Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10](B(O)O)[CH:9]=[N:8][C:7]=12)[CH3:2].O1CCOCC1.Br[C:22]1[S:23][C:24]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[C:29]([C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:28]([CH3:49])=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:45]([O:44][C@@H:38]([C:29]1[C:28]([CH3:49])=[CH:27][C:25]2[N:26]=[C:22]([C:10]3[CH:9]=[N:8][C:7]4[N:6]([N:5]=[CH:4][C:3]=4[CH2:1][CH3:2])[CH:11]=3)[S:23][C:24]=2[C:30]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:46])([CH3:47])[CH3:48]
Reactant: CCc1cnn2cc(B(O)O)cnc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(CC)cnn4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of the crude 3-ethylpyrazolo[1,5-a]pyrimidin-6-ylboronic acid in dioxane (˜0.18M, 0.68 mL, 0.123 mmol) was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.101 mmol), Pd(PPh3)4 (12 mg, 0.010 mmol) and 2M potassium carbonate (0.20 mL, 0.404 mmol) was heated in a microwave at 110° C. for 1 h. Reaction mixture was stored overnight at rt, diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 30% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C30H32ClN4O3S: 563.2 (M+H+); Found: 563.3 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:7](=[C:8]([C:32]([NH:34][CH2:35][C:36]3[C:37](=[O:46])[NH:38][C:39]([CH3:45])=[CH:40][C:41]=3[CH2:42][CH2:43][CH3:44])=[O:33])[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5]1)[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[N:17][C:16]([N:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:32]([NH:34][CH2:35][C:36]3[C:37](=[O:46])[NH:38][C:39]([CH3:45])=[CH:40][C:41]=3[CH2:42][CH2:43][CH3:44])=[O:33])[C:7]=2[CH:6]=[CH:5]1)([CH3:1])[CH3:3]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc2c1ccn2C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc2c1ccn2C(C)C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a suspension of 1,1-dimethylethyl 4-{5-[1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indol-6-yl]-2-pyridinyl}-1-piperazinecarboxylate (70 mg, 0.112 mmol) in dichloromethane (2 mL) was added TFA (0.5 ml, 6.49 mmol), and the mixture was stirred for 1 h. The mixture was concentrated and the residue was treated with saturated aqueous NaHCO3 solution and filtered. The solid was purified using column chromatography (silica gel, 0 to 15% (9:1 MeOH/NH4OH)/CH2Cl2) to give 1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide (51 mg, 84%) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (m, 3 H), 1.47 (d, J=4.00 Hz, 6H), 1.53-1.60 (m, 2 H), 2.14 (s, 3 H), 2.89-2.98 (m, 4 H), 3.51-3.59 (m, 4 H), 4.40 (d, J=5.05 Hz, 2 H), 4.93 (quin, J=6.63 Hz, 1 H), 5.92 (s, 1 H), 6.87 (d, J=3.03 Hz, 1 H), 6.94 (d, J=8.84 Hz, 1 H), 7.60 (d, J=3.03 Hz, 1 H), 7.66 (d, J=1.26 Hz, 1 H), 7.88 (s, 1 H), 8.00 (dd, J=8.84, 2.53 Hz, 1 H), 8.28 (t, J=5.05 Hz, 1 H), 8.58 (d, J=2.27 Hz, 1 H). MS: (M+H)+=527.2.
Reaction SMILES: [CH2:1]([C:4]1([C:19]([OH:21])=[O:20])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:2]=[CH2:3].[Li].[CH2:23](I)C=C.[Cl-].[NH4+]>C1COCC1.CCCCCC.C1COCC1>[CH2:1]([C:4]1([C:19]([O:21][CH3:23])=[O:20])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Reactant: C=CCI
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC1(C(=O)OC)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesis of (RS)-2-allyl-N-(benzyloxycarbonyl)proline ##STR5## N-benzyloxycarbonylproline methyl ester (13 g) in THF (20 ml) was added dropwise to lithium dilsopropylamide (27.5 ml, 2M in hexane/THF) in THF (100 ml) at -78° C. under nitrogen. The mixture was stirred for 30 minutes and then allyl iodide (5.5 ml) was added dropwise and the mixture stirred for a further 30 minutes and then allowed to warm to ambient temperature. The mixture was then added to aqueous ammonium chloride (200 ml) and extracted with ether (2×200 ml). The ether layer was evaporated and the residue was purified by chromatography on silica using a gradient of hexane increasing to 20% ethyl acetate:hexane. The appropriate fractions, evaporated to dryness, gave methyl (RS)-2-allyl-N-(benzyloxycarbonyl)prolinate (9 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: Cc1nc(NC(=O)c2cccc(C(F)(F)F)c2)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-trifluoromethylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 27% yield; m.p. 195-196° C.; 1H NMR (CDCl3, 300 MHz) δ 8.15 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.40-7.27 (m, 5H), 5.97 (t, J=4.7 Hz, 1H), 4.59 (d, J=5.5 Hz, 2H), 2.49 (s, 3H); MS (ES+) m/z 420 (M+1).
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].C1C=CC(CCBr)=CC=1>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:20](=[O:25])[C:19]2=[O:26]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Agent: BrCCc1ccccc1
Product: O=C1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using the commercially available 5-chloroisatin (purchased from Fisher Scientific) and 2-phenethyl bromide (purchased from Fisher scientific). 1H NMR δ 7.54 (s, 1H), 7.44 (d, 1H), 7.27 (m, 5H), 6.64 (d, 1H), 3.95 (t, 2H), 2.99 (t, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[C:12]=2[Cl:19])[N:8]=[C:7]1[CH:20]=O)(=[O:5])=[O:4].Cl.[CH2:24]([O:27][NH2:28])[CH:25]=[CH2:26].Cl.NO>>[CH2:24]([O:27][N:28]=[CH:20][C:7]1[N:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:22])[CH3:1])[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[C:12]=2[Cl:19])[N:8]=1)[CH:25]=[CH2:26]
Reactant: C=CCON
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccc(Cl)c(Cl)c2Cl)nc1C=O
Agent: Cl
Agent: NO
Product: C=CCON=Cc1nc(-c2ccc(Cl)c(Cl)c2Cl)cn1S(=O)(=O)N(C)C

