Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]#[N:14].COC1C=CC(C[NH2:22])=CC=1>CN(C=O)C>[NH2:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]#[N:14]
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Solvent: CN(C)C=O
Product: N#Cc1c(N)c2ccccc2[nH]c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
4-chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile (example 72) (0.66 g, 3.23 mmol) was suspended in DMF (7 mL), and 4-methoxybenzylamine (0.94 mL, 7.26 mmol) was added. The reaction was heated at 100° C. for 1 hour and the DMF was removed under vacuum. The residue was dissolved in TFA (6 mL) and stirred at room temperature for 30 minutes and dichloromethane (10 mL) was added. The solid product that formed was collected, suspended in water and the solution stirred overnight. The solid was collected by filtration to give 4-amino-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.150 g, 25%) as a white solid. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (m, 2H), 7.57 (m, 1H), 7.88 (bs, 2H), 8.12 (d, J=7.6 Hz, 1H), 11.23 (s, 1H). MS 186 (MH+).
Reaction SMILES: O.Cl.Cl[CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15]3[CH:19]=[CH:20][CH:21]=[C:14]3[C:13](=[N:22][OH:23])[C:12]=2[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15]3[CH:19]=[CH:20][CH:21]=[C:14]3[C:13](=[N:22][O:23][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])[C:12]=2[CH:11]=1
Reactant: CN(C)CCCl
Reactant: ON=C1c2cc(Cl)ccc2-n2cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CCON=C1c2cc(Cl)ccc2-n2cccc21

Procedure:
Add 5 ml of water, 0.94 g (6.5 mmol) of 1-chloro-2-(N,N-dimethylamino)ethane hydrochloride and 1.19 g (5.44 mmol) of 7-chloro-9-hydroxyiminopyrrolo[1,2-a]indole (Preparation 46) in succession to a solution of 1.56 g (14.7 mmol) of sodium carbonate in 100 ml of acetone, then heat the reaction mixture at reflux for 36 hours. The acetone is removed under reduced pressure and the residue is taken up in 50 ml of water and extracted with diethyl ether. The ethereal phase is washed with water, dried over magnesium sulfate, rendered colourless with animal charcoal, and then concentrated to dryness to yield the title product in the form of an oil (base).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22](Cl)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCl>[C:22]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:24])[CH3:23]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
A mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g, 1.66 mmol), acetyl chloride (0.118 ml, 1.67 mmol), triethylamine (1.2 ml, 8.61 mmol), and dichloromethane (50 ml) was stirred for three hours at room temperature. The reaction mixture was washed with 50 ml water. The organic extract was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in dichloromethane) to afford the product as a purple solid (0.327 g, 57%). M.p.=252-255° C.; 400 MHz 1H NMR (CDCl3) δ: 8.09-8.06 (m, 1H), 7.75-7.72 (m, 1H), 7.69-7.64 (m, 1H), 7.54-7.48 (m, 1H), 4.59-4.52 (m, 1H), 3.82-3.68 (m, 1H), 3.55-3.46 (m, 1H), 3.22-3.12 (m, 1H), 3.0-2.91 (m, 2H), 2.26-2.18 (m, 2H), 2.18 (s, 3H), 1.82-1.72 (m, 2H); LCMS: 344 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH2:32]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:33]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][O:34][CH2:32][CH3:33])[CH2:38][CH2:39]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCOCCN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCOCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2-ethoxy-ethyl)-piperazine following General Procedure C.
