Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:24]([NH:26][C:27]([C:29]2[N:30]=[C:31](Cl)[O:32][CH:33]=2)=[O:28])[CH3:25])[CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:16]1[CH:15]=[C:14]([CH:24]([NH:26][C:27]([C:29]2[N:30]=[C:31]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[O:32][CH:33]=2)=[O:28])[CH3:25])[CH:13]=[C:12]([F:11])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc(Cl)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 33.7 %

Procedure:
3-Chlorophenylboronic acid (40.7 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (20 mg, 34%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1). 1H NMR (300 MHz, CDCl3): δ8.31 (s, 1H), 8.05 (s, 1H), 7.93 (d, 1H, J=7.2 Hz), 7.45 (m, 2H), 7.29 (bs, 1H), 7.01 (d, 2H, J=8.7 Hz), 6.67 (s, 1H), 5.22 (m, 1H), 3.18 (s, 3H), 1.60 (d, 3H, J=6.9 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30](=[O:38])[N:31]([CH2:35][CH2:36][NH2:37])[CH2:32][CH2:33][F:34])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30](=[O:38])[N:31]([CH2:35][CH2:36][NH:37][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22])[CH2:32][CH2:33][F:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(CCN)CCF
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCN(CCF)C(=O)OC(C)(C)C)ccc21
Yield: 65.6 %

Procedure:
(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (70 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), (2-amino-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (90 mg), HBTU (100 mg), and DIEA (70 uL) in DMF (1.5 mL).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10]>>[OH:4][CH2:3][C:2]([NH:1][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: CCCC(=O)Cl
Product: CCCC(=O)NC(C)(C)CO
Yield: 32 %

Procedure:
Prepared according to the literature (Boyd, R. N.; Hansen, R. H. J. Am. Chem. Soc. 1953, 75, 5896) from 2-amino-2-methylpropan-1-ol and butyryl chloride in 32% yield. MS 160 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[Br:17]Br>C(Cl)Cl>[Br:17][C:13]1[CH:12]=[CH:11][C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH2:7][C:2]([CH3:16])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: COc1cccc(CC(C)(C)CC(=O)O)c1
Solvent: ClCCl
Product: COc1ccc(Br)c(CC(C)(C)CC(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 3,3-dimethyl-4-(3-methoxyphenyl)butanoic acid (6.7 g, 0.03 mol) in DCM (100 mL) at 0° C. was added a solution of bromine (1.55 mL, 0.03 mol) in DCM (13 mL) dropwise. After addition the solution was stirred at 0° C. for 1 h then the solution was washed with water (3×100 mL), dried (Na2SO4) and evaporated. The product (8.45 g, 94%) was isolated as a brown oil and used without further purification. 1H NMR (360 MHz, CDCl3) δ 1.12 (6H, s), 2.36 (2H, s), 2.98 (2H, s), 3.80 (3H, s), 6.65 (1H, dd, J=8.7 and 3.1 Hz), 6.85 (1H, d, J=3.1 Hz), 7.43 (1H, d, J=8.7 Hz).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])[CH3:5].Cl>CO>[CH3:5][N:4]([CH:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[OH:13])[CH3:3]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C(c1ccccc1)C1CCCCC1O
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A total of 28.3 g (747 mmole) sodium borohydride, dissolved in 650 ml methanol, were added in portions to 80.0 g (299 mmole) of the 2-(dimethylaminophenylmethyl)-cyclohexanone prepared according to Example 1 (2nd stage), and the mixture was subsequently stirred for one hour. For working up, 680 ml dilute hydrochloric acid (1 N) were added, and the mixture was extracted with 500 ml ether. The aqueous phase was rendered alkaline (pH≧10) with 25 vol. % ammonia solution and extracted three times with 250 ml ether each time. The combined organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator (500 to 10 mbar). 65.2 g (94% of theoretical) 2-(dimethylaminophenylmethyl)cyclohexanol were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:17][CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11]([O-])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:15][CH2:16][CH2:17]1)[CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)[O-])C1CCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCO)C1CCC1

