Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:11])[CH2:9][CH3:10].[NH2:12][C:13]1[N:21]=[C:20](Cl)[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Na+].O>[NH2:12][C:13]1[N:21]=[C:20]([S:11][CH2:8][CH2:9][CH3:10])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 88.8 %

Procedure:
To DMF suspension (50 ml) containing sodium hydride (917 mg, 23 mmol, 60% in mineral oil) were added propanethiol (5.0 ml, 55 mmol) and 6-amino-9-benzyl-2-chloropurine (500 mg, 1.9 mmol) in order. The mixture was stirred under heating at 110° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (505 mg, yield 87%).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:9]([CH2:20][CH3:21])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:20][CH3:21])[C:10]([OH:12])=[O:11])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Under an atmosphere of argon, (S)-benzyl 2-(dibenzylamino)butanoate (84 g, 191 mmol, Eq: 1.00) was combined with methanol (136 ml) to give a light yellow solution. Then cold (0° C.) NaOH solution (15.3 g in 150 ml water, 382 mmol, Eq: 2) was added at once to the reaction mixture. The reaction was stirred at 90° C. for 4 h. Upon cooling to RT, the reaction mixture was poured into water (75 ml) and extracted with tert-butyl methyl ether: heptane=1:1 (2×150 ml), to remove the benzylalcohol formed in the hydrolysis. The basic aqueous layer was acidified to pH 2 with HCl (conc.). The aqueous layer was then extracted with ethyl acetate (2×250 ml). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residual solvent was removed under vacuum. The title compound was obtained as a white solid (68.13 g, quant., MS (m/e)=284.1 [M+H+], MS (m/e)=282.3 [M−H+]).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]#[N:21])[CH2:6][CH:7]([N:9]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:11][C:12]#[N:13])[CH3:8])#[N:2].[H][H]>O1CCOCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:6][CH:7]([N:9]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8]
Reactant: CC(CN(CCC#N)CCC#N)N(CCC#N)CCC#N
Reactant: [H][H]
Solvent: C1COCCO1
Product: CC(CN(CCCN)CCCN)N(CCCN)CCCN
Yield: 96.9 %

Procedure:
20.05 g of N,N,N′,N′-tetrakis(2-cyanoethyl)-1,2-diaminopropane, 2.01 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 160° C. for 3 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 20.52 g of the title compound as a white solid.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.C(O)(=O)C.[F:10][C:11]([F:39])([F:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:27](=[O:33])[CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[F:39][C:11]([F:38])([F:10])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:27](=[O:33])[C:26]([Cl:4])=[C:25]([C:34]([F:35])([F:36])[F:37])[N:24]=1
Reactant: CCCCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Sulfuryl chloride (0.011 ml) was added to acetic acid (1.3 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-butyl-6-trifluoromethyl-4(3H)-pyrimidinone (60 mg, 0.13 mmol) which had been synthesized in accordance with the method of Example 24, followed by stirring at room temperature for 1 hour. After completion of the reaction, ether (20 ml) was saturated sodium bicarbonate aqueous solution (20 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (10 ml×2). The thus obtained ether layers were combined, washed with sodium bicarbonate aqueous solution (20 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (dichloromethane:hexane=10:3), white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-butyl-5-chloro-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 55] was obtained.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:19][NH:20][CH2:21][CH2:22][O:23]C(=O)C(C)(C)C)[CH:9]=[CH:10][C:11]=1[CH:12]=[CH:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>C(O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[CH:9]=[CH:10][C:11]=1[CH:12]=[CH:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CNCCO)ccc1C=Cc1cccs1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
NaOH (4.3 g, 107 mmol) was dissolved in ethanol (25 ml), and water (7 ml) was added thereto. Next, 2,2-dimethylpropionic acid 2-{[3-methoxy-4-(2-thiophene-2-ylvinyl)phenyl]methylamino}ethyl ester (4.0 g, 10.7 mmol) was dissolved in ethanol (8 ml) and added dropwise to the mixture. The mixture was stirred at room temperature for 2 hours and further at 45° C. for 1 hour. After the solvent was evaporated off, water (100 ml) was added and the oily matter was subjected to extraction with ethyl acetate. After 2 times of washing with water, drying over Na2SO4 and concentration were performed. The residue was purified by silica gel chromatography to give a yellow oily matter (yield: 3.1 g (100%)).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1
Reactant: CO
Reactant: N#Cc1ccc(C(N)CC(=O)O)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
436 mg (2.09 mmol) 3-amino-3-(4-cyano-3-fluorophenyl)propionic acid were suspended in 8.5 ml methanol and the mixture cooled to 0° C. 0.23 ml (3.14 mmol) thionyl chloride were slowly added. The mixture was stirred at room temperature for 20 hours and concentrated. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic part was dried with sodium sulfate and concentrated. Chromatography over silica gel (dichloromethane/ethanol 100/0-97/3-94/6) gave 245 mg (47%) 3-amino-3-(4-cyano-3-fluoro-phenyl)-propionic acid methyl ester.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[C:8]([CH2:20]Br)[CH:7]=1.O>CN(C)C=O>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[N+:2]=[N-:3]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2cc(Br)cc(CN=[N+]=[N-])c2nc1OC
Reaction time: 3 h

