactant: C/C=C/C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 100 °C

Procedure:
4-Nitroaniline (6 g, 38 mmol) was dissolved in HCl (6N, 200 mL), the mixture was heated at 100° C. A solution of (E)-but-2-enal (7.2 mL, 76 mmol) in toluene (60 mL) was added dropwise, and the reaction was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and basified with aqueous KOH until pH=12. The mixture was extracted with EtOAc and the organic layer was washed with brine and dried over anhydrous Na2SO4. 2-Methyl-6-nitroquinoline was obtained after purification by column chromatography (hexane: EtOAc=20:1) (5.8 g, 81.2%). MS [M++1]=189, LC-MS: tR=1.64 min.
Reaction SMILES: CS(OC[C@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC(C(O)(C)C(F)(F)F)=CC=1)(=O)=O.C1(NC)CC1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].[CH:44]1([CH2:47][NH:48][CH2:49][C@H:50]2[CH2:55][N:54]([S:56]([C:59]3[S:60][CH:61]=[CH:62][CH:63]=3)(=[O:58])=[O:57])[CH2:53][CH2:52][N:51]2[C:64]2[CH:69]=[CH:68][C:67]([C:70]([OH:76])([CH3:75])[C:71]([F:74])([F:73])[F:72])=[CH:66][CH:65]=2)[CH2:46][CH2:45]1>>[CH:44]1([CH2:47][N:48]([CH2:49][C@H:50]2[CH2:55][N:54]([S:56]([C:59]3[S:60][CH:61]=[CH:62][CH:63]=3)(=[O:58])=[O:57])[CH2:53][CH2:52][N:51]2[C:64]2[CH:69]=[CH:68][C:67]([C:70]([OH:76])([CH3:75])[C:71]([F:72])([F:73])[F:74])=[CH:66][CH:65]=2)[S:40]([CH3:39])(=[O:42])=[O:41])[CH2:45][CH2:46]1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNCC2CC2)cc1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: CNC1CC1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN(CC2CC2)S(C)(=O)=O)cc1)C(F)(F)F

Procedure:
This compound was synthesized following the scheme described for Example 195. The reaction of ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (Intermediate B) and cyclopropyl methylamine (Alfa Aesar, Ward Hill, Mass.), followed by sulfonamide formation (using MsCl) delivered 2-(4-((2S)-2-(((cyclopropylmethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of two isomers.
Reaction SMILES: [Na+].[N:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([O-:11])(=[O:10])=O.[CH3:12]I>>[CH3:12][N:5]1[CH:6]=[CH:7][NH:2][C:3](=[S:8](=[O:10])=[O:11])[CH2:4]1
Reactant: CI
Reactant: O=S(=O)([O-])c1cnccn1
Agent: [Na+]
Product: CN1C=CNC(=S(=O)=O)C1

Procedure:
4.0 g of Pyrazine-2-sulfonic acid sodium salt (1900) was added to a solution of 20 ml methyl iodide/40 ml methanol and the mixture refluxed for 7 days. The solvent was evaporated and the residue chromatographed (Biogel P-2/water) giving 3.5 g of product (2000) which was recrystallized from ethanol/water, m.p. 270°-2° (dec). UV H2O max: 282 (3.86).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22](O)=[C:21](C)[N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.O=S(Cl)Cl.[Na+].[I-].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl-].[CH2:42](Cl)Cl>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:27]([CH3:28])[CH3:29])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:42][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1CCNC1
Reactant: Cc1nnn(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)c1O
Reactant: ClCCl
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-dimethylamino-4-[3-(5-hydroxy-methyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 3) (123 mg, 0.3 mmol) by treatment with SOCl2 (0.044 mL, 0.6 mmol) in CH2Cl2 (2 mL) from 23° C. to reflux for 15 min, followed by evaporation to dryness. The crude chloride was dissolved in DMF (2 mL) and stirred with cat. amount of NaI and pyrrolidine (0.248 mL, 3.0 mmol) at 23° C. until tlc indicated complete conversion of the chloride. The reaction mixture was taken up in EtOAc, washed with water and brine, dried over Na2SO4. Removal of the solvent in vacuum left a yellow semisolid, which was purified by silica gel column chromatography. Obtained as a yellow solid (101 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[OH:27]/[N:28]=[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].[H-].[Na+].Cl>CN(C)C=O.O>[CH3:26][O:25][C:5]1[CH:4]=[C:3]([CH:22]=[C:21]([O:23][CH3:24])[C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])[CH2:2][O:27]/[N:28]=[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Reactant: COc1cc(CCl)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC/C(=N\OCc1cc(OC)c(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a stirred solution of 4-(4-chloromethyl-2,6-dimethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (585 mg) in N,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 115 mg) at 0° C. After stirring for 2 hours, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:3, v/v) gave methyl E-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (970 mg, yield 65%) as a colorless oil.