Procedure:
1-(Dimethylsulphamoyl)-2-formyl-4-(2,3,4-trichlorophenyl)imidazole was reacted with O-allylhydroxylamine hydrochloride in a similar manner to the reaction with hydroxylamine hydrochloride described in Example 1, to give 2-allyloxyiminomethyl-1-(dimethylsulphamoyl)-4-(2,3,4-trichlorophenyl)imidazole, m.p. 87°-88°. (Compound 9)
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:13]N.O.NN.C(O)CO>O>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][NH2:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: NN
Agent: Cl
Solvent: OCCO
Solvent: O
Product: Cc1cccc2sc(NN)nc12
Temperature: 140 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
4-Methyl-2-aminobenzothiazole (8.21 g.; 0.05 mole), hydrazine monohydrochloride (1.14 g.; 0.017 mole), 85% hydrazine hydrate (1.96 g.; 0.033 mole), and 41 ml. of ethylene glycol were mixed, and the mixture heated under N2 atmosphere to 140°C. These reaction conditions were continued for 15 hours; the reaction mixture was then permitted to cool slowly to romm temperature and, for convenience only, stored overnight under N2 atmosphere. Water (45 ml.) was added to the reaction mixture in the morning to force crystallization. The reaction mixture was then filtered to separate the desired 4-methyl-2-hydrazinobenzothiazole compound. It was dried in vacuo overnight at 60°C. The yield was 8.00 g., 89% yield, m.p. 143°-51°C. Non-aqueous titration showed the product to be 85.8% pure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O.[NH:12]1[C:20](=[O:21])[C:18](=O)[C:16](=[O:17])[NH:15][C:13]1=[O:14]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:16]([OH:17])[C:18]([C:20]([NH:12][C:13]([NH2:15])=[O:14])=[O:21])=[N:10]2
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NC(=O)c1nc2cc(Cl)c(Cl)cc2nc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,5-dichloro-o-phenylenediamine (36.2 mmole) and alloxan monohydrate (36.2 mmole) in 10% aqueous acetic acid was stirred at room temperature for a period of 2 hours. Concentration of the reaction mixture gave N-(6,7-dichloro-2-hydroxy-3-quinoxalinoyl)urea which was added to 50% aqueous sulfuric acid and the mixture was heated at a temperature of 135° C. for a period of 3 hours. After cooling the precipitated material was collected by filtration, washed with water and then was slowly added to a 5% aqueous solution of sodium bicarbonate. The insoluble material was collected by filtration and was washed successively with water and ethanol to give 6,7-dichloro-2-hydroxyquinoxaline.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][C:7]1[CH:8]=[C:9](O)[C:10]2[CH:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[N:12]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Br:3][C:9]1[CH:8]=[C:7]([CH3:6])[N:12]=[C:11]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=12
Reactant: Cc1cc(O)c2cnn(Cc3ccccc3)c2n1
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Br)c2cnn(Cc3ccccc3)c2n1