Procedure:
This compound was prepared from N-tertbutoxycarbonyl-3-cyclobutylamino-propanoate (4a, 1.71 9, 6.3 mmol) using the procedure described in Example 2b. Yield: 0.94 g (65%). ESI-MS: 230.2 (M+H)+. 252.3 (M+Na)+, 174.2 (M+H—C4H8)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.37.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([O:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][C:34]=2[C:40]([F:43])([F:42])[F:41])=[CH:28][CH:27]=1.CN1CCCC1=O>C(OCC)(=O)C>[CH3:25][C:26]1[N:31]=[CH:30][C:29]([O:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:22]3[C:23]4[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:35][C:34]=2[C:40]([F:43])([F:41])[F:42])=[CH:28][CH:27]=1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Reactant: Cc1ccc(Oc2ccc(N)cc2C(F)(F)F)cn1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2C(F)(F)F)cn1
Temperature: 140 °C
Yield: 57.5 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (150 mg), 4-[(6-methylpyridin-3-yl)oxy]-3-(trifluoromethyl)aniline (175 mg) and 1-methyl-2-pyrrolidone (0.863 mL) was stirred with heating at 140° C. for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (80 mL) and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10). The object fraction was concentrated under reduced pressure. The obtained residue was dissolved in methanol (1.9 mL), 1N sodium hydroxide (0.433 mL) was added, and the mixture was stirred at room temperature for 1.5 hrs. 1N hydrochloric acid (0.433 mL) was added, and the mixture was diluted with ethyl acetate (80 mL) and washed with saturated brine (30 mL). The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and crystallized from diisopropyl ether to give the title compound (118 mg).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:44])=[C:41]([CH:43]=1)[NH2:42]>O1CCCC1>[Br:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:44])=[C:41]([NH:42][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)=[CH:26][CH:25]=2)[CH:43]=1
Reactant: O=C(Cl)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: Cc1ccc(Br)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride (1.0 g, 2.8 mmol) and Hunig's base (600 μL, 3.4 mmol) in tetrahydrofuran (25 mL) was added 5-bromo-2-methylaniline (600 mg, 3.2 mmol), and the reaction was allowed to stir at rt overnight. The mixture was concentrated on a rotary evaporator and purified by flash column chromatography to give N-(5-bromo-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (1.0 g, 70%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.77 (s, 1H), 8.18 (d, 2), 7.98 (d, 2H), 7.82 (m, 6H), 7.65 (m, 4H), 7.41 (dt, 1H), 7.35 (dd, 1H), 7.25 (d, 1H), 2.24 (s, 3H). MS (EI) for C28H21BrN4O: 511.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:42])[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([F:41])[CH:35]=2)=[CH:28][CH:27]=1>>[F:41][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[F:40])[C:33]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:31][CH:30]=1)=[O:42]
Reactant: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Reactant: Nc1ccc(NC(=O)c2ccc(F)c(F)c2)cc1
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4ccc(NC(=O)c5ccc(F)c(F)c5)cc4)c3c2c1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 296 (40 mg, 0.12 mmol), and N-(4-amino-phenyl)-3,4-difluoro-benzamide (36 mg, 0.12 mmol) to provide 298. LC-MS (M+H=557, obsd.=557).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][N:22]4[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]4)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1ccc(-c2nc3ccc(Br)cc3o2)cc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4ccc(Br)cc4o3)cc2)CC1

Procedure:
Preparation is carried out analogously to 4.1.g-2 from 6-bromo-2-(4-bromomethyl-phenyl)-benzoxazole and tert.-butyl piperazine-1-carboxylate.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][C:26]=1[F:31]
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)c(F)c3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.38 g (5.90 mmol) of potassium cyanide was added to 1.30 g (2.95 mmol) of the compound from Example 110A in 27 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.95 g (86% of theory) of the target compound was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH:26]=[O:27])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propen-1-ol (0.80 g), activated manganese dioxide (2.40 g) and tetrahydrofuran (100 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenaldehyde (0.71 g, yield 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:22]([OH:24])=[O:23])=[C:7](/[CH:10]=[CH:11]/[CH2:12][N+:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH2:8][S:9][C@H:4]12.C([O-])(O)=O.[Na+].N1([CH2:41][O:42][N:43]=[C:44]([C:48]2[N:52]=[C:51]([NH2:53])[S:50][N:49]=2)[C:45]([O-])=[O:46])C2C=CC=CC=2N=N1.Cl>CN(C=O)C.CC(C)=O>[NH2:53][C:51]1[S:50][N:49]=[C:48]([C:44](=[N:43][O:42][CH3:41])[C:45]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[NH2:20])=[CH:17][CH:18]=4)[CH2:8][S:9][C@H:4]23)=[O:46])[N:52]=1
Reactant: NC(=O)c1cc[n+](C/C=C/C2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)cc1
Reactant: Nc1nc(C(=NOCn2nnc3ccccc32)C(=O)[O-])ns1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 7-amino-3-[3-(4-carbamoylpyridinio)-1-(E)-propenyl]-3-cephem-4-carboxylic acid hydrochloride (XXII-H, 397 mg, 1 mmole) and NaHCO3 (168 mg, 2 mmoles) in aqueous DMF (water, 3.5 ml and DMF, 7.5 ml) was added benzotriazol-1-yl-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetate (479 mg, 1.5 mmoles) (from Preparation No. 28). The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was adjusted to pH 3-4 with 3N HCl and diluted with 200 ml of acetone to give a precipitate, which was collected by filtration. The crude product was dissolved in a small volume of aqueous THF and the solution was adjusted to pH 6.8 with NaHCO3, treated with decolorizing carbon, concentrated to ca. 1 ml and seeded with a few pieces of crystalline I-1H. After stirring overnight, the crystalline precipitate was collected by filtration to afford the title compound I-1H (zwitterion form). Yield 83 mg (16%). Mp. >185° C. (dec.). Physico-chemical data of this product were identical to those of the compound in Example 10.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:30])[CH:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:31]([O:30][CH:10]([CH:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:12])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(C)C(COCc1ccccc1)OC(C)=O
Yield: 95.7 %

