Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:24][CH:23]=2)[CH:8]=1.Cl.O>CC(C)=O>[CH:2]([C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:24][CH:23]=2)[CH:8]=1)=[O:1]
Reactant: CCOC(=O)COc1ccc(C2OCCCO2)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
In 200 ml of acetone was dissolved 8.69 g of ethyl 4-(1,3-dioxan-2-yl)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Reference Example 41. To the solution was added 6 ml of 6% hydrochloric acid. The mixture was stirred at room temperature for 2 hours. After adding 30 ml of water thereto, the mixture was cooled and the precipitated crystals were taken by filtration, washed with 50% acetone to obtain 6.0 g of ethyl 4-formyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:31][O:30][C:22]1[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=[C:20]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:10][CH:9]=2)[C:5]2[NH:4][C:3](=[O:2])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of 6.02 g of [2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 50 ml of DMF there were added 1.24 g of 2-hydrazinopyrimidine and 1.9 ml of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 50 ml of methanol and 5 ml of acetic acid. After then adding 3.4 g of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (3.317 g) as a light yellow solid.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29]>>[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([O:24][C:34]3[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 38 %

Procedure:
The title compound (0.15 g, 38%) was prepared as a yellow liquid from 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.77 mmol) obtained in example 29 and 4-nitrophenol by an analogous procedure to that described in example 32.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][N:19]3[CH2:23][CH2:22][N:21]=[CH:20]3)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[BrH:24]>C(O)(=O)C>[BrH:24].[BrH:24].[CH3:17][C:16]1[C:11]2[NH:10][CH:9]=[N:8][C:12]=2[CH:13]=[CH:14][C:15]=1[NH:18][N:19]1[CH2:23][CH2:22][N:21]=[CH:20]1
Reactant: Cc1c(NN2C=NCC2)ccc2c1ncn2C(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Product: Cc1c(NN2C=NCC2)ccc2nc[nH]c12
Temperature: 25 °C

Procedure:
To a solution of 1 -tert-butoxycarbonyl-4-methyl-5-(2-imidazolinylamino)benzimidazole (2.40 g) in glacial acetic acid (50 mL) is added a solution of hydrobromic acid in glacial acetic acid (30%, 6 mL). The mixture is stirred at room temperature and gas evolution is monitored. After the gas evolution has stopped (about 1 hour), the precipitate is filtered and washed with ether. The solid is recrystallized from methanol/ether and dried in vacuo to afford 4-methyl-5-(2-imidazolinylamino)benzimidazole dihydrobromide as a pale rose solid.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[C:3]([N:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1)=O>C1COCC1>[O:12]=[S:8]1(=[O:11])[CH2:9][CH2:10][N:5]([CH2:3][C@@H:2]([NH2:1])[CH3:13])[CH2:6][CH2:7]1
Reactant: CC(N)C(=O)N1CCS(=O)(=O)CC1
Solvent: C1CCOC1
Product: C[C@H](N)CN1CCS(=O)(=O)CC1
Temperature: 25 °C
Yield: 128.6 %

Procedure:
A mixture of 2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g, 18.2 mmol) and BH3 (1 M in THF, 110 mL) was heated to reflux for 48 h, then cooled to room temperature and quenched by MeOH. The volatile was removed under vacuum. 2 N HCl (100 mL) was added to the residue and heated to reflux for 18 h. Solvent was removed under vacuum to give (S)-2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine (4.5 g) as white solid, yield 90%. MS (M+H)=193.
Reaction SMILES: C[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[C:18]([Cl:19])=[C:17]([Cl:20])[N:16]=[C:15]3[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:9][CH:8]=2)[C:3]=1[C:25]([O-:27])=[O:26]>CO.[OH-].[Na+].O>[CH2:21]([C:15]1[N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH:5]=[CH:6][CH:2]=[C:3]3[C:25]([OH:27])=[O:26])=[CH:8][CH:9]=2)[C:18]([Cl:19])=[C:17]([Cl:20])[N:16]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1nc(Cl)c(Cl)n1Cc1ccc(-n2ccc(C)c2C(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(Cl)c(Cl)n1Cc1ccc(-n2cccc2C(=O)O)cc1

