Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl.[C:29]([NH2:32])(=[NH:31])[CH3:30].CCN(C(C)C)C(C)C.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[CH:25]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][N:32]=[C:29]([CH3:30])[N:31]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:26][CH2:27]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Reactant: CC(=N)N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)ns3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
A mixture of N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 121B, 0.042 g, 0.111 mmol), acetamidine hydrochloride (10.49 mg, 0.111 mmol), and Hünig's Base (0.058 mL, 0.333 mmol) in DMF (0.617 mL) was stirred at rt ON. Diethyl azodicarboxylate (0.088 mL, 0.222 mmol) was added and stirring continued at room temperature for 16 h. The reaction mixture was concentrated. The residue was taken up in MeOH and purified by preparative HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (4.32 mg, 9% yield) was isolated as a pale yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[C:14]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl>[C:14]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:7]2[CH2:8][CH2:9][C:4]3[CH:3]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[O:1][C:5]=3[CH2:6]2)=[O:27])=[CH:29][CH:30]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Reaction time: 8 h

Procedure:
To a solution of 72 mg (0.40 mmol) of methyl 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-carboxylate, 0.11 g (0.48 mmol) of 4-benzoylbenzoic acid and 0.11 ml (0.79 mmol) of triethylamine in 30 ml of dichloromethane, 0.07 ml (0.48 mmol) of diethyl cyanophosphonate was added dropwise at room temperature, followed by overnight stirring. After the reaction mixture was evaporated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:25])[F:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17](O)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:24])[F:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
220 mg of crude product of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoic acid (racemate) and 89 mg (0.46 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 48 mg (21% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:22])[C:20]=1[OH:21])[CH:16]=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH:10]=[CH:16][C:15]1[CH:18]=[C:19]([CH3:22])[C:20]([OH:21])=[C:13]([CH3:12])[CH:14]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1ccccc1C(C)=O
Product: COc1ccccc1C(=O)C=Cc1cc(C)c(O)c(C)c1

Procedure:
This compound was synthesized from 2′-methoxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: S(=O)(=O)(O)O.[Na].O[CH:8]=[CH:9][C:10]#[N:11].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH:12]([CH:8]=[CH:9][C:10]#[N:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: N#CC=CO
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: N#CC=CNc1ccccc1
Reaction time: 5 h
Yield: 67.4 %

Procedure:
12.25 g (0.125 mol) of sulfuric acid in 30 ml of ethanol is added drop by drop, at 0° C., to a suspension of 32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile and 32.6 g (0.35 mol) of aniline in 150 ml of ethanol, and the mixture is held at 25° C. for 5 h. After removal of the solid by filtration and withdrawal of the solvent, the product is dissolved with water, acidified with dilute sulfuric acid, and extracted with ether. After recrystallization of the concentrated ether extract from carbon tetrachloride, 24.3 g (67.6%) of 3-anilinoacrylonitrile is obtained.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.[CH2:21]([O:23][CH:24]([O:30][CH2:31][CH3:32])[C:25](OCC)=[O:26])[CH3:22].Cl>O1CCCC1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:25](=[O:26])[CH:24]([O:30][CH2:31][CH3:32])[O:23][CH2:21][CH3:22])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CC(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)CC(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A 1.0M solution of lithium hexamethyldisilazide in THF (310 mmol, 310 mL) was diluted with 20 mL of THF and cooled to -70° C. (internal temperature) with an acetone/dry ice bath under N2. A solution of 4'-methylacetophenone (150 mmol, 20.1 g, 20 mL) in 50 mL of tetrahydrofuran (THF) was added dropwise over a 15 min period, keeping the internal temperature below -60° C. After 1 h, the cooling bath was removed and the temperature was allowed to rise to -25° C. The reaction flask was immersed in an ice/acetone bath and a solution of ethyl diethoxyacetate (160 mmol, 28 g, 28.6 mL) in 20 mL of THF was added dropwise; during the addition, the internal temperature was kept below 0° C. The brown-red solution was stirred for 24 h and was re-cooled to 0° C. Aqueous HCl (3N, 618 mmol, 206 mL) was added carefully (temperature kept below 20° C.) to bring the pH to 3-4. The layers were separated and the aqueous layer was extracted with 200 mL of ether. The combined organic layers were washed twice with brine, dried over Na2SO4, and concentrated to give 40.3 g (100%) Cpd. 46 as an orange oil; 1H NMR (CDCl3, 300 MHz) 1.30 (t, 6H, J=7), 2.42 (s, 3H), 3.5-3.8 (complex, 4H), 4.90 (s, 1H), 6.58 (s, 1H), 7.28 (d, 2H, J=8), 7.74 (d, 2H, J=8), 15.8 (broad s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: C1CCOC1
Solvent: CO
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: -50 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
Under an argon flow, 8-benzyloxy-5-(2-bromoacetyl)-1H-quinolin-2-one (374 g, 1.00 mol) was suspended in dehydrated tetrahydrofuran (3.8 L), CBS catalyst (27.8 g) was added thereto, and the mixture was stirred at −55 to −45° C. for 40 minutes. After adding dropwise a 0.9 M tetrahydrofuran solution of borane-tetrahydrofuran complex (1.27 L) at the same temperature, the reaction mixture was gradually warmed to 0° C. After adding methanol (1.3 L) dropwise, insoluble matter was removed by filtration and washed with tetrahydrofuran. The filtrate and the washing were mixed and concentrated under reduced pressure. To the residue was added purified water (6.3 L), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with purified water. Further, the precipitate was suspension-washed with ethyl acetate (4.8 L), collected by filtration, and dried under reduced pressure to obtain 8-benzyloxy-5-((R)-2-bromo-1-hyroxyethyl)-1H-quinolin-2-one (278 g). 1H-NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.08 (d, J=10.0 Hz, 1H), 7.37-7.45 (m, 5H), 7.28 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.72 (d, J=10.0 Hz, 1H), 5.33 (dd, J=9.0 Hz, 4.0 Hz, 1H), 5.19 (s, 2H), 3.71-3.74 (m, 2H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:21](=[O:22])[CH2:20][N:19]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=3)[C:18](=[O:36])[CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>>[ClH:37].[CH2:34]([O:33][C:31]([CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:19]2[CH2:20][C:21](=[O:22])[N:16]([CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:17][C:18]2=[O:36])=[CH:24][CH:25]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)COc1ccc(N2CC(=O)N(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2=O)cc1
Agent: Cl
Product: CCOC(=O)COc1ccc(N2CC(=O)N(CCC3CCNCC3)CC2=O)cc1