Procedure:
In chloroform, 4.33 g of 1-benzyloxy-3-hexadecyloxy-2-butanol, 26.34 g of acetic anhydride and 10.42 g of triethylamine were heated under reflux for 17 hours. The reaction mixture was treated in a conventional manner and purified by silica gel column chromatography to give 4.56 g of 2-acetyloxy-1-benzyloxy-3-hexadecyloxybutane.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][C@@H:48]([CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:47][C@@H:48]([CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (4.13 g, 13.18 mmole) and hydroxybenzotriazole (2.23 g, 16.48 mmoles) were dissolved in 70 mL THF and then dicyclohexyl-carbodiimide(2.71 g, 13.18 mmoles) was added in one portion to the stirred solution under nitrogen atmosphere. This mixture was stirred for 4 h at room temperature and then filtered to remove dicyclohexylurea precipitate. The product of Example 69B (5.1 g, 11.99 mmoles) was dissolved in 100 mL THF under nitrogen atmosphere. To this stirred solution was added the filtrate of HOBT-active ester and the resulting solution was stirred at room temperature for 4 h, and the solvent removed via rotary evaporation. The residue was dissolved in 150 mL ethyl acetate and washed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4 and the solvent was removed by rotary evaporation to afford a residue. The residue was dissolved in 175 mL 1N HCL, and the solution filtered to remove the small quantity of dicyclohexylurea. The filtrate solution was added to 175 mL ethyl acetate and the two phase mixture rapidly mixed. The pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH. The organic layer was isolated, washed with 100 mL brine, dried over Na2SO4, filtered, and the solvent was removed to afford 8.6 g of a colorless foam. This material was crystallized from 42 mL EtOAc and 21 mL hexane to give 7.85 g of the desired product as a white solid. mp=122-123 °C. CIMS m/z 721 (M+H) +.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:16]1[S:17][C:18]([Sn](CCCC)(CCCC)CCCC)=[CH:19][N:20]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])[CH3:3].Cl[C:35]1[N:40]=[C:39]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[CH:38]=[C:37]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[N:36]=1>C1(C)C=CC=CC=1.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>[CH3:47][C@H:42]1[CH2:43][O:44][CH2:45][CH2:46][N:41]1[C:39]1[CH:38]=[C:37]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[N:36]=[C:35]([C:18]2[S:17][C:16]([N:8]([C:9]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:15])[C:6](=[O:7])[O:5][C:2]([CH3:4])([CH3:1])[CH3:3])=[N:20][CH:19]=2)[N:40]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)n1
Yield: 93.3 %

Procedure:
A mixture of tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(5-tributylstannyl-1,3-thiazol-2-yl)carbamate (3 g, 5.1 mmol), 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1 g, 3.2 mmol) and palladium tetrakis (triphenylphosphine) (50 mg), in toluene (10 mL) was heated at 105° C. for 2 hours under nitrogen. The mixture was chromatographed on silica to give the desired material (1.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:23][CH:22]=[CH2:21])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrocinnamic acid (5.0, 25.9 mM) was dissolved in DMF (50 ml), and anhydrous K2CO3 (7.15 g, 51.8 mM) added with stirring. Allyl bromide (3.36 ml, 38.8 mM) was run in, and the mixture stirred for 18 hours at ambient temperature. After filtration, the solvent was evaporated, the residue treated with water, and product extracted into diethyl ether (2 ×100 ml). The organic solution was washed with an aqueous solution of NaHCO3, water, and brine, and dried (MgSO4). Evaporation of the solvent gave title compound (6 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][NH:11][NH2:12]>CO>[NH2:8][C:6]1[N:5]=[C:4]([NH2:9])[CH:3]=[C:2]([N:11]([CH3:10])[NH2:12])[N:7]=1
Reactant: CNN
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: CO
Product: CN(N)c1cc(N)nc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a refluxing solution of 6-chloro-2,4-diaminopyrimidine (4.0 g) in anhydrous methanol (40 ml) was added methylhydrazine (3.2 g). After 18 hours the refluxing mixture was allowed to cool to room temperature under a nitrogen atmosphere in order that the product could crystallise out. The white solid (3.0 g) was collected by filtration and dried under reduced pressure at 70° C. Recrystallisation of the product from methanol/methylhydrazine (50/l) gave straw-coloured crystals of 2,4-diamino-6-(1-methylhydrazino)pyrimidine (1.92 g; 56% of theoretical yield; M.P. 214°-217° C. decomposition).