Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([OH:30])=O)=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:35][CH2:36][C@H:37]([OH:46])[CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([NH:35][CH2:36][C@H:37]([OH:46])[CH2:38][N:39]5[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]5)=[O:30])=[C:21]5[C:25]=4[O:24][C:23]([CH3:26])([CH3:27])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Reactant: CN1CCN(C[C@@H](O)CN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C)CC4)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 41.4 %

Procedure:
The crude compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylic acid 4f (160 mg, 0.35 mmol), (2S)-1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 21c (60 mg, 0.35 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (111 mg, 0.35 mmol) and diisopropylethylamine (89 mg, 0.69 mmol) were dissolved in 25 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting solution was added dropwise with saturated sodium bicarbonate solution to adjust pH to 8-9 and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with water (50 mL), saturated sodium chloride solution (50 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2S)-3-(4-methylpiperazin-1-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-benzofuran-4-carboxamide 21 (90 mg, yield: 45.0%) as a white solid.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:27]([OH:32])(=[O:31])[CH:28]([CH3:30])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:28]([C:27]([OH:32])=[O:31])[CH3:30])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)O)cc1

Procedure:
A flask containing 10.0 g. (27.7 m moles) 4-(hexadecylamino)benzoic acid, 3.3 g. (36 m moles) lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28]C)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].ClCCl.B(Br)(Br)Br.O>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][OH:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc(CO)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
4′-{[4-Butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.0 g) was dissolved in dichloromethane (20 mL), and 1.0 M boron tribromide dichloromethane solution (1.0 M, 16 mL) was added at 0° C. After stirring at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and diethyl ether to give the title compound (1.7 g, 86%) as a colorless solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[CH3:10][O:11][C:12]1[C:13]([F:23])=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:15]([OH:17])=[O:16]>>[CH3:10][O:11][C:12]1[C:13]([F:23])=[C:14]([C:18]([N+:1]([O-:4])=[O:2])=[C:19]([F:22])[C:20]=1[F:21])[C:15]([OH:17])=[O:16]
Reactant: COc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5.0 mL of conc. HNO3 at 0° C. was slowly treated with 10.0 mL of conc. H2SO4, then 4.12 g (20 mmol) of 3-methoxy-2,4,5-trifluoro-benzoic acid. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured in to a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to produce 4.0 g (16 mmol, 80%) of 3-methoxy-6-nitro-2,4,5-trifluoro-benzoic acid. LCMS: 252 (M+1)+.
Reaction SMILES: CO[C:3](=[O:37])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:16][S:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)(=[O:19])=[O:18])=[CH:10][CH:9]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][N:40]=[C:39]1[NH2:44]>CN(C)C=O>[C:33]([O:32][C:30](=[O:31])[C@@H:15]([NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3](=[O:37])[NH:44][C:39]2[NH:40][CH2:41][CH2:42][CH2:43][N:38]=2)=[CH:9][CH:10]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: COC(=O)CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
145 mg of 4{-4-[(2S)-2-tert-butoxycarbonyl-2-(naphthalene-2-sulfonylamino)-ethyl]-phenoxy}-butyric acid methyl ester were dissolved in 2 ml of DMF (dimethylformamide) and 134 mg of 1,4,5,6-tetrahydropyrimidin-2-ylamine were added. The reaction mixture was stirred overnight, and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane, followed by dichloromethane/methanol (10/1). Yield 127 mg. Rf (dichloromethane/methanol/water/acetic acid (85/15/1.5/1.5)): 0.63. MS (ES+): m/e=595.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8](C(=O)C)[NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13](O)(=O)[CH3:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:4]([C:13]([CH3:14])=[N:9][N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(N)c1ncccc1Br
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nnc2c(Br)cccn12
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 0.17 g (0.74 mmol) of N-(3-bromopyridin-2-yl)acetohydrazide from step A above in 40 mL of anhydrous toluene was added 3 mL of glacial acetic acid and the resulting mixture was heated to reflux for 20 h employing a Dean-Stark trap. The reaction mixture was cooled to ambient temperature then evaporated to dryness in vacuo to afford the title compound (0.13 g, 84%) LC-MS: m/z (ES) 212, 214 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:45][C@@H:46]([CH3:49])[CH2:47][OH:48].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:48][CH2:47][C@@H:46]([NH:45][C:19]([C:8]1[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:9]=1)=[O:20])[CH3:49]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: C[C@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(C(=O)N[C@@H](C)CO)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (35 mg, 0.12 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (47 mg, 0.25 mmol), 1-hydroxybenzotriazole hydrate (19 mg, 0.12 mmol), and CH2Cl2 (3 mL) were added (S)-2-aminopropan-1-ol (10 mg, 0.14 mmol) and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol). The mixture was stirred at room temperature overnight, and then concentrated. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2].FC(F)(F)S(O)(=O)=O>ClC(Cl)(Cl)C(=N)OCC#CC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][CH2:2][C:1]#[C:3][CH3:4])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CC#CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CC#CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)C(F)C(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-20-fluoro-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylene chloride in cyclohexane), 2-butynyl trichloroacetimidate (20 μl neat) is added and the reagents are allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) is added slowly via syringe acid (2 μl neat) is added and the mixture is stirred at room temperature. After 16 hours the reaction is quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organic are washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].[C:38](=O)([O-])[O-].[K+].[K+].CC(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:38])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C=O)c2)c1F
Reactant: O=C([O-])[O-]
Agent: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (90 mg, 0.160 mmol) and potassium carbonate (66.2 mg, 0.479 mmol) in Methanol (5 ml) was added dimethyl-1-diazo-2-oxopropylphosphonate (46.0 mg, 0.240 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (48 mg, 0.086 mmol, 54% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.87 (s, 1H), 7.54 (s, 1H), 7.31-7.45 (m, 2H), 7.25 (s, 1H), 7.20 (s, 1H), 5.57 (s, 3H), 4.59 (s, 2H), 3.75 (s, 1H), 3.47 (t, 2H), 0.80 (t, 2H), −0.07 (s, 9H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+].C([O-])([O-])=O.[K+].[K+].C[N:21](C)CCN>[Cu-]=O.C(O)CO>[NH2:21][C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1cccc(Br)n1
Reactant: CN(C)CCN
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: CC(C)(O)c1cccc(N)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 555.8 %