Procedure:
Prepared from 4-[2-(1-tert-butyloxycarbonylpiperidin-4-yl)ethyl]-1-(4-ethoxycarbonylmethyloxyphenyl)piperazin-2,5-dione and ethereal hydrochloric acid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][N:15]1[S:19](=[O:21])(=[O:20])[N:18]2[CH2:22][CH2:23][CH2:24][CH:17]2[C:16]1=[O:25]>CN(C=O)C>[C:1]1([N:7]2[C:11]([S:12][CH2:14][N:15]3[S:19](=[O:21])(=[O:20])[N:18]4[CH2:22][CH2:23][CH2:24][CH:17]4[C:16]3=[O:25])=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C2CCCN2S(=O)(=O)N1CCl
Reactant: Sc1nnnn1-c1ccccc1
Solvent: CN(C)C=O
Product: O=C1C2CCCN2S(=O)(=O)N1CSc1nnnn1-c1ccccc1
Temperature: 0 °C
Yield: 84.6 %

Procedure:
The Na salt of 1-phenyl-5-mercapto-1H-tetrazole (0.57 g) was added to a solution of 2-chloromethyl-tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3 (2H)-one 1,1-dioxide (0.5 g) in DMF (10 ml) at room temperature, and the mixture was allowed to react at 60° C. for 6 hours and then cooled. The mixture was poured into ice/water containing saturated sodium bicarbonate, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried over sodium sulfate. The solvent was concentrated in vacuo and the residue was purified by silica gel flash chromatography (40% ethyl acetate/hexane) to afford 0.69 g of 2-(1-phenyl-1H-tetrazol-5-yl-thiomethyl)tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3 (2H)-one 1,1-dioxide (Formula I: R4 =1-phenyl-1H-tetrazol-5-yl; X=S; R1 =H; R2 and R3 together=--(CH2)3 --) as a solid, m.p.99.5°-100.5° C.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][O:39]C=O)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:42]>CO.O1CCCC1>[ClH:42].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][OH:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCO)c3csc(N)n3)[C@H]2SC1
Yield: 97.7 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 5.0 g.) and conc. hydrochloric acid (3.34 g.) in methanol (35 ml.) and tetrahydrofuran (5 ml.) was treated in a similar manner to that of Example 2-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 4.73 g.).
Reaction SMILES: [Si]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21]4[NH:26][C:25](=[O:27])[C:24]([C:28]([O:30][CH3:31])=[O:29])=[C:23]([OH:32])[C:22]=4[CH2:33][CH3:34])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:33]([C:22]1[C:23]([OH:32])=[C:24]([C:28]([O:30][CH3:31])=[O:29])[C:25](=[O:27])[NH:26][C:21]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:12]3[CH2:11][CH2:10][CH:9]([OH:8])[C:13]3=[CH:14][C:15]=2[CH:16]=1)[CH3:34]
Reactant: CCc1c(-c2ccc3c(c2)cc2n3CCC2O[Si](C)(C)C(C)(C)C)[nH]c(=O)c(C(=O)OC)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1c(-c2ccc3c(c2)cc2n3CCC2O)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a suspension of methyl 6-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate (1.4 g, 3.0 mmol) in THF (20 mL) was added a solution of TBAF (3.2 mL, 1M, 3.2 mmol) in THF. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The crude residue was triturated with THF to afford the title compound as an off-white solid (0.9 g, 80%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:41])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][C:29]([C:32](=[O:37])[NH:33][CH2:34][CH2:35][OH:36])([CH3:31])[CH3:30])=[CH:17][CH:16]=3)=[C:12]([C:38]#[N:39])[CH:11]=[N:10][N:9]2[CH:40]=1)=[O:5])C.[OH-].[Na+].O>CCO>[C:38]([C:12]1[CH:11]=[N:10][N:9]2[CH:40]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH3:41])=[C:8]2[C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:29]([C:32](=[O:37])[NH:33][CH2:34][CH2:35][OH:36])([CH3:31])[CH3:30])=[CH:19][CH:20]=1)#[N:39]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c12
