Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([C:25]4[CH:26]=[N:27][CH:28]=[C:29]([C:31]#[C:32][Si](C)(C)C)[CH:30]=4)[CH2:22][C:23]#[N:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].[OH-].[K+].CO>>[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[C:31]([C:29]1[CH:30]=[C:25]([CH:21]([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][NH:7][C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:22][C:23]#[N:24])[CH:26]=[N:27][CH:28]=1)#[CH:32]
Reactant: C[Si](C)(C)C#Cc1cncc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cncc(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}propanenitrile (0.050 g, 0.000092 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol). The reaction mixture was stirred at room temperature, for 90 minutes and was concentrated in vacuo. The dry residue dissolved in methanol cooled in an ice bath and a solution of potassium hydroxide (0.482 g, 0.00859 mol) in methanol (10 mL, 0.2 mol) was added. The reaction solution was stirred for 30 min was concentrated and the crude product was purified by preparative HPLC eluting with a water:ACN gradient with 0.2% TFA, to give the title compound as a white amorphous solid (15 mg, 35.85%). LCMS (M+1)+: 340, 1H NMR (400 MHz, DMSO-d6): δ 12.1 (bs, 1H), 9.02 (s, 1H), 8.80 (s, 1H), 8.70 (m, 2H), 8.48 (s, 1H), 8.00 (s, 1H), 7.80 (d, 1H), 7.15 (d, 1H), 6.20 (m, 1H), 4.82 (s, 1H), 3.90 (m, 1H), 3.70 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:12]1[CH:17]=[C:16](F)[CH:15]=C(F)C=1)(C)[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:28][C:29]1([C:36](OC)=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=O)(C)(C)C>>[O:10]=[C:9]1[C:8]2([CH2:12][CH2:17][CH2:16][CH2:15]2)[N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])[CH2:36][C:29]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[NH:28]1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCCCCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Product: CC(C)(C)OC(=O)N1CC2(CCCCCC2)NC(=O)C12CCCC2

Procedure:
Essentially following the procedures described for Intermediate 1, but using methyl 1-[(tert-butoxycarbonyl)amino]cycloheptanecarboxylate in place of tert-butyl 2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propanoate, the title compound was obtained. MS: m/z=337 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:17]([O:21][C:22]([N:24]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.N1C=CC=C(CC(O)=O)C=1>>[C:17]([O:21][C:22]([N:24]([CH2:26][CH2:27][CH2:28][C:29]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:30])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)Cc1cccnc1
Product: CN(CCCC(=O)Nc1ncn(Cc2ccccc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 67 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 17, using 1.44 g (6.72 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 4-(N-t-butyloxycarbonyl-N-methylamino)butanoic acid, instead of 3-pyridylacetic acid hydrochloride, to obtain 1.86 g of 4-(4-(N-t-butyloxycarbonyl-N-methylamino)butanoylamino)-1-benzyl-5-imidazole carboxamide (yield 67%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.[BrH:18]>C(O)(=O)C>[Br:18][CH2:4][CH2:5][CH:6]([CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[C:2]([OH:3])=[O:1]
Reactant: Br
Reactant: COC(=O)c1ccc(CC2CCOC2=O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CC(CCBr)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
9.00 g (38.42 mmol) of methyl 4-[(2-oxotetrahydro-3-furanyl)methyl]benzoate from Ex. VI are suspended in 54 ml of a 33 percent strength HBr solution in glacial acetic acid, and the mixture is stirred at 80° C. for 40 min. The reaction solution is poured into ice-water and the resulting precipitate is filtered off with suction, washed with water and dried under reduced pressure at 40° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9]O)[CH2:7][S:8][C@H:3]12.[SH:16][C:17]1[N:21]([CH3:22])[N:20]=[N:19][N:18]=1.C(N)=O.P1(OC2C=CC=CC=2O1)(OC)=O.N.O>C(Cl)Cl.C(#N)C.C(N(CC)CC)C>[NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:7][S:8][C@H:3]12
Reactant: Cn1nnnc1S
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: COP1(=O)Oc2ccccc2O1
Agent: N
Solvent: O
Solvent: NC=O
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Yield: 85.4 %

Procedure:
