Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[S:19][C:18]2[C:17](=[O:20])[N:16]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:15](=[O:34])[N:14]([CH2:35][C:36]3[N:37]=[N:38][N:39]([CH2:41][CH3:42])[N:40]=3)[C:13]=2[CH:12]=1.[ClH:43]>O1CCOCC1>[ClH:43].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[S:19][C:18]2[C:17](=[O:20])[N:16]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:15](=[O:34])[N:14]([CH2:35][C:36]3[N:37]=[N:38][N:39]([CH2:41][CH3:42])[N:40]=3)[C:13]=2[CH:12]=1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4cc(OC)ccc4OC)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cc(OC)ccc4OC)cc32)n1

Procedure:
Tert-butyl 4-[6-(2,5-dimethoxyphenyl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (331 mg, compound B58) and a solution of hydrogen chloride in 1,4-dioxane (1.4 ml+0.9 ml, 4.0 M) in 1,4 dioxane (20 ml) are reacted according to the procedure described in example B79 to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].C[O:11][CH:12](OC)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C(O)C.N>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:11]
Reactant: CNc1ccncc1N
Reactant: COC(CCCCCO)OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CCO
Solvent: O
Product: Cn1c(CCCCCO)nc2cnccc21
Yield: 30.1 %

Procedure:
3-Amino-4-(methylamino) pyridine (1.23 g), 6,6-dimethoxyhexanol (1.62 g), copper (II) acetate monohydrate (4 g), ethanol (30 ml) and water (30 ml) were mixed and then heated at 150° in a sealed tube for 3 hours. To the cold reaction mixture was added concentrated aqueous ammonia (5 cm3) and the mixture was then filtered through "Hyflo" (Trade Mark), diluted with water (50 ml) and extracted with methylene chloride (3×200 ml). The combined organic extracts were dried over Na2SO4, filtered, and evaporated under vacuum. The residue was chromatographed on silica eluting with a mixture of methylene chloride and methanol. The fractions containing the product were evaporated to leave the title compound, (0.66 g).
Reaction SMILES: C([O:3][C:4]1[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:6]([CH3:22])=[C:7]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][N:10]=2)[N:8]=1)C.Cl>CC(C)=O>[CH3:22][C:6]1[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:4](=[O:3])[NH:8][C:7]=1[C:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[N:12]=[CH:11][N:10]=1
Reactant: CCOc1nc(-c2ncnn2-c2ccc(C#N)cc2)c(C)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1c(-c2ncnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
4-{5-[2-Ethoxy-5-methyl-1-(3-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-[1,2,4]triazol-1-yl}-benzonitrile (Intermediate 14, 130 mg, 0.30 mmol), acetone (4 ml) and 5M HCl (3 ml) were heated together at 60° C. for 2 h and allowed to cool. The acetone was removed in vacuo and the aqueous solution basified with NaHCO3 solution.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][N+:8]=1[O-:15].[N+:16]([O-])([OH:18])=[O:17].C(=O)([O-])O.[NH4+]>O>[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:16]([O-:18])=[O:17])[C:10]([CH3:14])=[CH:9][N+:8]=1[O-:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 0.83 h
Yield: 81.5 %

Procedure:
To 98% sulfuric acid (4.93 kg, 49.3 mol), 2,3,5-trimethylpyridine 1-oxide (1.38 kg, 10.1 mol) was added. After 97% nitric acid (1.44 kg) was added dropwise thereto over 50 minutes, the mixture was heated at 85° C. for 4 hours. The reaction mixture was poured to a mixture of ammonium hydrogen carbonate (10.6 kg) and water (9.0 L). The mixture was extracted with ethyl acetate (3.0 L×3). The obtained organic layer was concentrated and dried under vacuum overnight to obtain a desired product (1.50 kg).
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=CC(C#N)=CC=3)CC2)=CC=1OCC.C(OC([N:34]1[CH2:39][CH2:38][CH:37]([N:40](C(OC(C)(C)C)=O)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]3[CH2:53][O:52]C(C)(C)[O:50]3)=[CH:43][N:42]=2)[CH2:36][CH2:35]1)=O)(C)(C)C.Cl>O1CCOCC1.C(O)C>[NH:34]1[CH2:35][CH2:36][CH:37]([NH:40][C:41]2[N:42]=[CH:43][C:44]([O:47][CH2:48][CH:49]([OH:50])[CH2:53][OH:52])=[CH:45][CH:46]=2)[CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OCC3COC(C)(C)O3)cn2)CC1
Agent: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: OCC(O)COc1ccc(NC2CCNCC2)nc1

