Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH2:12])[NH:8][C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[C:54]([N:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:55])[C:48](O)=[O:49].N.BrBr>O1CCCC1.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][C:48](=[O:49])[C:47]3[CH:51]=[CH:52][C:53]([C:54]([N:56]4[CH2:57][CH2:58][CH2:59][CH2:60]4)=[O:55])=[C:45]([CH3:44])[CH:46]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NCc1nc2cc(Br)cnc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)NCc2nc3cc(Br)cnc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from C-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)methylamine, TBTU, diisopropylethylamine, and 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid in tetrahydrofuran. Yield: 190 mg (76%); Rf value: 0.67 (silica gel; dichloromethane/ethanol=8:2+2% ammonia solution); C20H20BrN5O2 (442,32); mass spectrum: (M+H)+=442/444 (bromine isotope).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14](Cl)=[N:15][OH:16])[CH:10]=[CH:11][CH:12]=1.O1CCCC1.[C:23]([C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][C:14]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[O:16][N:15]=1
Reactant: ON=C(Cl)Cc1cccc(-c2ccccn2)c1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2cccc(-c3ccccn3)c2)no1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
To a mixture of (3-(pyridin-2-yl)-phenyl)-acetohydroximoyl chloride (100 mg) described in Manufacturing Example 84-1-3 and tetrahydrofuran (2 mL) were added 3-ethynyl-pyridin-2-ylamine (10 mg, 0.20 mmol) described in Manufacturing Example 1-2-3 and triethylamine (71 μL, 0.51 mmol) at room temperature, which was stirred for 2.5 hours at 55° C. The reaction mixture was cooled to room temperature, and water was added at that temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound as a crude product. This was then purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound (7.2 mg, 15%) as a ditrifluoracetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[C:12]([OH:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:20]([O:13][C:12]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cnc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of ethyl 6-chloro-5-hydroxynicotinate (2 g, 0.01 mol) in Toluene (50.0 mL) were added K2CO3 (2.76 g, 0.02 mol, Rankem, India) and benzyl bromide (2 g, 0.0012 mol). The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 20% EtOAc in hexane), the reaction mixture was quenched with water (50 mL), extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and purified by column chromatography, silica gel (60-120 mesh) using 12-16% EtOAc in petroleum ether as the eluent to give the title compound. MS (ESI, positive ion) m/z: 292.2 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:18]1([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
The mixture of 2-[(5,6,7,8-Tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (37) (400 mg, 1.1 mmol) and KOH (1 g, 17.8 mmol) is dissolved in EtOH (10 mL) and water (2 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (38) as white solid (300 mg, 82%).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[CH3:11]COCC>CO>[ClH:1].[CH3:11][O:9][C:8](=[O:10])[C@@H:5]1[CH2:4][C@@H:3]([OH:2])[CH2:7][NH:6]1
Reactant: CCOCC
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h
Yield: 93 %

Procedure:
Anhydrous HCl was bubbled through a stirred suspension of trans-4-hydroxy-L-proline (80 g, 0.61 mol) in 500 ml anhydrous methanol until the mixture was homogeneous. The reaction was heated to reflux for five hours, and the volume of the solvent then reduced by one half. Ether (100 ml) was added, and the mixture kept in a freezer overnight. The resulting precipitate was filtered, washed with ether and dried under reduced pressure to yield 111 g of present title product (93% yield). mp 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Cl)[O:17][CH3:18]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([O:9][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(Cl)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(Cl)nc1F
Temperature: 60 °C
Yield: 82.3 %