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 433E (180 mg, 0.323 mmol) and 1N NaOH (0.68 ml, 0.68 mmol) in EtOH (4 ml) was heated to reflux for 2 days, cooled to rt. Removal of the solvent in vacuo gave a gray oil. Treated with H2O (4 ml), the aqueous solution was washed with EtOAc (3×2 ml) and added to a mixture of 6N HCl (1.5 ml) and brine (5 ml). The resulting suspension was cooled to 0° C. and filtered, dried in vacuo to gave 433F (171 mg, 96%) as a dim dark solid. It has a retention time of 5.31 min (standard LC1 method, 8 min run). MS Found: (M+H)+=530.0
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20](O)=[O:21])=[C:13]([O:23][CH3:24])[CH:12]=3)[CH2:4][CH3:5])[CH3:2].[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.Cl.CNC>O>[CH2:4]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20]([N:27]([CH3:28])[CH3:25])=[O:21])=[C:13]([O:23][CH3:24])[CH:12]=3)[CH2:1][CH3:2])[CH3:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)O)c(OC)cc3n12
Agent: CNC
Agent: Cl
Solvent: O
Product: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)N(C)C)c(OC)cc3n12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
1-(1-Ethylpropyl)-8-methoxy-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxaline-7-carboxyic acid as synthesized in above Example 32, 329 mg, N,N-diimethylformamide 5 mL and 1,1′-carbonyldiimidazole 275 mg were mixed and stirred for an hour at room temperature in nitrogen atmosphere. Dimethylamine hydrochloride 816 mg was added, followed by 5.5 hours' stirring. The reaction mixture was diluted with water, extracted with ethyl acetate and washed with saturated saline. The extract was dried over anhydrous sodium sulfate, and from which the solvent was distilled off. To the residue tert-butyl methyl ether was added, heated under stirring, and the precipitate was recovered by filtration, followed by washing with tert-butyl methyl ether. The product was dried in flowing air (40° C.) to provide 223 mg of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[CH3:27])=[CH:14][CH:13]=2)[C:9](=[O:28])[CH2:8]1.C(N(CC)CC)C>ClCCl>[Cl:3][CH2:6][CH:7]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[CH3:27])=[CH:14][CH:13]=2)[C:9](=[O:28])[CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: CC1CCCN1CCCOc1ccc(N2CC(CO)CC2=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCN1CCCOc1ccc(N2CC(CCl)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
Thionyl chloride (0.24 ml, 3.25 mmol, 1.5 eq) is added into a cold solution of 4-(hydroxymethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 72 (0.78 g, 2.16 mmol, 1 eq) and triethylamine (0.3 ml, 2.16 mmol, 1 eq) in dichloromethane (30 ml). The mixture is warmed to room temperature and stirred overnight. The solution is washed once with water and once with a saturated solution of aqueous sodium chloride. The organic layer is dried over magnesium sulfate and concentrated under vacuum to give 0.54 g of 4-(chloromethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one a56 as a dark-red oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH3:7][O:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:24])[C:13]=2[C:12](OC)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:12]1[C:13]2[C:14](=[O:24])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:23])[C:22]=2[C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: NCCCCN
Reactant: COc1ccc(OC)c2c1C(=O)c1ccccc1C2=O
Solvent: ClCCl
Product: COc1ccc(NCCCCN)c2c1C(=O)c1ccccc1C2=O
Yield: 50.8 %