Reaction SMILES: C([O:4][C:5]1[CH:40]=[CH:39][C:8]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)[CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][C:5]1[CH:40]=[CH:39][C:8]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)[CH2:25][CH2:26]4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4Cc3ccc(OC(C)=O)cc3)CC2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4Cc3ccc(O)cc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
1-(4-Acetoxybenzyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (2 g) was dissolved in methanol (20 ml). To the solution was added a solution of potassium carbonate (1.53 g) in water (20 ml) and the mixture was stirred at room temperature for 30 minutes. After completion of reaction, the reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethanol to give 1-(4-hydroxybenzyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (950 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[CH:10]1([C:13]#[N:14])[CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ncc(Cl)cc2F)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of argon, 5-chloro-2,3-difluoropyridine (6 g, 4.17 ml, 40.1 mmol, Eq: 1.00) was combined with toluene (60.0 ml). Then cyclopropanecarbonitrile (2.69 g, 3.02 ml, 40.1 mmol, Eq: 1.00) was added to the solution. At −5° C., potassium bis(trimethylsilyl)amide (80.3 ml, 40.1 mmol, Eq: 1.00) was added dropwise over 30 min. The dark brown reaction was stirred for 1 hour at −5° C., and then for 2 h at room temperature. The reaction mixture was poured into satd. NH4Cl solution (50 ml) and extracted with 2×100 ml ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, from 100% to 50% heptane in ethyl acetate). The title compound was obtained as a orange oil (1.55 g, 13.8%, MS (m/e)=197.2 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[O:14].[F:15][C:16]([F:40])([F:39])[C:17]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:18]=1[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[F:40][C:16]([F:15])([F:39])[C:17]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:18]=1[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[CH:29]=[C:11]3/[C:12](=[O:13])[N:8]([CH2:7][C@@H:3]4[CH2:4][CH2:5][CH2:6][N:2]4[CH3:1])[C:9](=[O:14])[S:10]/3)=[CH:26][CH:27]=2)[CH:22]=[N:21]1
Reactant: CN1CCC[C@H]1CN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from {[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (from Example 23) and [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) following General Procedure F.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14]([OH:17])(=O)[CH3:15].N([O-])=O.[Na+]>O>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][CH:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][OH:17])=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OCC(Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 80 °C

Procedure:
2.89 g. of 2-(biphenylyl-4-oxy)-2-phenyl-ethylamine (obtainable by reacting 4-hydroxy-biphenyl with 2-bromophenylacetenitile and subsequently reducing the resulting nitrile) are dissolved in 50 ml. of 15% aqueous acetic acid and a solution of 1 g. of NaNO2 in 5 ml. of water is added while cooling with ice. The mixture is heated at 80° C. for 1 hour, worked up in the usual manner and purified by chromatography on silica gel to give 2-(4-biphenylyloxy)-2-phenyl-ethanol, m.p. 126°-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:34]=[CH:33][C:16]([CH:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])[N:20]=3)O)=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(S(F)(F)[F:41])CC)C.O>C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:34]=[CH:33][C:16]([CH:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])[N:20]=3)[F:41])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1C(O)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(F)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of 0.9 g of 5-{4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-α-hydroxybenzyl}-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of benzene at room temperature, were added 0.85 g of diethylaminosulfur trifluoride (DAST). After stirring at room temperature for 1 hour, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.8 g of 5-{4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-α-fluorobenzyl}-3-(2-chloro-6-fluorophenyl)-1 methyl-1H-1,2,4-triazole.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]N)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C(O)(=[O:17])C.N([O-])=O.[Na+]>O.C(OCC)(=O)C>[CH2:1]([O:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:17])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCOCc1ccc(CN)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 4-butoxymethyl-benzylamine (250 mg) described in Manufacturing Example 43-2, acetic acid (2 mL), and water (2 mL) was added sodium nitrite (1.1 g) at 0° C., which was stirred for 40 minutes at room temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and then extracted. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with saturated brine. The solvent was evaporated from the organic layer under a reduced pressure. Methanol (2 mL) and potassium carbonate (360 mg) were added to the residue, and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the titled compound (200 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:21]1=[O:37]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][C:30]([OH:32])=[O:31])[C:21]1=[O:37]