Procedure:
A heavy walled resealable tube was loaded under an argon atmosphere with copper (I) oxide (53.0 mg, 370 μmol), 2-(6-bromopyridin-2-yl)propan-2-ol (1600 mg, 7.4 mmol), ammonium hydroxide 28% solution (16.5 M) (8.98 mL, 148 mmol), K2CO3 (205 mg, 1.48 mmol), N,N-dimethylethylenediamine (65.3 mg, 81.3 μA, 740 μmol) and ethyleneglycol (14.8 mL). The reaction was stirred for 6 h at 60° C. After cooling to room temperature, the reaction mixture was extracted with dichloromethane (3×25 mL), combined organics dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (spherical silica 20-45 μM, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (10% ammonium hydroxide in methanol)/dichloromethane to give 2-(6-aminopyridin-2-yl)propan-2-ol (626 mg, 55.5% yield) as a light yellow liquid. 1H NMR (CHLOROFORM-d) δ: 7.44 (t, J=7.7 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.38 (d, J=7.9 Hz, 1H), 5.12 (s, 1H), 4.38-4.55 (m, 2H), 1.49 (s, 6H); LC-MS 153.1, 155.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-])=O)[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)(=O)C>C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([NH2:22])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCOc1cc(CNc2c(N)n[nH]c(=O)c2Cl)ccc1OC
Temperature: 25 °C

Procedure:
1.00 g of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, was dissolved in a solvent mixture of 20 ml of ethanol and 20 ml of a 10% sodium carbonate aqueous solution, 3.30 g of sodium hydrosulfite was gradually added thereto at room temperature under stirring. The mixture was stirred at room temperature for 1 hour, and was neutralized with glacial acetic acid. Then, ethanol was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off to obtain light yellow crystals This product was crystallized from a solvent mixture of methanol-diethyl ether, to obtain 634 mg of the above identified compound having a melting point of from 187.5° to 189.5° C. as colorless crystals
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:4]2[C:5]([C:13]([OH:15])=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12.[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.CS(C)=O>[NH2:1][C@@H:2]1[C:16](=[O:17])[N:4]2[C:5]([C:13]([O:15][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 68 h
Yield: 53.9 %

Procedure:
To a suspension of 7β-amino-3-azidomethyl-3-cephem-4-carboxylic acid (20.7 g, 81 mmol) in a mixture of dichloromethane (250 ml) and dimethyl sulfoxide (250 ml) was added dropwise a solution of diphenyldiazomethane (17.53 g, 90 mmol) in dichloromethane (150 ml). The mixture was stirred at room temperature for 68 h, filtered, the filtrate was concentrated under reduced pressure. The residual sticky mass was taken in ethyl acetate (250 ml) and washed successively with saturated sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate; solvent was removed under reduced pressure to give a residue which was purified over a silica column using dichloromethane-ethyl acetate (1:1) to give 18.4 g (54%) of a mixture of Δ2 and Δ3 -cephems. The mixture was directly used for the next step without further separation.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)O[CH:10]=1.O.[NH4+:21]>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[NH:21][CH:10]=1
Reactant: [NH4+]
Reactant: O=c1cc(COC2CCCCO2)occ1CCCO
Solvent: O
Solvent: CCO
Product: O=c1cc(COC2CCCCO2)[nH]cc1CCCO
Reaction time: 0.5 h