Procedure:
The title compound was prepared in analogy to the procedure described for (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediate B16/step 2) from rac-4-{tert-butoxycarbonyl-[5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-pyridin-2-yl]-amino}-piperidine-1-carboxylic acid tert-butyl ester by cleavage of both the BOC and the isopropylidene group with 4 M HCl in dioxane and ethanol at rt followed by ion exchange chromatography on Q-Sepharose Fast Flow. MS (ISP): 268.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([CH3:20])[CH:11]=1)[CH2:8][OH:9].C(N(CC)CC)C.C([O-])(C)(C)C.[K+]>C(#N)C.O>[Br:27][C:23]1[CH:22]=[C:21]([C:7]2([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:18])[F:19])=[C:12]([CH3:20])[CH:11]=3)[NH:6][C:3](=[O:4])[CH2:2][O:9][CH2:8]2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C(N)(CO)c2cccc(Br)c2)ccc1OC(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C2(c3cccc(Br)c3)COCC(=O)N2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Chloroacetylchloride (1.81 ml, 1.2 eq) was added dropwise to a solution of (RS)-2-amino-2-(3-bromo-phenyl)-2-(4-difluoromethoxy-3-methyl-phenyl)-ethanol (intermediate VIII-4) (4.81 g, 1 eq) and triethylamine (2.78 ml, 1.5 eq) in acetonitrile (70 ml) at −2° C. After complete addition, the solution was left to warm to room temperature and stirring was continued for 5 hours. The reaction mixture was concentrated, washed with brine (3×20 ml), dried over sodium sulphate and concentrated in vacuo. The crude was dissolved in tert-butanol (50 ml), then treated in one portion with potassium tert-butanolate (4.9 g, 3.3 eq) and stirred at 35° C. overnight. The reaction mixture was then treated with water (50 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel using a 9:1-mixture of cyclohexane and ethyl acetate as the eluent. The (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-morpholin-3-one was obtained as a white solid (4.5 g, 81% of theory). MS (ISP): m/z=413.8 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[NH2:13][C:14]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:15]=1[C:16](OCC)=[O:17]>>[NH2:13][C:14]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:15]=1[C:16](=[O:17])[CH2:6][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1]
Reactant: CCOC(=O)c1cc(OC)ccc1N
Reactant: CN(C)S(C)(=O)=O
Agent: [Li]CCCC
Product: COc1ccc(N)c(C(=O)CS(=O)(=O)N(C)C)c1

Procedure:
In a similar manner to that described in Example 12(a), N,N-dimethylmethanesulphonamide was reacted with n-butyl lithium and the product was reacted with ethyl 2-amino-5-methoxybenzoate to give the novel compound 1-(2-amino-5-methoxyphenyl)-2-(N,N-dimethylsulphamoyl)ethanone, m.p. 198°-200°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[CH2:15]([N:17]([CH2:32][CH3:33])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[C:21]1=[O:22])[CH3:16].[NH4+].[Cl-]>C1COCC1>[CH2:32]([N:17]([CH2:15][CH3:16])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23]([OH:24])([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:21]1=[O:22])[CH3:33]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: c1ccc2scnc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2nc3ccccc3s2)c2c(Br)cccc21
Temperature: -78 °C
Reaction time: 7.5 h
Yield: 14.6 %