Procedure:
A solution of 250 mg of the methyl ester from Example 1, Step (i) in 25 mL of methanol and 25 mL of sodium hydroxide in water (10%) was stirred at ambient temperature overnight. The methanol was removed in vacuo and the pH adjusted to 4 with hydrochloric acid which caused the acid to precipitate. The product was collected by filtration: m.p. 181°-182° C.; MS(FAB) m/e(rel intensity 392 (60, M+H+), 200(100); HRMS. Calcd for M+H: 392.0933; found: 392.0967.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16](=[O:30])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>ClCCl.C(OCC)C>[CH3:31][N:15]1[C:14]([CH:13]=[O:12])=[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:30]
Reactant: Cn1c(CO)c(-c2ccccc2)c2ccccc2c1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(C=O)c(-c2ccccc2)c2ccccc2c1=O
Reaction time: 1.75 h
Yield: 69.7 %

Procedure:
A stirred suspension of pyridinium chlorochromate (23.36 g) in dichloromethane (250 ml) was treated with a suspension of 3-hydroxymethyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline (19.1 g) in dichloromethane (1000 ml), and stirred for 1.75 hours. Then the reaction mixture was diluted with diethyl ether (3000 ml), stirred for 20 minutes, and filtered through diatomaceous earth. The filter pad was washed with diethyl ether (1000 ml) and the combined filtrate and washings were filtered through a 3 inch thick pad of silica gel. The filtrate was evaporated and the resulting residue was crystallised from ethyl acetate, to give 2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-carbaldehyde (13.22 g) in the form of white crystals, m.p.181°-182° C. [Elemental analysis: C,77.4; H,4.94; N,5.29%; calculated: C,77.6; H,4.98; N,5.32%].
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=2)=[C:5]([O:21][CH3:22])[CH:4]=1)=[CH2:2]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=2)=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: C=Cc1cc(OC)c2ccn(-c3ccc(OC)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(OC)c2ccn(-c3ccc(OC)c(F)c3)c2c1
Yield: 89.7 %

Procedure:
A solution of 6-ethenyl-1-[3-fluoro-4-(methyloxy)phenyl]-4-(methyloxy)-1H-indole (D9) (200 mg, 0.67 mmol) in ethanol (7 mL) and ethyl acetate (7 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated and the product purified by silica gel chromatography eluting with 5-70% dichloromethane in hexane to yield the title compound (D10), (180 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.C[CH2:19][O:20]CC.C([Li])CCC.CN(C)C=O>O>[S:12]1[CH:13]=[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]1=2
Reactant: CCOCC
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C=Cc2csc3ccccc23)s1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To a chilled (-70° C.), stirred solution of 3-[2-(5-bromo-2-thienyl)-ethenyl]benzo[b]thiophene (16.98 g) and ether (300 ml) was added n-butyllithium (23 ml of a 2.5M solution in hexanes), under nitrogen, over 5 mins. After stirring for 1.5 hrs, the mixture was added via canula to a solution of N,N-dimethylformamide (19.3 g) and ether (500 ml). The mixture was allowed to warm to room temperature, stirred overnight, and then poured into water (500 ml). The aqueous phase was separated, and the organic phase was washed with 10% aqueous hydrochloric acid, water, and 5% aqueous sodium bicarbonate solution. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give 14.9 g of solid. A lot of similarly prepared material (4.1 g) was combined with the solid, and the combined material was purified by high performance liquid chromatography (silica gel, loaded and eluted with 10% hexane in dichloromethane). The appropriate fractions were combined and evaporated. The residue was recrystallized from toluene/hexane to give 9.25 g (51%) of product, mp 105°-107° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([OH:11])[CH:4]=1.[Na+].[CH3:13][S:14]([O-:16])=[O:15].CN(C=O)C>C(#N)C>[CH3:10][S:9][C:7]1[N:6]=[C:5]([OH:11])[CH:4]=[C:3]([CH2:2][S:14]([CH3:13])(=[O:16])=[O:15])[N:8]=1
Reactant: CSc1nc(O)cc(CCl)n1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CSc1nc(O)cc(CS(C)(=O)=O)n1
Temperature: 100 °C