Reactant: Cn1c(=O)n(CC(=O)OC(C)(C)C)c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Temperature: 25 °C

Procedure:
A solution of tert-butyl 3-{2-bromo-5-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy}phenyl}tetrahydro-5methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (7.00 g, 0.012 mol) in trifluoroacetic acid (40 mL) is refluxed for 2.5 hours, cooled to room temperature and concentrated in vacuo to give the title product which is identified by 1HNMR spectral analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCCC(=O)O
Product: O=C(O)CCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 80.1 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and β-alanine (0.23 g, 0.0026 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.55 g (80%) 121 as a pale yellow powder: mp=146–148° C.; Rf 0.73 (A): Rf 0.87 (C): Rf 0.57 (D): 1H NMR (DMSO-d6) δ 2.60 (t, J=7.4 Hz, 2H), 3.78 (t, J=7.4 Hz, 2H), 8.07 (dd, J=7.5, 8.0 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.27 (d, J=8.0, 1H); IR (cm−1): 2800–3200 (OH), 3097 (C═CH), 2620 (C—H), 1781 (C═O), 1725 (bs, C═O), 1617 (C═C), 1545 (N═O), 1468 (C═C), 1450 (C═C), 1395 (C—O), 1360 (N═O), 1235 (C—O), 723 (C═CH); MS m/z (rel intensity) 264 (76), 263 (100), 191 (90).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=1.[N+:15]([O-])([OH:17])=[O:16]>C(OCC)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[C:7]([OH:10])=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C(=O)OC)ccc1O
Solvent: CCOCC
Product: CCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-ethoxy-4-hydroxy-benzoic acid methyl ester (5.3 g, 27.0 mmol, 1.0 equiv) in diethyl ether (60 mL) was added dropwise nitric acid 65% (3.71 mL, 5.24 g, 54.0 mmol, 2.0 equiv) over a period of 30 min. After the addition was completed the reaction mixture was stirred for 4 h at rt. The reaction product precipitated out of solution, was filtered off, washed with cold diethyl ether (3×20 mL) and dried yielding 4.61 g (%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.53 (t, J=7.0 Hz, 3H), 3.94 (s, 3H), 4.21 (q, J=7.0 Hz, 2H), 7.75 (d, J=1.8 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 11.01 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.56, 52.59, 65.77, 118.37, 118.54, 121.36, 133.59, 149.44, 149.83, 165.09. MS (ISN): 240.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([CH2:33][N:34]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.NN>>[NH2:34][CH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:28][CH2:29]1
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Product: NC[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ethanolic solution of trans-2-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione (265 mg, 0.46 mmol) was charged with an excess of hydrazine (0.14 mL, 4.6 mmol) and allowed to stir at rt for 16 h. The solution was filtered through a fritted glass funnel and the solids were washed with EtOH (4×). The filtrate was concentrated and the crude material was purified by silica gel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge, eluting with 2%˜7 N NH3 in MeOH/CH2Cl2 to 4%˜7N NH3 in MeOH/CH2Cl2]. The purified material was recrystallized from CH2Cl2/hexanes to afford the desired product as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.16-1.26 (m, 2H), 1.58-1.65 (m, 1H), 1.87-1.99 (m, 2H), 2.02-2.09 (m, 2H), 2.13-2.22 (m, 2H), 2.72 (d, 2H, J=6.4 Hz), 2.92-3.01 (m, 1H), 7.10 (d, 1H, J=5.2 Hz), 7.25-7.28 (m, 1H), 7.42-7.55 (m, 3H), 7.89-7.94 (m, 3H), 8.18-8.20 (m, 2H), 8.24 (d, 1H, J=8.8 Hz), 8.39-8.41 (m, 1H); MS (ES+): m/z 449.0 [MH+]; HPLC: tR=2.0 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1>>[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1
Reactant: O=C1Nc2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Reactant: BrCc1ccccn1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 6-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 197-199° C.; 1H NMR (300 MHz, CDCl3) δ8.60 (d, J=2.1 Hz, 1H), 7.60 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.25-7.15 (m, 3H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.79 (s, 1H), 5.35 (d, J=16.2 Hz, 1H), 5.00 (d, J=9.3 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.74 (d, J=9.0 Hz, 1H), 4.16-3.86 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.9, 155.8, 151.7, 149.5, 141.8, 138.6, 138.3, 136.7, 130.9, 128.9, 123.6, 123.4, 122.6, 121.4, 118.2, 116.8, 109.4, 106.8, 81.7, 64.5, 63.8, 57.7, 46.3; MS (ES+) m/z 421.2 (M+1), 423.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH2:9]([OH:11])[CH3:10]>C(Cl)(Cl)Cl>[C:1](=[NH:2])([O:11][CH2:9][CH3:10])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ccncc1
Reactant: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccncc1
Reaction time: 8 h

Procedure:
A solution of 4-cyanopyridine (135 g) and ethanol (83.3 ml) in chloroform (1000 ml) is cooled in an ice bath for 30 min. Anhydrous HCl (143 g) is bubbled into the cold mixture over a period of 7 hours with stirring continued overnight with cooling. The reaction mixture is filtered and the filtered solid added portionwise to an ice cold 10% K2CO3 solution (500 g in 5 l H2O) with stirring. A liter of ether is added to the mixture after 20 min with stirring. The aqueous layer is extracted with ether and the organic extracts combined and dried overnight. The dried solution is filtered, evaporated in vacuo and vacuum distilled giving as a main fraction 75.5 g of a colorless liquid, b.p. 63°-65° C. (0.14 mm).