Procedure:
1,4-Diaminobutane (1.65 g, 19 mmol) was added to a solution of 1,4-dimethoxyanthracene-9,10-dione (1.0 g, 3.7 mmol) in CH2Cl2 (700 ml). After seven, hours of irradiation, the solvent was removed and the residue chromatographed on silica gel. Starting material was eluted with CHCl3 and the product with 5% CH3OH in CHCl3. A purple solid (0.61 g, 50%) was obtained which was converted to the benzyloxycarbonyl derivative.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.[C:22]1([CH2:28][C@H:29]2[CH2:33][O:32][C:31](=[O:34])[NH:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC>ClCCl.C1COCC1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([N:30]2[C@@H:29]([CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33][O:32][C:31]2=[O:34])=[O:15])=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CCCC(=O)O)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1ccc(CCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 60.8 %

Procedure:
4-(4-(1-n-Propyl)phenyl)butanoic acid (19.3 g) was disolved in dichloromethane and 25 mL of oxalyl chloride was added. After gas evolution ceased (~3 h) the mixture was concentrated in vacuo. To a solution of 4(S)-phenylmethyl-2-oxazolidinone (16.6 g, 93.6 mmol) in 250 mL of dry THF at -78° C. was added butyl lithium (64.4 mL, 1.6M, 102.99 mmol). After 5 min, a solution of the acid chloride in THF was added via cannula. After 15 min, the reaction was partitioned between ethyl acetate and 2N hydrchloric acid and the layers separated. The organics were washed twice with 2N hydrochloric acid and three times with dilute sodium bicarbonate then dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by flash filtration through silica-gel eluting with 10% ethyl acetate in hexane to give a pale-yellow oil which crystallized upon dissolution in 5% ethyl acetate in hexane. The mixture was concentrated and recrystallized from hexane to afford the title compound as colorless needles (20.8 g): 400 MHz 1H NMR (CDCl3) δ 7.4-7.0 (m, 9H), 4.63 (m, 1H), 4.14 (m, 2H), 3.20 (dd, 1H, J=3.30, 13.27 Hz), 2.97 (m, 2H), 2.73 (dd, 1H, J=9.72, 13.42 Hz), 2.67 (t, 2H, J=7.68 Hz), 2.53 (t, 2H, J=7.61 Hz), 2.00 (m, 2H), 1.61 (m, 2H), 0.92 (t, 3H, J=7.33 Hz).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[F:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1[C:45]([CH3:51])([CH2:48][CH2:49][OH:50])[CH2:46]O.[K]>ClCCl.O>[F:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1[C:45]1([CH3:51])[CH2:48][CH2:49][O:50][CH2:46]1
Reactant: CC(CO)(CCO)c1cc([N+](=O)[O-])ccc1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC1(c2cc([N+](=O)[O-])ccc2F)CCOC1
Temperature: 25 °C

Procedure:
To a solution of triphenylphosphine (2 eq) in dichloromethane at 0° C. under nitrogen was added dropwise triflic anhydride (1 eq). After 15 minutes 2-(2-fluoro-5-nitrophenyl)-2-methylbutane-1,4-diol (1 eq) was added in dichloromethane followed by potassium carbonated (1 eq). The resulting mixture was allowed to warm to room temperature for 5 h. To the mixture was added water and extracted with dichloromethane. The organic layer was washed with brine and dried with sodium sulfate and concentrated. Crude product was purified using flash chromatography (85% Hex:15% EtoAc) on silica to afford 3-(2-fluoro-5-nitrophenyl)-tetrahydro-3-methylfuran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29]O)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29][Br:32])[CH2:10][CH2:11][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CN2CCC(CCCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(CN2CCC(CCCBr)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 57.7 using 4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine (5 mmol), carbon tetrabromide (6.3 mmol), and triphenylphosphine (7.5 mmol). Purify to obtain the title compound.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:13]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]([P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(=O)Oc1ccc(Cl)cc1

Procedure:
From 20 g (0.12 mole) of triethylphosphite and 19.1 g (0.10 mole) of 4-chlorophenyl chloroformate (prepared according to M. J. Zabik and R. D. Scheutz J. Org. Chem. 32 (1967) 300). (125°, 2 hours) yield 26.3 g (90%). B.P.0.01 153°-6°, nD21 1.4980. Analysis for C11H14Cl O5P. Found (calculated): C 44.85 (45.14), H 4.83 (4.82), P 10.54 (10.59). NMR (CDCl3)δ: 1.45 (t, CH3), 4.17-4.63 (CH2), 7.03-7.48 (C6H4).