Procedure:
A solution of 6-chloro-2-fluoropyridin-3-ol (1.4 Kg, 9.49 mol) was dissolved in acetone (13 L), and treated with K2CO3 (1574 g, 11.39 mol, 1.2 eq) and MOMCl (840 g, 10.44 mol, 1.1 eq). The mixture was heated at 60° C. for 2 hrs. After cooling to RT, the reaction mixture was filtered to remove inorganic salts. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% EtOAc/hexanes), affording 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (1496 g) as a colorless oil in 80% yield over two steps.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Nc2ccccc2Oc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A −78° C. solution of Example 1C (236 mg, 1.0 mmol) and 2-phenoxyaniline (370 mg, 2.0 mmol) in THF (10 mL) was treated with 1M lithium hexamethyldisilazide in THF (4 mL, 4.0 mmol), warmed to room temperature over 4 hours, diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 384 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[Br-:34].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[C:27]([Br:34])[C:28]=2[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: [Br-]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(Br)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.9 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (1.01 g) was dissolved in CH2Cl2 (40 mL) under N2 and tetrabutylammonium tribromide (1.21 g) was added and the mixture was stirred at room temperature overnight. More tetrabutylammonium tribromide (0.55 g) was added and the mixture was stirred for 1 day. The mixture was then washed with water (25 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: hexane and AcOEt) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-bromophenyl)-L-phenylalanine methyl ester (1.17 g).
Reaction SMILES: [CH3:1][CH:2]1[O:7][C@@H:6]([O:8][C@H:9]2[CH2:25][C@:24]3([OH:26])[C@@:12]([CH:35]=[O:36])([CH:13]4[CH:21]([CH2:22][CH2:23]3)[C@:20]3([OH:27])[C@@:16]([CH3:34])([C@@H:17]([C:28]5[CH2:33][O:32][C:30](=[O:31])[CH:29]=5)[CH2:18][CH2:19]3)[CH2:15][CH2:14]4)[CH2:11][CH2:10]2)[CH2:5][CH:4]2[O:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([CH3:40])[O:39][C@H:3]12.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCOCC1>[CH3:1][CH:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[CH2:25][C@:24]3([OH:26])[C@@:12]([CH2:35][OH:36])([CH:13]4[CH:21]([CH2:22][CH2:23]3)[C@:20]3([OH:27])[C@@:16]([CH3:34])([C@@H:17]([C:28]5[CH2:33][O:32][C:30](=[O:31])[CH:29]=5)[CH2:18][CH2:19]3)[CH2:15][CH2:14]4)[CH2:11][CH2:10]2)[CH2:5][CH:4]2[O:37][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([CH3:40])[O:39][C@H:3]12
Reactant: CC1O[C@@H](O[C@@H]2CC[C@]3(C=O)C4CC[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)C4CC[C@]3(O)C2)CC2OC(C)(c3ccccc3)O[C@H]12
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1O[C@@H](O[C@H]2CC[C@]3(CO)C4CC[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)C4CC[C@]3(O)C2)CC2OC(C)(c3ccccc3)O[C@H]12
Reaction time: 1 h

Procedure:
1.5 g. acetophenone-helveticoside are dissolved in 20 ml. of 80% aqueous dioxane and treated dropwise over a period of 1 hour with a solution of 0.35 g. sodium borohydride in 20 ml. of 75% dioxane. The reaction mixture is stirred for 1 hour, after which no more acetophenone-helveticoside can be detected. The solution is adjusted to pH 7 with dilute sulfuric acid, and the dioxane is removed under reduced pressure in a rotating evaporator. The aqueous phase is repeatedly extracted with chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated. The residue is purified chromatographically over silica gel, using chloroform as solvent. Yield: 750 mg. acetophenone-helveticosol, melting point: 154°-164°C⟦alpha.D20 ](C = 1, chloroform): ±0°.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:5]=1[NH:6][C@@H:7]([CH3:10])[CH2:8][OH:9].C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:3][C:4]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:5]=1[N:6]([CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@@H:7]([CH3:10])[CH2:8][OH:9]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
At room temperature, potassium hydroxide (330 mg) and tetrabutylammonium hydrogensulfate (82.7 mg) were dissolved in DMF (15 ml). After adding a solution (5 ml) of (2S)-2-(2,3,4-trifluoroanilino)propanol (1 g, 99.8% ee) and diethyl ethoxymethylenemalonate (2.09g) in DMF, the resultant mixture was stirred for 1 hour. After adding water, the liquid reaction mixture was extracted with a solvent mixture of ethyl acetate and n-hexane (3:2). The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, IPE was added to the obtained residue and the mixture was stirred at 0° C. for 1 hour. The crystals thus precipitated were collected by filtration and the moist product thus obtained was dried under reduced pressure. Thus, the title compound (1.7 g, 99.8% ee) was obtained as colorless crystals. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 63.
Reaction SMILES: C1(COC(=O)[NH:10][CH:11]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:12](=[O:19])[NH:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)C=CC=CC=1>CO.[Pd]>[C:22]([O:21][CH2:20][CH:11]([NH2:10])[C:12]([NH:13][N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)=[O:19])(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCC(N)C(=O)Nn1cccc1
Yield: 48.5 %

Procedure:
(±)-Phenylmethyl-[1-(acetyloxymethyl)-2-oxo-2-(1H-pyrrol-1-ylamino)ethyl]carbamate (4.18 g) was dissolved in 100 ml of methanol and 5% Pd/C (450 mg) was added. The solution was hydrogenated at atmospheric pressure and room temperature until absorption of 90% of the theoretical amount of hydrogen. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by flash column chromatography (silica gel, ethyl acetate/methanol, 19:1) and the desired fractions combined and evaporated. Recrystallization of the residue from ethyl acetate/methanol/hexane afforded the product obtained as a powder (1.24 g), m.p. 147°-148° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]1([C:31]2[N:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:28]3[CH2:29][CH2:30][N:25]([C:31]4[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][N:36]=4)[CH2:26][CH2:27]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: N#Cc1ccc(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)nc1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 6-(piperazino)pyridine-3-carbonitrile to give the title compound as a colorless solid. MS: 523.5 ([M+H]+)
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C([Li])CCC.[C:25](=[O:27])=[O:26].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:17][C:13]1[CH:12]=[C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:25]([OH:27])=[O:26])[C:3]=3[O:18][CH3:19])[NH:7][N:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C=O
Reactant: COc1c(Br)ccc2[nH]nc(-c3cccc(F)c3)c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(=O)O)ccc2[nH]nc(-c3cccc(F)c3)c12
Temperature: -78 °C