Procedure:
6-(Chloromethyl)-2-methylsulfanyl-pyrimidin-4-ol (19.07 g, 100 mmol) was suspended in acetonitrile (400 ml). To this stirring suspension was added methanesulphinic acid sodium salt (12.255 g, 120 mmol) and DMF (100 ml). The reaction was then heated to 100° C. to give a dark suspension and monitored by LCMS. Once complete, the solvents were removed and the resultant product added to 1:1 MeOH:DCM (200 ml) and acidified with acetic acid (10 ml). The resultant precipitate was collected, washed with water (200 ml) and MeOH (100 ml) and dried overnight in vacuo to afford the title compound as a white solid, 16.45 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([OH:31])=O)([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:4]=1.CCN=C=NCCCN(C)C.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:57][S:54]([CH:51]5[CH2:53][CH2:52]5)(=[O:56])=[O:55])=[O:31])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:4]=1
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of the acid 13e (150 mg, 0.28 mmol) and EDAC (65 mg, 0.34 mmol) in dry DCM (3 ml) was stirred overnight. Cyclopropane sulphonamide (72.7 mg, 0.6 mmol) and DBU (120 mg, 0.8 mmol) was added and the mixture was stirred overnight at room temperature. 5% Citric acid was added and the mixture was extracted with ethyl acetate. The organic phase was washed two times with 5% citric acid and water, dried with sodium sulphate and evaporated under reduced pressure. Purification by HPLC gave the title compound, (100 mg, 56%), (M+H)+638
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=O)[C:8](=[O:17])[CH2:7][CH2:6]1)=[O:4].[CH2:18]([OH:21])[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH2:18]1[O:21][C:12]([CH:9]2[CH2:10][CH2:11][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7][C:8]2=[O:17])([O:14][CH2:15][CH3:16])[O:20][CH2:19]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCN(C(=O)OC)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC1(C2CCN(C(=O)OC)CCC2=O)OCCO1
Reaction time: 4 h

Procedure:
A mixture of ethyl 1-methoxycarbonyl-4-oxoperhydroazepine-5-carboxylate (VI; cf: Krogsgaard-Larsen, et al., Eur. J. Med. Chem.. 14 (1979) pp. 157-164) (26.9 g; 0.11 mol), ehtylene glycol (30.7 mL; 0.55 mol), 4-toluenesulphonic acid hydrate (2.11 g; 11 mmol), and toluene (200 mL) was refluxed in a Dean-Stark water separator for 4 h. Upon addition of toluene (200 mL) the reaction mixture was washed with a saturated solution of sodium bicarbonate (50 mL), dried (K2CO3) and evaporated to give crude (V), which was used without further purification as starting material for the synthesis of (IV).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[C:7]1[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3](=[O:25])[CH:2]([NH:1][C:34]([NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=2)=[O:35])[N:8]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Product: COc1cc(C)cc(OC)c1C1=NC(NC(=O)Nc2cccc(C)c2)C(=O)N(C)c2ccccc21
Yield: 94 %

Procedure:
By using 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one as above and by condensing it as above with 3-methylphenyl isocyanate, 1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-3-(3-methylphenylureido)-1,4-benzodiazepin-2-one is obtained; m.p.=260° C.; Yield=94%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].[CH3:16][O:17][CH2:18][C@H]1COC(=O)O1>CS(C)=O>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:16][O:17][CH3:18])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)NCc1ccccc1
Reactant: COC[C@H]1COC(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: COC[C@H]1CN(Cc2ccccc2)C(=O)O1
Temperature: 140 °C
Reaction time: 28 h
Yield: 83.5 %

Procedure:
Benzylurethane (15.0 g, 83.9 mmol) was dissolved in dimethyl sulfoxide (40 mL), and thereto were added cesium fluoride (1.16 g, 7.63 mmol) and (S)-4-methoxymethyl-1,3- dioxolan-2-one (10.0 g, 76.3 mmol, optical purity 98.4%ee), in order. The mixture was stirred for 28 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by silica gel chromatography to give the subject (R)-3-benzyl-5-methoxymethyloxazolidin-2-one (14.1 g, yield 83.5%, optical purity 98.2%ee).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([O:17][CH3:18])[C:14]([O-])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.N1C=CC=CC=1>[N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([O:17][CH3:18])[C:14]([Cl:25])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reaction time: 2 h

Procedure:
Sodium N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycinate (0.92 g, 3 mMol) is suspended in dry CH2Cl2 (25 ml) and cooled in an ice-water bath. Oxalyl chloride (0.38 g, 3 mMol) and 2 drops of pyridine are added. The resulting mixture is stirred in the cold for 2 hours, and then filtered. The filtrate, which contains N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycyl chloride, is used directly in the next step.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)(=O)C>[CH2:13]([N:21]1[C:22]([C:3]2[C:4](=[O:11])[C:5]3[C:10]([C:1](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:23][CH:24]=[C:25]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CCCCCCCCn1cccc1
Solvent: CC(=O)O
Product: CCCCCCCCn1c(C2=CC(=O)c3ccccc3C2=O)ccc1C1=CC(=O)c2ccccc2C1=O
Yield: 49 %