To the mixture of 230 mg of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid, 174 mg of 5-mercapto-1-methyl-1H-tetrazole, 4 ml of formamide and 1 ml of acetonitrile was added 253 mg of triethylamine under stirring and cooling with ice bath. To the resulting solution were added a solution of 650 mg of methyl o-phenylene phosphate in 2 ml of methylene chloride and 5 ml of acetonitrile under stirring and cooling at -10° C. to 0° C., followed by stirring for 0.5 hour at 0° C. to 5° C. The resulting precipitate was collected by filtration, washed with 5 ml of acetonitrile and suspended in a mixed solution of 6 ml of water and 2 ml of acetonitrile. To this suspension was added about 0.1 ml of 35% hydrochloric acid to obtain a clear solution. After adjusting the pH of the solution to 4 by addition of 25% ammonia-water under cooling with ice bath, the resulting crystals were collected by filtration, washed with 2 ml of cold water and dried in vacuo to give 280 mg (yield 85.3%) of 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]N(C)C=O.[H-].[Na+].CI>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][CH3:23])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COCc1cccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To the solution of 0.20 g (0.65 mmol) (R)-2-(3-hydroxymethyl-benzyl)-morpholine-4-carboxylic acid tert-butyl ester in 3 mL N,N-dimethylformamide 31 mg (0.71 mmol; 55% dispersion in mineral oil) sodium hydride was added. After 30 min. 81 μL (1.3 mmol) methyl iodide was added. After 2 h the reaction mixture was diluted with ethyl acetate and extracted with 10% aqueous ammonium chloride solution followed by brine. The organic layer was dried over magnesium sulfate, filtered and evaporated and the residue was purified by column chromatography on silica gel with n-hexane:ethyl acetate (1:1) as eluant to give the title compound as a colorless oil (76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]O)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:22])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][F:22])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CF)cs1
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl[4-(hydroxymethyl)-1,3-thiazol-2-yl]carbamate (1.21 g) in dichloromethane (15 mL) was added diethylaminosulfur trifluoride (0.73 mL) under cooling in a dry ice-acetone bath, followed by stirring for 30 minutes under cooling as it is in a dry ice acetone bath. To the reaction mixture was added saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to obtain t-butyl[4-(fluoromethyl)-1,3-thiazol-2-yl]carbamate (480 mg) as a white solid.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH2:8][CH2:9][CH2:10][SH:11].[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][CH2:10][CH2:9][NH2:8])[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: NCCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
To sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added DMF (10 ml), 2-aminoethanethiol (620 mg, 8 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred at 100° C. for 3 hours. After addition of saturated brine the reaction mixture was extracted with chloroform and the organic layer was dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (10% methanol/chloroform) to give the subject compound (126 mg, yield 54%).
Reaction SMILES: CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:28]([O:32][C:33]([NH:35][CH:36]([CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C:37]([OH:39])=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C.Cl.[CH3:59][NH:60][O:61][CH3:62]>C1COCC1>[C:28]([O:32][C:33](=[O:34])[NH:35][CH:36]([C:37](=[O:39])[N:60]([O:61][CH3:62])[CH3:59])[CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
N,N-Dimethylaminopyridine (2.60 g, 21.3 mmol) and BOP reagent (18.15 g, 41.0 mmol) are added to a solution of 2-tert-butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propionic acid (12.37 g, 38.7 mmol), diisopropylethylamine (8.1 mL, 46.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.53 g, 46.4 mmol) in THF (260 mL) at RT. The resulting suspension is stirred at RT overnight then concentrated to dryness. The residue is diluted with EtOAc and washed with saturated NH4Cl, saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the crude product which is purified by flash chromatography eluting with 10-30% EtOAc/Hexanes to yield the title compound (11.86 g, 30.37 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ5.35 (bd, 1H), 4.71 (bs, 1H), 3.78-3.85 (m, 2H), 3.72 (s, 3H), 3.20 (s, 3H), 1.42 (s, 9H), 0.90 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[CH2:14][N:15]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl>C(O)C>[NH2:15][CH2:14][C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=2[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CN