Procedure:
Phosphorus oxybromide (5.31 g, 18.54 mmol) was added to a suspension of 6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.08 g, 12.87 mmol) and toluene (25 mL). The contents were heated to reflux for 1 h, wherein 10 mL DMF were added during this process. The solvent was removed under reduced pressure. The crude residue was suspended in 30 mL water containing ice. The contents were adjusted to pH=10 by addition of sat. NaHCO3. The solid product was filtered and dried under hi-vacuum. The final product was collected as 3.55 g (91%). LCMS E-S (M+H)=302.1/304.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (s, 3 H), 5.65 (s, 2 H), 7.16-7.35 (m, 5 H), 7.48 (s, 1 H), 8.12 s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.O1CCOCC1.[N:19](OCCC(C)C)=[O:20]>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:19][OH:20])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)CCON=O
Reactant: Cc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=O)C(=NO)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
6-Methylindan-1-one (5.00 g, 34.2 mmol) and 4N hydrochloric acid-dioxane solution (2 ml) were added to ethanol (30 ml), isoamyl nitrite (5.1 ml, (37.6 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The precipitated solid was collected by filtration and washed with diisopropyl ether to give the title compound (5.36 g, yield 89%) as a pale-yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.C(O[CH:20]=[CH:21][C:22]#[N:23])C>C(O)(C)(C)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[CH:21][C:22]([NH2:23])=[N:16]2)=[CH:11][CH:10]=1
Reactant: CCOC=CC#N
Reactant: NNc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccn(-c2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 44 %

Procedure:
To a hot solution of potassium tert-butoxide (2.54 g, 23 mmol) in tert-butanol (30 ml) was added 4-fluorophenylhydrazine hydrochloride (1.67 g, 10 mmol). After cooling to ambient temperature, a solution of 3-ethoxyacrylonitrile (1.0 g, 10 mmol) in tert-butanol (5 ml) was added and the mixture was refluxed for 3 h. After cooling to ambient temperature, the solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with water. The organic phases were combined, dried and evaporated. Silica gel chromatography using a heptane/ethyl acetate gradient yielded the amine as orange solid (0.78 g, 42%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23](O)=[O:24])[C:12]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[C:29]([O:37][CH3:38])=[CH:30][C:31]([O:35][CH3:36])=[C:32]([CH:34]=1)[NH2:33]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23](=[O:24])[NH:33][C:32]2[CH:34]=[C:28]([Cl:27])[C:29]([O:37][CH3:38])=[CH:30][C:31]=2[O:35][CH3:36])[C:12]1=[O:26])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)NCCn1c(=O)c2ccccc2n(CC(=O)O)c1=O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCNC(=O)OC(C)(C)C)c(=O)c3ccccc32)cc1Cl

Procedure:
This compound is made analogously to Example 1-2 by replacing Intermediate A with [3-(2-tert-butoxycarbonylamino-ethyl)-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl]-acetic acid and by replacing cyclopentylamine with 5-chloro-2,4-dimethoxyaniline to afford the title compound. The reaction is carried out in DCM.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][OH:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:17][CH:18]=3)[C:9]([CH:11]=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Yield: 84.8 %

Procedure:
N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (40.0 mg, 0.09 mmol) was dissolved in THF (5.0 mL) and to it was added Dess-Martin Periodinane reagent (44.0 mg, 0.10 mmol). The reaction was stirred at rt until HPLC indicated completion of reaction. Reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3/Na2S2O3 1:1 (3×). The aqueous layer was back extracted with EtOAc (2×). Organic was dried (Na2SO4) and evaporated to give a crude oil that was purified via HPLC (10-90% ACN/H2O) to give a yellow solid (35.0 mg, 88%). 1H-NMR (CD3OD) δ 9.76 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H); MS [M+H]+=459; LCMS RT=2.95 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(=O)C=Cc1coc2ccc(C=O)cc12
Product: CCOC(=O)C=Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-(5-Formyl-benzofuran-3-yl)-acrylic acid ethyl ester (intermediate 60) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[N:17]=[CH:16][C:15]([C:22]([NH2:24])=[O:23])=[C:14]3[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>COCCOC.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>[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:11]3[CH:12]=[C:13]4[C:18](=[C:19]([CH3:21])[CH:20]=3)[N:17]=[CH:16][C:15]([C:22]([NH2:24])=[O:23])=[C:14]4[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)(=[O:10])=[O:9])[CH:3]=2)=[CH:38][CH:37]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(Br)c4)cc23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a suspension of Intermediate 62 (0.95 mmol) and 4-(hydroxymethyl)phenylboronic acid (290 mg, 1.90 mmol) in DME (10 mL) at room temperature was added 2 M Na2CO3 (1.4 mL, 2.85 mmol) and PdCl2(PPh3)2 (33 mg, 0.005 mmol). The reaction mixture was stirred at reflux for 2 h and then cooled to room temperature. After the addition of 60 mL of chloroform, a white precipitate formed which was collected by filtration. The crude product was purified by flash column chromatography (0-15% MeOH in dichloromethane) to give the title compound (357 mg, 68% for 3 steps). ES/MS calcd. for C31H28N3O5S+ 554.2. Found m/z=554.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:17])=[C:4]([S:9]([N:12]([O:15][CH3:16])[CH2:13][CH3:14])(=[O:11])=[O:10])[C:5](Cl)=[CH:6][CH:7]=1.[H][H]>CCO.[Pd]>[NH2:1][C:2]1[C:3]([OH:17])=[C:4]([S:9]([N:12]([CH2:13][CH3:14])[O:15][CH3:16])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCN(OC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: [Pd]
Solvent: CCO
Product: CCN(OC)S(=O)(=O)c1cccc(N)c1O
Reaction time: 5 h