Procedure:
743 mg (2 eq.) of sodium azide are added at 20° to 2.07 g (5.72 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxyquinoxaline in 25 ml of dimethylformamide. After 3 hours, the mixture is poured into water, extracted with diethyl ether, and the extract is washed with water and brine and dried using magnesium sulfate. The solvent is evaporated.
Reaction SMILES: [NH2:1][NH2:2].C[N:4]([CH:6]=[N:7][C:8](=O)[CH3:9])[CH3:5].[C:11]([OH:14])(=[O:13])C>>[CH3:9][C:8]1[N:2]([C:6]2[N:4]=[CH:5][C:9]([C:11]([OH:14])=[O:13])=[CH:8][N:7]=2)[N:1]=[CH:6][N:7]=1
Reactant: NN
Reactant: CC(=O)N=CN(C)C
Reactant: CC(=O)O
Product: Cc1ncnn1-c1ncc(C(=O)O)cn1
Temperature: 90 °C

Procedure:
2-Chloropyrimidine-5-carboxylic acid (1.5 g) is dissolved in MeOH (25 mL) and hydrazine (5 mL) is added at r.t. An exothermic reaction occurs and a solid precipitate forms. The solid is filtered off washing with a little MeOH and is dried by suction to give the hydrazine intermediate. The hydrazine is dissolved in acetic acid (4 mL) and N-((dimethylamino)methylene)acetamide [made from acetamide and N,N-dimethylformamide-dimethylacetal by procedure in US2007/0111984A1] (2.0 g) is added and heated at 90° C. for 1 h. After cooling and concentrating the residue is purified by HPLC to give the title compound. LC (method 20): tR=1.24 min; Mass spectrum (APCI): m/z=206 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:11]1([NH:14][C:15]2[N:20]3[N:21]=[CH:22][C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/4)=[C:19]3[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH2:13][CH2:12]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1>CN1C(=O)CCC1>[CH:11]1([NH:14][C:15]2[N:20]3[N:21]=[CH:22][C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/4)=[C:19]3[N:18]=[C:17]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)[N:16]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccc(CN)cc1C
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CN1CCCC1=O
Product: Cc1ccc(CNc2nc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cc1C
Temperature: 80 °C

Procedure:
A solution of (3,4-dimethylphenyl)methanamine in NMP (106 μl, 0.4 M, 1.5 eq, 0.042 mmol) was transferred in a glass reaction vial. A solution of a (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione in NMP (100 μl, 0.282M, 1.0 eq, 0.0282 mmol) was added. The mixture was heated at 80° C. for 5 hours. NMP was added (0.7 ml) and the solution subjected to preparative HPLC purification. Genevac evaporation provided (Z)-5-((4-(cyclopropylamino)-2-(3,4-dimethylbenzylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a solid (5.8 mg). LCMS (ES): >85% pure, m/z 419 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[CH2:28](N)CC.C1(N2C3C=CC=C(NCC4(C(F)(F)F)CO4)C=3C=N2)C=CC=CC=1>>[F:7][C:6]([F:9])([F:8])[C:5]([CH2:4][NH:3][CH2:1][CH2:2][CH3:28])([OH:10])[CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: CCCN
Agent: FC(F)(F)C1(CNc2cccc3c2cnn3-c2ccccc2)CO1
Product: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 15 from n-propylamine and 1-phenyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[C:9]1[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1.C1COCC1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>CC#N.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:9]1([C@@H:4]2[C@H:3]([CH3:2])[CH2:8][CH2:7][N:6]([C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:5]2)[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@@H]1CCNC[C@@H]1c1ncc2cnc3[nH]ccc3n12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H]1CCN(C(=O)Oc2ccccc2)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 25 °C
Yield: 12.9 %