Yield: 82.3 %

Procedure:
A mixture of 2-methyl-7-nitro-3-phthalimidomethylbenzo[b]furan (575 mg) and hydrazine monohydrate (172 mg) in ethanol (10 ml) was refluxed for 5 hours. The reaction mixture was cooled, acidified with 1N-hydrochloric acid and filtered. The filtrate was neutralized with aqueous saturated sodium bicarbonate and the ethanol in the mixture was evaporated in vacuo. The separated solid was collected, washed with water and dried to give 3-aminomethyl-2-methyl-7-nitrobenzo[b]furan (290 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1N(C1COCOC1)C([C@H]1CC[C@H](C)CC1)=O)=[O:4].C1(B(O)O)CCCCC=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)C1=CCCCC1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cccs1
Yield: 496.5 %

Procedure:
Nitrogen was bubbled through a solution of 5-bromo-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (15 mg, 0.034 mmol) containing cyclohexen-1-ylboronic acid (8 mg, 0.063 mmol) in 2M aqueous Na2CO3 (0.9 mL) and DME (1.8 mL) for 10 min. Pd(PPh3)4 (3 mg) was added and the mixture was refluxed for 1 h 10 min. It was cooled, diluted with ethyl acetate (50 mL), washed with water and brine, dried and evaporated yielding the crude 5-cyclohex-1-enyl-3-[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:46]([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:47].CCOCC>C(Cl)Cl>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:19][O:18][C:17]1[CH:36]=[CH:37][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:46]([O:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:47])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.5 g, 0.93 mmole) and triethylamine (0.16 g, 1.6 mmole) in methylene chloride (20 ml) at 0° was added, dropwise, a solution of phenyl chloroformate (0.16 g, 1.02 mmole) in methylene chloride (2 ml). After 1 hour at 0°, an additional portion of phenyl chloroformate (0.05 g, 0.32 mmole) was added and stirring continued for a further 0.5 hour. The reaction was subsequently quenched by the addition of 2N sodium hydroxide solution, methylene chloride added, the organic phase separated, washed with water, dried over magnesium sulphate and concentrated under reduced pressure to yield a foam. Trituration of this foam with ether yielded the desired product as a buff solid, (0.42 g, 68%), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](/[N:9]=[CH:10]/[N:11](C)C)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.N[OH:16]>CO>[Br:1][C:2]1[C:3](/[N:9]=[CH:10]/[NH:11][OH:16])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: CN(C)/C=N/c1ncc(Cl)cc1Br
Agent: Cl
Solvent: CO
Product: ON/C=N/c1ncc(Cl)cc1Br
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A mixture of 108a (2 g, 10 mmol) and hydroxylamine hydrochloride (1.4 g, 20 mmol) in MeOH (10 mL) was stirred at 100° C. for 0.5 h. The mixture was extracted with Ethyl acetate (20 mL×4) and the combined organic phase was washed with water. It was then concentrated under reduced pressure to afford 108b (2 g, 80%), which was used for next step without further purification. LCMS: [M+H]+ 250.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:34]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1.C(Cl)Cl.O>[CH:34]1([NH:40][C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
A solution of carbobenzoxy-(S)-valine (1.26 g, 5 mmol) in anhydrous THF (20 ml) was vigorously stirred and thereto were added triethylamine (0.70 ml, 5 mmol) and isobutyl chloroformate (0.66 ml, 5 mmol) at 0° C. To this mixture was added cyclohexylamine (0.57 ml, 5 mmol) and this mixture was stirred for 2 hours at 0° C. and further for 24 hours at room temperature. The solvent was removed to obtain white crystals. These crystals were dissolved in a mixture of CH2Cl2 (80 ml) and water (30 ml). The organic layer was washed with 0.5M boric acid, a saturated aqueous sodium chloride solution, a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution and water (50 ml each) in succession, dried over Na2SO4 and concentrated under reduced pressure to obtain crude carbobenzoxy-(S)-valine cyclohexylamide (1.45 g, 87%), which was used as it was for the following reaction.