Procedure:
To benzothiazole (83.3 mg, 2.0 eq) in anhydrous THF (2 mL) under a nitrogen atmosphere and with stirring was added n-BuLi (0.40 mL, 2.0 eq, 1.53 M in hexanes) at −78° C. (bath temperature). The resulting bright yellow coloured reaction mixture was stirred for 1 hour after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added dropwise. The resulting red coloured solution was stirred at −78° C. for 7.5 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1% to 3% MeOH in CHCl3) to give the title compound as a light yellow solid (20.7 mg, 15%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[N:9](COC)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1
Reactant: COCn1c(-c2ncc(CO)s2)cc2cccc(N(C)S(=O)(=O)c3cccs3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 49.9 %

Procedure:
A mixture of N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1-(methoxymethyl)-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.20 g), concentrated hydrochloride (0.3 mL) and ethanol (8 mL) was heated under reflux for 8 hr. The reaction mixture was neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.09 g, yield 50%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 201-202° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O>O.CN(C=O)C.CCOC(C)=O.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.[Zn]>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[NH2:13]
Reactant: CC(C)Sc1ccc([N+](=O)[O-])c(Cl)c1F
Agent: Cl[Fe](Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Sc1ccc(N)c(Cl)c1F
Temperature: 100 °C
Yield: 59.7 %

Procedure:
A solution of iron trichloride hexahydrate (32.7 g) in water (100 ml) was added to a mixture of 2-chloro-3-fluoro-4-(isopropylsulphanyl)nitrobenzene (Method 78; 10.07 g) and zinc dust (26.36 g) in DMF (100 ml). The mixture was heated to 100° C. for two hours and then allowed to cool to ambient temperature. It was then diluted with EtOAc (500 ml) filtered through diatomaceous earth, washed with brine (4×250 ml), dried over magnesium sulphate and volatile material was removed by evaporation to leave an oil. This was purified by chromatography on silica gel, eluted with 10% EtOAc in hexane to give the title compound (5.29 g) as a solid. NMR: 1.11 (d, 6H), 3.10 (septet, 1H), 5.92 (s, 2H), 6.57 (d, 1H), 7.11 (t, 1H); m/z 219 (M+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:16])=[N:6][C:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:8][CH:9]=1)([O-])=O.O>C1COCC1.O>[NH2:1][C:4]1[C:5]([OH:16])=[N:6][C:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc(-c2cccnn2)nc1O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(-c2cccnn2)nc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a solution of 5-nitro-2-(pyridazin-3-yl)pyrimidin-4-ol, 35i-g, (3.0 g, 13.6 mmol) in THF/H2O (100 mL, VTHF/H2O=1:1) was added Na2S204 (4.77 g, 27.4 mmol) and stirred at room temperature for 4 h. The reaction mixture was extracted with EA (100 mL), washed with brine (50 mL), and concentrated under vacuum. The residue was purified by column chromatography to afford the product, 35i-h, (0.8 g, 30%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ5.66 (s, 2H), 7.39 (s, 1H), 7.80 (dd, J=4.8, 8.4 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 9.26 (d, J=4.8 Hz), LC-MS (M+H)+ 190.1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:36][CH3:37])[CH2:4][N:5]1[CH2:9][CH2:8][C@@H:7]([N:10]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](=[O:35])[NH:27][O:28]C3CCCCO3)=[CH:20][N:19]=2)C(=O)OC(C)(C)C)[CH2:6]1)[CH3:2].[ClH:38]>CO>[ClH:38].[ClH:38].[CH2:36]([CH:3]([CH2:1][CH3:2])[CH2:4][N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:18]2[N:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([NH:27][OH:28])=[O:35])=[CH:22][CH:23]=2)[CH2:6]1)[CH3:37]
Reactant: CCC(CC)CN1CC[C@@H](N(C(=O)OC(C)(C)C)c2ccc(/C=C/C(=O)NOC3CCCCO3)cn2)C1
Agent: Cl
Solvent: CO
Product: CCC(CC)CN1CC[C@@H](Nc2ccc(/C=C/C(=O)NO)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate (128 mg) in methanol (2.5 mL) was added hydrogen chloride in methanol (0.248 mL). After stirring at room temperature for 1 hour, the reaction mixture was evaporated in vacuo. ii) To a mixture of above product and dioxane (2.5 mL) was added 4N hydrogen chloride in dioxane (1.02 mL). After stirring at room temperature for 2 hours, the reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give (2E)-3-(6-{[(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride (92.0 mg). 1H-NMR (300 MHz, DMSO-d6) δ 0.85 (6H, t, J=7 Hz), 1.28-1.52 (4H, m), 1.58-1.72 (1H, m), 2.02-2.15 (1H, m), 2.32-2.67 (2H, m), 3.06-4.78 (6H, m), 6.37 (1H, d, J=16 Hz), 6.91-7.08 (1H, m), 7.43 (1H, d, J=16 Hz), 7.94-8.02 (1H, m), 8.21 (1H, brs), 10.4 (1H, brs). MS (ES+) m/z 333 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.[CH3:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:29](=[O:30])[CH:28]([CH3:32])[CH3:27])=[C:4]([F:26])[CH:5]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Solvent: C1CCOC1
Product: CC(C)C(=O)NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-70, 0.100 g), 2-methylpropanoyl chloride (0.1 mL), TEA (0.1 mL), dry THF (5 mL) to afford 0.028 g of the desired product. 1H NMR (300 MHz, DMSO): δ 1.01 (s, 6H), 4.32 (d, J=7.6 Hz, 2H), 7.67-7.71 (m, 2H), 7.85 (d, J=11.2 Hz, 2H), 8.17 (d, J=11.6 Hz, 2H), 8.36 (m, 1H), 12.73 (s, 1H); MS (m/z): 457.37 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O-:9])=O)[C:2]=1[C:10]([O:12]C)=O.[NH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17]>CCO>[OH:17][CH2:16][CH:15]([NH:14][C:7]([C:3]1[C:2]([C:10]([NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])=[O:12])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:9])[CH2:18][OH:19]
Reactant: COC(=O)c1nccnc1C(=O)[O-]
Reactant: NC(CO)CO
Solvent: CCO
Product: O=C(NC(CO)CO)c1nccnc1C(=O)NC(CO)CO
Yield: 62.4 %