Procedure:
The same procedure as in Example 7 was followed by stirring 10 millimol of 1,4-naphthoquinone with 2.5 millimol of N-octylpyrrole in 40 ml of acetic acid at 50° C. for 5 hours. The 1-octyl-2,5-bis(1,4-naphthoquinon-2-yl)pyrrole was thus obtained in a yield of 49% after chromatography on a column of silica.
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:4][C:3](=[O:5])[C:2]([NH2:1])([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH3:6])[CH3:16]
Reactant: CC(N)(C(=O)O)c1ccc(Br)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)(N)c1ccc(Br)cc1
Reaction time: 24 h
Yield: 72 %

Procedure:
To a solution of 2-amino-2-(4-bromo-phenyl)-propionic acid (1.0 g, 4.1 mmol) in ethanol (20 mL) was bubbled through HCl gas for five minutes. The mixture was stirred at ambient for 24 hours, then refluxed for 18 hours. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL), washed with NaHCO3 solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (800 mg, 72%). m/z 271.7, 273.7 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:18].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:22].C(N(CC)CC)C>CO>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:21]([CH2:20][N:15]1[CH2:14][CH2:13][CH:12]([N:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2][C:3]2=[O:18])[CH2:17][CH2:16]1)=[O:22]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(N2Cc3ccccc3NC2=O)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In this example, 2.67 g of 4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine mono-hydrochloride, 2.33 g of α-bromo-m-chloroacetophenone, 2.8 ml of triethylamine and 30 ml of methanol are mixed and stirred at room temperature overnight. Then, the white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 2.89 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 1.93 g of the desired product.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13]C3N=CNC=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)C=CC=3)=O)[CH2:8][C:7]=2[CH:31]=1.[OH-].[Na+].C(Cl)(=[O:36])C>ClCCl>[C:10]([N:9]1[CH2:8][C:7]2[CH:31]=[C:3]([Br:2])[CH:4]=[CH:5][C:6]=2[NH:12][CH2:13][CH:19]1[CH2:21][C:30]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:36])[CH3:11]
Reactant: CC(=O)Cl
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Br)ccc2NCC1Cc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of Compound B (200 mg, 0.63 mmol), dichloromethane (5 mL), and aqueous sodium hydroxide (1 ml, 1N) was combined and cooled to 0° C. Acetyl chloride (66 mL, 0.94 mmol) was added to the mixture, and after stirring for 2 hour at 0° C. aqueous sodium hydroxide (20 ml, 1N) and dichloromethane (50 mL) were added, followed by extraction with dichloromethane (50 mL). The organic portions were combined, dried (Na2SO4), and concentrated to a crude oil (230 mg, 100%).
Reaction SMILES: C(O[C:9]1C=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.Cl.[NH2:29]N>C(O)C>[N:29]1[CH:9]=[CH:10][CH:11]=[C:12]([C:15]2[CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:21])[NH:19][N:20]=2)[CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]c1=O
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccnc2)n[nH]c1=O

Procedure:
Working as in example 19 for the preparation of ethyl 6-[4-(benzyloxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate, but starting with 8.85 g of diethyl hydroxy(pyridin-3-oxoethyl)malonate, 3.67 g of hydrazine dihydrochloride and 250 cm3 of ethanol, and after recrystallization from ethanol, 3.6 g of ethyl 6-pyridin-3-yl-3-oxo-2,3-dihydropyridazine-4-carboxylate were obtained in the form of a green solid melting at a temperature in the region of 150° C.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][O:9]C(=O)C)(=[O:6])[O:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][P:3]([CH2:7][CH2:8][OH:9])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CCOC(C)=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COP(=O)(CCO)OC
Yield: 75 %

Procedure:
A solution of 100 g of 2-acetoxyethane-phosphonic acid dimethyl ester in 100 ml of anhydrous methanol -- 4 g of p-toluenesulfonic acid being added -- is heated for 5 hours to 65°-75°C while removing simultaneously by distillation a mixture of methyl acetate/methanol. After distillation under reduced pressure, 59 g of 2-hydroxyethane-phosphonic acid dimethyl ester are obtained, corresponding to a yield of 75% of the theoretical.