Reaction SMILES: C(OC(NCC1(O)CCN([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:16]=2[F:33])C1)=O)(C)(C)C.C(OC(=O)C)(=O)C>>[CH:26]1([N:22]2[C:23]3[C:18](=[CH:17][C:16]([F:33])=[CH:15][C:24]=3[F:25])[C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21]2)[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)cc(F)cc2c1=O

Procedure:
Analogously to example 30 7-(3-tert.-butoxycarbonylaminomethyl-3-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-4-oxo-3-quinolinecarboxylic acid are reacted with acetic acid anhydride, yielding 7-3-acetoxy-3-tert.-butoxycarbonylaminomethyl-3-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 215° C. (decomposition).
Reaction SMILES: [C:1](Br)#[C:2][CH3:3].[Na].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[H-].[Na+]>O.CN(C)C=O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([CH2:3][C:2]#[CH:1])[CH2:16][CH2:17]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC#CBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1CCN(c2ccccn2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Propynylbromide (11.9 g.) was added to the sodium salt of N-(2-pyridyl)piperazine prepared from 16.3 g. of N-(2-pyridyl)piperazine and 4.8 g. of sodium hydride/50% mineral oil dispersion in 50 ml. of dry dimethylformamide. The mixture was stirred at 50° C. for 3 hours and then carefully poured into 3 volumes of cold water. This mixture was extracted with several portions of either and the combined ether extracts were washed twice with 10% aqueous hydrochloric acid. The acidic extract was made strongly alkaline by adding 40% aqueous sodium hydroxide under cooling. The mixture was then extracted several times with ether and the combined extracts were dried over magnesium sulfate. The latter was then removed by filtration, and the filtrate was evaporated to produce a brown oil. Distillation under reduced pressure gave N'-(2-pyridyl)-N-(2-propynyl)piperazine, b.p. 153°-4° C./3.5 mm, as a yellow oil which showed the expected NMR and IR spectra.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C1CCN2C(=NCCC2)CC1.C1N=[CH:26][N:25]([C:28](N2C=NC=C2)=[O:29])[CH:24]=1.CNC>C(#N)C>[CH3:24][N:25]([CH3:26])[C:28]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1)=[O:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Agent: CNC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (10 g, 59 mmol), DBU (18 mL, 0.12 mol) and CDI (24 g, 0.15 mol) in 400 mL acetonitrile is stirred for 5 h at 100° C. Then dimethylamine (150 mL, 2M in THF) is added and the reaction mixture is stirred overnight at 100° C. The reaction mixture is concentrated under reduced pressure and the residue is poured in water. The mixture is acidified to pH 5 with 6 M HCl in water and extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue is triturated with diethyl ether. Yield: 9.1 g.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Cc1ccc(-n2cnc3ccc(O)nc32)c(C)c1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,4-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([C:10]1[C:11]([OH:16])=[CH:12][CH:13]=[CH:14][C:15]=1[C:1]1([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=2[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:22]2[C:17](=[O:23])[CH2:18][CH:19]=[CH:20][C:21]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1O
Reactant: Oc1ccccc1
Product: CCCCCCCCCc1c(O)cccc1C1(c2cccc(O)c2CCCCCCCCC)C2=C(C=CCC2=O)c2ccccc21

Procedure:
Ortho-n-nonyl-phenol should be substituted for the phenol of Example 8 in this Example and the procedure of Example 8 should be followed in this Example to obtain the product herein.
Reaction SMILES: [C:1]([C:5]1[N:10]2[C:11]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:12]=3[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][CH2:15][C:9]2=[N:8][C:7](=[O:27])[CH:6]=1)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:2][CH2:1][C:5]1[N:10]2[C:11]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:12]=3[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:14][CH2:15][C:9]2=[N:8][C:7](=[O:27])[CH:6]=1
Reactant: COC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(CO)n2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
A solution of 1 mmole of 1-carbomethoxy-9-chloro-7-phenylpyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one in tetrahydrofuran was reacted at room temperature with the stoichiometric amount of lithium aluminum hydride and stirred for several hours. It was decomposed with water and 15% sodium hydroxide and worked up to give 1-hydroxymethyl-9-chloro-7-phenylpyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.