Procedure:
Methyl pyrazine-2,3-dicarboxylate (2 g, 10.2 mmol) was dissolved in EtOH (5 mL). 2-Amino-1,3-propanediol (1.86 g, 20.4 mmol) was added and the mixture was heated under reflux for 4 h. After cooling the solvent was evaporated and the residue was purified by silica gel chromatography (CHCl3 /MeOH, 8:2) to afford the title compound (2 g, 62.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([Cl:18])[C:3]=1[N:19]1[C:23]([NH2:24])=[CH:22][C:21]([C:25]#[N:26])=[N:20]1.[Br:27]N1C(=O)CCC1=O>C(#N)C>[Cl:18][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[N:19]1[C:23]([NH2:24])=[C:22]([Br:27])[C:21]([C:25]#[N:26])=[N:20]1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)n1
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)c(N)c1Br
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
A mixture of 1-[2,6-dichloro-4-(4-trifluoromethylphenyl)phenyl]-3-cyano-5-aminopyrazole (1 g), N-bromosuccinimide (0.5 g) and acetonitrile was stirred at 20° C. for 90 minutes, then concentrated and the residue was mixed with diethyl ether, washed with saturated aqueous NaHCO3 solution, dried, filtered and the filtrate concentrated and purified via chromatography. The desired product as a solid (1.04 g, mp 178-180° C.) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH3:20][NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1)=[O:23]>>[N:14]1([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[CH:30][CH:29]=3)[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Product: CNC(=O)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 11 %