Reaction SMILES: N(C[C:5]1[CH2:6][S:7][C@@H:8]2[CH:15](NC(=O)/C(/C3N=C(N)SC=3)=N\OC)[C:14](=[O:29])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+]=[N-].CO.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>[Ni].CO>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[S:7]1[C@@H:8]2[CH2:15][C:14](=[O:29])[N:9]2[C:10]([C:11]([OH:13])=[O:12])=[CH:5][CH2:6]1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1
Agent: [Ni]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Yield: 45 %

Procedure:
To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at 0° was added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was diluted with MeOH and filtered through paper. The filtrate was evaporated, the residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v as eluant and the product dried over P2O5 to give 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate (yield 45%) having the following n.m.r. in solvent A:- 3.5-4.2 (m, 4H); 3.9 (s, 3H); 5.15 (d, 1H); 5.85 (d, 1H); 6.75 (s, 1H). 12. HPLC eluant MeOH/water/HOAc 10:89:1 v/v/v. 13. n.m.r. in solvent B: 3.46 (d,1H), 3.72 (d,1H); 3.97 (s,3H); 4.25 (s,3H); 4.11 (d,1H); 4.63 (d,1H); 5.13 (d,1H); 5.73 (d,1H); 6.97 (s,1H); 7.57 (d,1H); 7.98 (dd,1H); 8.93 (d,1H). 14. HPLC eluant MeOH/water/HOAc 15:84:1 v/v/v. 15. n.m.r. in solvent B: 3.43 (d,1H); 3.69 (d,1H); 3.97 (s,3H); 4.19 (s,3H); 4.23 (d,1H); 4.66 (d,1H); 5.12 (d,1H); 5.69 (d,1H); 7.0 (s,1H); 7.98 (d,1H); 8.2 (s,1H); 8.6 (d,1H). 16. The starting material was prepared by reaction of 3,6-difluoropyridazine and trimethyloxonium tetrafluoroborate in CH2C 12 for 15 hours at ambient temperature to give 3,6-difluoro-1-methylpyridazinium tetrafluoroborate. This compound in acetonitrile was treated with a solution of ammonia in chloroform in the presence of 1 equivalent of NaHCO3 for 0.5 hours at ambient temperature to give 3-amino-6-fluoro-2-methyl pyridazinium tetrafluoroborate. 17. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v. 18. n.m.r. in solvent B: 1.53 (s,6H); 3.5 (m,2H); 3.7 (s,3H); 3.95 (d,1H); 4.5 (d,1H); 5.15 (d,1H); 5.8 (d,1H); 7.0 (s,1H); 7.3 (s,2H). 19. The starting material was prepared by reaction of 2,5-dimethyl-3-fluoropyrazine and trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 5 hours to give 3-fluoro-1,2,5-trimethylpyrazinium tetrafluoroborate. 20. n.m.r. in solvent B: 1.53 (s,6H); 2.38 (s,3H); 2.53 (s,3H); 3.5 (m,2H); 4.1 (s,3H); 4.2 (d,1H); 4.85 (d,1H); 5.1 (d,1H); 5.85 (d,1H); 7.05 (s,1H); 7.9 (s,1H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][CH:5]([O:9][CH3:10])[C:6](=[O:8])[CH3:7]>CO>[Br:1][CH2:7][C:6](=[O:8])[CH:5]([O:9][CH3:10])[O:4][CH3:3]
Reactant: BrBr
Reactant: COC(OC)C(C)=O
Solvent: CO
Product: COC(OC)C(=O)CBr
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Bromine (80 g, 0.5 mol) is added dropwise to a solution of 1,1-dimethoxy-propan-2-one 205 (59 g, 0.5 mol) in anhydrous methanol (400 mL) at 0° C. and the solution is continued stirring at room temperature for 48 h. The solvent is removed under reduced pressure and the residue is dried in vacuo and used without further purification.