Procedure:
To a solution of 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.06 g, 0.21 mmol) in MeCN (1 mL) at about 0° C. was added TEA (0.06 mL, 0.41 mmol), THF (0.6 mL) and DMAP (0.006 g, 0.050 mmol) then phenyl chloroformate (0.026 mL, 0.206 mmol) and stirred for about 1 h. The reaction mixture was warmed to ambient temperature and concd under reduced pressure. The crude residue was dissolved in DCM (3 mL) and washed with water (2 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude residue was dissolved in DCM (5 mL) and washed with water (2 mL) and brine (2 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by RP-HPLC (Table 1, Method g) to give (3R,4R)-phenyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (0.010 g, 11%): LC/MS (Table 1, Method b) Rt=1.95 min; MS m/z 376 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:19])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:20]Br>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:19])[CH:11]([Br:20])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethanone of Step B (2 g, 7.83 mmol) in acetic acid (15 mL) was slowly added a solution of bromine (0.40 mL, 1 equiv) in acetic acid (5 mL). The resulting reaction mixture was stirred at ambient temperature for 1 h, concentrated in vacuo, diluted with diethyl ether (20 mL) and methylene chloride (10 mL). The resulting suspension was stirred at ambient temperature for 16 hours, and then filtered to yield the title compounds as a light beige solid (3.0 g, 92%).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45]([OH:47])=[O:46].C(N(CC)C(C)C)(C)C>ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45]([OH:47])=[O:46])=[O:12])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
A solution of Boc-D-Cha-OH (50.4 g, 185 mmol) in dichloromethane (360 mL) was cooled to 0° C. and N-hydroxysuccinimide (22.3 g, 194 mmol) was added. Then 1,3-dicyclohexylcarbodiimide (39.0 g, 189 mmol) was added in two portions as a solution in dichloromethane (90 mL). After stirring for 3 h at 0° C., L-Pro-OH (27.6 g, 240 mmol) and N,N-diisopropylethylamine (30.9 g, 239 mmol) were added. After stirring an additional 3 h between 0° C. and 10° C., the mixture was filtered over diatomaceous earth. The filter cake was rinsed with dichloromethane (100 mL); then the combined filtrates were concentrated in vacuo. The residual oil was partitioned between ethyl acetate (100 mL) and 0.625 M aqueous NaHCO3 (320 mL). The layers were separated, and the organic phase was washed with 0.625 M aq. NaHCO3 (80 mL). The combined bicarbonate extracts were then washed with ethyl acetate (100 mL). The aqueous phase was then stirred with ethyl acetate (300 mL) and acidified with 12 N HCl (approximately 37 mL). The layers were separated and the acidic aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were concentrated in vacuo. The residue was slurried with a minimal amount of ethyl acetate, filtered, washed again with ethyl acetate and dried to give 50.1 g (73%) of white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([Cl:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c(C)c(Cl)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (4.54 g) in DMF (34.0 mL) was added N-chlorosuccinimide (2.47 g), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]COCCOC)[CH:6]=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:23][C:24]#[N:25]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[C:23](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=2)/[C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COCCOCOc1ccc(C=O)cc1OC
Product: COc1cc(/C=C(\C#N)c2ccc(OC)c(OC)c2)ccc1O
Yield: 48.2 %

Procedure:
The hydroxyl group of 4-hydroxy-3-methoxybenzaldehyde (1.4 g) was protected by use of 2-methoxyethoxymethyl chloride (1.7 g) in accordance with (production process 1), to thereby produce 3-methoxy-4-methoxyethoxymethoxybenzaldehyde (0.8 g, yield: 31%). The thus-produced 3-methoxy-4-methoxyethoxymethoxybenzaldehyde (0.8 g) and 3,4-dimethoxybenzyl cyanide (0.6 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (0.5 g, yield: 51%).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.C(N([CH:12]([CH3:14])[CH3:13])CC)(C)C.[C:15](=O)(O)[O-:16].[Na+].[C@H:20](O)(C([O-])=O)[C@@H:21](O)[C:22]([O-])=[O:23].[Na+].[K+]>ClCCl>[CH3:15][O:16][CH:13]1[CH2:12][CH2:14][CH2:20][CH2:21][C:22]1=[O:23]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: O=C([O-])O
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: COC1CCCCC1=O
Reaction time: 0.17 h