Procedure:
The title compound was prepared by following the procedure of example 473 step 2 using 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine and 1-Methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 13 mg, 11% yield; HPLC: Rt=1.98 min; MS 400 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[C:10](Br)[CH:11]=1)[CH3:2].CC1(C)C(C)(C)OB([C:23]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]=2[CH:25]=[O:26])O1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[C:10]([C:23]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]=2[CH:25]=[O:26])[CH:11]=1)[CH3:2]
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C=O)OC1(C)C
Reactant: CCOC(=O)Cc1cc(Br)cnc1Cl
Product: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2C=O)cnc1Cl

Procedure:
(5-Bromo-2-chloro-pyridin-3-yl)-acetic acid ethyl ester and 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzaldehyde were reacted as described in Example 3, Step 6 to provide [2-chloro-5-(2-formyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)\[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.Cl.[NH2:54][C@@H:55]1[C:80](=[O:81])[N:57]2[C:58]([C:64]([O:66][CH:67]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])=[C:59]([CH2:62][Br:63])[CH2:60][S:61][C@H:56]12>ClCCl.O>[Br:63][CH2:62][C:59]1[CH2:60][S:61][C@@H:56]2[C@H:55]([NH:54][C:12](=[O:13])/[C:11](=[N:10]\[O:9][CH2:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])/[C:15]3[N:16]=[C:17]([NH:20][C:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[S:18][CH:19]=3)[C:80](=[O:81])[N:57]2[C:58]=1[C:64]([O:66][CH:67]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)=[O:65]
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.08 h
Yield: 85.6 %

Procedure:
(Z)-2-(t-Butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (1.1 g) (described in Example 3 of South African Specification No. 78/1630) was added to a stirred solution of phosphorus pentachloride (0.46 g) in dichloromethane (20 ml) at -20°. The solution was kept at -15°±5° for 40 35 minutes. More phosphorus pentachloride (0.05 g) was added after 30 minutes. The solution was cooled to -20° and triethylamine (0.6 ml) was added. The solution was stirred at -20° for 5 minutes and then added to a stirred solution of diphenylmethyl (6R,7R)-7-amino-3-bromomethylceph-3-em-4-carboxylate, hydrochloride salt (1 g) in dichloromethane (20 ml) containing triethylamine (0.3 ml) at -20°. The temperature did not exceed -20° during the addition. The mixture was stirred at -20° for 10 minutes and then warmed to 22° over 45 minutes. The mixture was diluted with water (25 ml) and dichloromethane (20 ml) and shaken. The organic phase was separated and the aqueous layer was backwashed once with dichloromethane. The organic phase was washed with dilute sodium bicarbonate solution and the aqueous phase was backwashed. The combined organic solutions were washed with dilute brine, dried over sodium sulphate, and evaporated to a foam. This was triturated with diisopropyl ether, filtered, and dried in vacuo at 60° for 2 hours followed by room temperature overnight to give the title compound, (1.7 g), [α]D21 -28° (c 1.0 CHCl3); λinf. (ethanol) 239 nm, E1 cm1% 252; 260 nm, E1 cm1% 196; 265.5 nm, E1cm1% 193; 273 nm, E1 cm1% 181.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:39])=[C:8]([S:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])=[CH:18][C:17]=2[O:32][CH2:33][C:34]([O:36]CC)=[O:35])(=[O:12])=[O:11])[CH:9]=1)(=[NH:3])[NH2:2].[OH-].[Na+].[ClH:42]>C(#N)C>[ClH:42].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:39])=[C:8]([S:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])=[CH:18][C:17]=2[O:32][CH2:33][C:34]([OH:36])=[O:35])(=[O:11])=[O:12])[CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)N)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C(=N)N)ccc2O)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 290 mg of ethyl [4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonoyl-biphenyl-3-yloxy]acetate in 1.0 mL of acetonitrile was added 0.756 mL of 2 mol/L sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1.26 mL of 2 mol/L hydrochloric acid, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was purified by column chromatography on trimethylaminopropylated silica gel (eluent: 10% 1 mol/L hydrochloric acid-acetonitrile). The eluent was concentrated under reduced pressure to give 260 mg of [4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]acetic acid hydrochloride as a white solid.