Procedure:
To a solution of 1.2 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 5 mL of ethanol, 16 mL of 25% ammonium water was added, and the mixture was heated under reflux while stirring for 9 hours 30 minutes. The solvent was distilled off under reduced pressure, and the resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=95:5 to 90:10 to obtain 0.42 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-4(1H)-one as a brown oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[C:28]([F:30])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([F:31])[CH:3]=1.Cl[CH2:33][C:34]1[C:39]([F:40])=[CH:38][C:37]([CH3:41])=[CH:36][N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:29]=[C:28]([F:30])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:33][C:34]4[C:39]([F:40])=[CH:38][C:37]([CH3:41])=[CH:36][N:35]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([F:31])[CH:3]=1
Reactant: Cc1cnc(CCl)c(F)c1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(O)cc2n1Cc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(OCc3ncc(C)cc3F)cc2n1Cc1c(F)cc(Br)cc1F
Temperature: 100 °C

Procedure:
To a mixture of racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate (110 mg, 0.22 mmol), 2-(chloromethyl)-3-fluoro-5-methylpyridine (35 mg, 0.22 mmol) in acetonitrile (5 mL) was added Cs2CO3 (79 mg, 0.24 mmol) and heated at 100° Celsius. After 1 hr the mixture was concentrated to dryness and the residue was purified by FCC to provide racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-((3-fluoro-5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate. To the resulting ethyl ester was added MeOH (2 mL), and NaOH (1 mL, 1 N). The mixture was heated to 110° Celsius. After 1 h the mixture was concentrated to dryness and purified by FCC to provide the title compound and the trans-isomer see Example 124. MS (ESI): mass calcd. for C28H25BrF3N3O3, 587.10; m/z found, 588.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.22 (5, 1H), 7.52-7.45 (m, 2H), 7.28 (d, J=7.6, 2H), 6.99 (d, J=2.0, 1H), 6.88 (dd, J=8.7, 2.3, 1H), 5.54 (two d, J=16.4, 2H), 5.18 (5, 2H), 3.79 (d, J=4.6, 1H), 2.78-2.63 (m, 1H), 2.40 (s, 3H), 2.36-2.20 (m, 1H), 2.12-1.86 (m, 3H), 1.86-1.67 (m, 2H), 1.51-1.39 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:23][F:24])([CH2:21][F:22])[CH:9]=1)=O)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1C=CC=CC=1>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:23][F:24])([CH2:21][F:22])[CH:9]=1)=[S:34])#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Solvent: c1ccccc1
Product: N#CCCNC(=S)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Yield: 36.4 %

Procedure:
A mixture of 0.11 g of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxamide and 0.17 g of a Lawesson's reagent and 10 ml of benzene was refluxed with heating for 2 hours. The solvent was distilled and the obtained residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) and further recrystallyzed by a mixed solvent of ethyl acetate and hexane to obtain 42 mg of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carbothioamide with a melting point of 114°-116° C.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[NH:20][N:21]=[CH:22][C:14]=12.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.C(Cl)Cl>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[N:20]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[N:21]=[CH:22][C:14]=12
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2cn[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
pTsOH (30.2 mg, 0.159 mmol) was added to a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.587 mmol) and 3,4-dihydro-2H-pyran (200 mg, 2.381 mmol) in a mixture of tetrahydrofuran (ratio: 1.000, volume: 5 ml) and CH2Cl2 (ratio: 1.000, volume: 5 ml). The reaction mixture was stirred for 12 h at room temperature after which the solvent was removed in vacuo. The residue was taken in CH2Cl2 (20 mL) and poured into water (20 ml). The organic phase was separated, the aqueous phase was extracted with CH2Cl2 (20 mL), and the organic phases were combined. The combined organic phases were washed with water (40 mL), washed with brine (40 mL), dried over Na2SO4 and then concentrated. The resulting crude material was purified by flash chromatography (CH2Cl2/MeOH 99/1 increasing) to yield the title compound (397 mg, 1.454 mmol, 92% yield) as a pale white oil. 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 5.99 (dd, 1H, J=2.4 & 10.4 Hz), 4.12 (m, 1H), 3.79 (m, 1H), 2.53 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H), 1.76 (m, 2H), 1.64 (m, 1H). ESI-MS: 273.0 [M+H]+.