Procedure:
A solution of 2(S) 2-methoxycyclohexanone (4.089 g) and (3S,4R)-4-acetoxy-3[(R)-(t-butyldimethylsilyloxy)ethyl]azetidinone (4.63 g) in dichloromethane (140 ml) was prepared at -16°. Tin tetrachloride (14.3 g) was added dropwise via syringe at such a rate that the temperature was kept beetween -16° and -13°. The mixture was stirred for 10 minutes, then the temperature was increased to +3°. A solution of di-isopropylethylamine (5.33 g) dissolved in dichloromethane (40 ml) was added over 20 minutes. The reaction mixture was stirred for 10 minutes at +3°, then the reaction mixture was poured into 300 ml of a 1:1 mixture of sodium bicarbonate (saturated) and Rochelle's salt (saturated) and extracted into diethylether (500 ml) with vigorous stirring over 1 h. The organic layer was washed with saturated brine(150 ml), dried and the solvent removed to give an white solid (7.10 g). The crude solid was taken up in hot n-hexane (175 ml), filtered and the volume reduced to 75 ml. The resulting mixture was warmed to completely dissolve the solid. The resultant solution was cooled and stirred and the title compound was isolated by filtration as a white solid (3.03 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16]C)[C:10]([O:14]C)=[N:11]2)=[C:6]([CH2:18][N:19]([CH2:28][CH3:29])[CH:20]([P:22](=[O:27])([O:25]C)[O:23]C)[CH3:21])[CH:5]=1)([O-:3])=[O:2].C([Si](CC)(CC)[Br:33])C>ClCCl>[BrH:33].[O:14]=[C:10]1[C:9](=[O:16])[NH:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:18][N:19]([CH2:28][CH3:29])[CH:20]([P:22](=[O:23])([OH:25])[OH:27])[CH3:21])[NH:11]1
Reactant: CCN(Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)C(C)P(=O)(OC)OC
Reactant: CC[Si](Br)(CC)CC
Solvent: ClCCl
Product: Br
Product: CCN(Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)C(C)P(=O)(O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
160 mg (0.37 mmol) of dimethyl N-(7-nitro-2,3-dimethoxyquinoxalin-5-ylmethyl)-α-(ethylamino)ethylphosphonate are dissolved in 8 ml of dichloromethane and stirred at room temperature for one hour with 0.19 ml (4 eq.) of triethylbromosilane. The solvent and excess reagent are evaporated and the residue is briefly dried in a high vacuum, dissolved in 5 ml of an about 33% hydrogen bromide solution in acetic acid, and stirred at room temperature for 18 hours. The reaction mixture is diluted with diethyl ether, and the solid is filtered off, washed with diethyl ether and dried. The title compound is obtained as a beige solid; m.p.=191° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13]C)=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[C:3]=1[F:16].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[C:3]=1[F:16]
Reactant: COC(=O)c1c(Cl)c(F)c(=O)n2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(Cl)c(F)c(=O)n2c1CCC2
Yield: 86.4 %

Procedure:
Compound 1c (460 mg, 1.9 mmol) was stirred in a solution of THF (10 mL), MeOH (5 mL), and 1N NaOH (5 mL) at RT for 20 h. The solution was made acidic with 1N HCl and extracted (3×) with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo to give 380 mg (88%) of compound 1d as a white solid. 1H NMR (400 MHz, CDCl3): δ 4.15 (t, 2H, J=7.6 Hz), 3.31 (t, 2H, J=7.6 Hz), 2.19-2.27 (m, 2H). MS (ES) [m+H] calc'd for C9H7ClFNO3, 232, 234. found 232, 234.
Reaction SMILES: [C:1]([C:6](=[NH:8])[O-])([O:3][CH2:4][CH3:5])=[O:2].[NH2:9][C:10]1[C:19]([C:20](OCC)=[O:21])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>C(O)C>[N:9]1[C:10]2=[N:11][C:12]3[C:17]([CH:18]=[C:19]2[C:20](=[O:21])[NH:8][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCOC(=O)c1cc2ccccc2nc1N
Reactant: CCOC(=O)C(=N)[O-]
Solvent: CCO
Product: CCOC(=O)c1nc2nc3ccccc3cc2c(=O)[nH]1

Procedure:
The same compound is obtained by: (a) refluxing equimolar amounts of 1-carbethoxyformimidate and ethyl 2-aminoquinoline-3-carboxylate in ethanol for three hours. The reaction mixture is concentrated, the product collected by filtration and recrystallized from hot chloroform; or (b) refluxing equimolar amounts of 1-carbethoxyformamidine and 2-aminoquinoline-3-carboxamide in ethanol for 3-4 hours in the presence of an equimolar amount of sodium ethoxide. The reaction mixture is worked up as described in (a) above.