Procedure:
A dispersion of 10% Pd/C (200 mg) in a solution of 3-amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Int. FA step 2) (400 mg, 11.425 mmol) in EtOH (50 ml) was placed under a positive pressure of hydrogen at 0.5 bar above atmospheric pressure. After 5 hours, the catalyst was removed by filtration through Celite® (filter material), and the filtrate was reduced in vacuo. The resulting solid was used in the next step, without further purification.
Reaction SMILES: Cl.[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:36]=[C:35]([CH:37]=O)[O:34][N:33]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:36]=[C:35]([CH2:37][N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:13]3[N:14]=[N:15][CH:16]=[C:11]4[O:10][N:9]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:12]=34)[CH2:20][CH2:21]2)[O:34][N:33]=1
Reactant: c1ccc(-c2noc3cnnc(NCC4CCNCC4)c23)cc1
Reactant: O=Cc1cc(-c2ccccc2Cl)no1
Agent: Cl
Product: Clc1ccccc1-c1cc(CN2CCC(CNc3nncc4onc(-c5ccccc5)c34)CC2)on1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 84 instead of the compound obtained in Example 11 and 3-(2-chlorophenyl)isoxazole-5-carbaldehyde instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](COCC[Si](C)(C)C)[N:11]=[C:10]2[N:24]([CH2:26][CH2:27][O:28][CH3:29])[CH3:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[N:24]([CH2:26][CH2:27][O:28][CH3:29])[CH3:25]
Reactant: COCCN(C)c1nn(COCC[Si](C)(C)C)c2ccc(C3OCCCO3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: COCCN(C)c1n[nH]c2ccc(C3OCCCO3)cc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 245 mg (0.583 mmol) 5-(1,3-dioxan-2-yl)-N-(2-methoxyethyl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-amine (Example 46A) in anhydrous THF (12 ml) were added 8.5 ml (8.5 mmol) tetrabutylammonium fluoride solution (1 M in THF) and ethane-1,2-diamine (200 μl). The solution was stirred at 50° C. for 3 h. After addition of further 8.5 ml tetrabutylammonium fluoride solution (1 M in THF), stirring at 50° C. was continued for 24 h. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution and with water. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The remaining solid (200 mg, 87% of th.) was used in the next step without further purification.
Reaction SMILES: I[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:58])[C:29](=[N:55][O:56][CH3:57])[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[SH:60][C:61]1[S:62][C:63]([C:66]2[CH:71]=[CH:70][C:69]([O:72]COCCOC)=[C:68]([O:79]COCCOC)[CH:67]=2)=[N:64][N:65]=1.C(=O)([O-])O.[Na+:90].OC[C@@]1(OC[C@H](O)[C@@H](O)[C@@H]1O)O>O>[NH2:35][C:32]1[S:33][CH:34]=[C:30]([C:29](=[N:55][O:56][CH3:57])[C:28]([NH:27][C@@H:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][S:60][C:61]4[S:62][C:63]([C:66]5[CH:71]=[CH:70][C:69]([OH:72])=[C:68]([OH:79])[CH:67]=5)=[N:64][N:65]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1.[Na+:90]
Reactant: COCCOCOc1ccc(-c2nnc(S)s2)cc1OCOCCOC
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])O
Agent: OC[C@]1(O)OC[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nnc(-c4ccc(O)c(O)c4)s3)CS[C@H]12)c1csc(N)n1

Procedure:
A trifluoroacetate obtained by the same operation as in EXAMPLE 1 by using 1.0 g (1.07 mmol) of benzhydryl 3-iodomethyl-7β-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl) acetamido]-3-cephem-4-carboxylate (syn-isomer) and 0.43 g (1.07 mmol) of 2-mercapto-5-[3,4-di(2-methoxyethoxymethoxy)phenyl]-1,3,4-thiadiazole, was suspended in water and adjusted to pH6.5 with a saturated sodium hydrogencarbonate aqueous solution. Then, the suspension was subjected to ODS column chromatography (LC Sorb RP-18, manufactured by Kemco Co.) and eluted with a 20% methanol aqueous solution. The fraction containing the desired compound was concentrated and freeze-dried to obtain 168 mg (yield: 24.3%) of the above identified compound.