Procedure:
A total of 230 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1H-indazole obtained in Production Example II-2-c was dissolved in 4.78 ml of tetrahydrofuran, and 0.99 ml of a 1.59 M solution of n-butyllithium in hexane was added under stirring at −78° C. After stirring at −78° C. for 30 minutes, dry ice was added. After stirring at the same temperature for 10 minutes, saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:1), to give 41.1 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12])=[C:2]([NH:1][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)Nc1ccc(Br)cc1N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Br)ccc2N[C@@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 113.6 %

Procedure:
A 1-L, round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and thermocouple was charged with (S)-2-(2-amino-4-bromophenylamino)propane-1-ol (47.55 g, 194 mmol), and pyridine (475 mL). The mixture was cooled to 0° C. and p-toluene sulfonyl chloride (37.0 g, 194 mmol) was added in portions of 12.6 and 24.4 g. The internal temperature rose from 1.5 to 15.6° C. following each addition. The reaction mixture stirred at 0° C. for 1.5 h and was then warmed to room temperature. The pyridine was removed under reduced pressure, and the residue was diluted with ethyl acetate (300 mL) and washed with water (100 mL). The combined organic phases were washed with half saturated brine (100 mL) and concentrated under reduced pressure. The residue was dissolved in toluene (250 mL), and the solution concentrated under reduced pressure (in order to remove some residual pyridine). The crude product was purified by column chromatography on silica gel (eluting with 1:1 hexanes-ethyl acetate). The product-containing fractions were combined and concentrated under reduced pressure. Toluene (250 mL) was added, and the mixture was concentrated under reduced pressure to removed trace pyridine. The material was dried under vacuum (ca 17 Torr) to afford (S)-N-(5-bromo-2-(1-hydroxypropan-2-ylamino)phenyl)-4-methylbenzenesulfonamide (88 g, 110%) as a viscous yellow oil that contains 11 wt % toluene. MS (ESI, pos. ion) m/z 399 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][CH2:16][CH2:17]N=C=O>O1CCCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:17][CH2:16][Cl:15])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCCCl)CC1
Yield: 116.1 %

Procedure:
A solution of 4-amino-1-t-butoxycarbonylpiperidine (200 mg, 1.0 mmol) in tetrahydrofuran (5 mL) was treated with 2-chloroethyl isocyanate (0.090 mL, 1.0 mmol) overnight. The solvent was evaporated to provide the title compound as a white solid (305 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:13][C:5]1[C:6]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][C:7]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC1(C)Cc2c(Cl)ccc([N+](=O)[O-])c2O1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Cc2c(Cl)ccc(N)c2O1
Temperature: 50 °C
Yield: 68.9 %

Procedure:
A solution of 4.0 g (0.018 mole) of 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran in approximately 60 mL of glacial acetic acid was heated to 50° C. To this solution were added 10 mL of water, and, while maintaining the temperature at 50° C., 4.0 g (0.072 mole) of powdered iron. Upon completion of addition, the reaction mixture was allowed to cool to room temperature at which it stirred for an hour. Then the reaction mixture was diluted with 100 mL of water and filtered. The filtrate was extracted with diethyl ether, and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from this filtrate under reduced pressure, leaving 2.45 g of 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran as a residue.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:33])[CH:12]([NH:13][C:14](=[O:32])[C:15](=[N:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:16]3[N:17]=[C:18]([NH:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.Cl>CO.O1CCCC1>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:33])[CH:12]([NH:13][C:14](=[O:32])[C:15](=[N:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Agent: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC=O)[nH]1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution of 2-methyl-7-[2-hexyloxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-hexyloxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (5.3 g) and concentrated hydrochloric acid (4.2 g) in a mixture of methanol (53 ml) and tetrahydrofuran (40 ml) was stirred for 2 hours at 30° C., and then evaporated to dryness. The residue was dissolved in an aqueous solution of sodium bicarbonate (500 ml) and then filtered. The filtrate was adjusted to pH 3.5 with 10% hydrochloric acid with stirring under ice-cooling and further stirred for 30 minutes at the same temperature. The precipitates were collected by filtration, washed with water and then dried to give 2-methyl-7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-hexyloxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (4.45 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1cccnc1
Product: CC(C)(C)c1cc2ncc(C#Cc3cccnc3)cn2n1

Procedure:
The title compound, white solid, MS: m/e=277.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 3-ethynylpyridine.