Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCN.[CH:7]1([O:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C.[C:28]([C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[NH:38][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])(=O)[CH3:29]>CCO>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([NH:38][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])=[C:31]([C:28](=[N:13][O:12][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH3:29])[CH:36]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NOC1CCCC1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.1 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(cyclopentyloxy)phthalimide (345 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (302 mg, 1.0 mmol) in EtOH (2 mL), and the reaction stirred for 2.25 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-[4-chloro-2-(1-cyclopentyloxyiminoethyl)phenyl]trifluoromethanesulfonamide 163 (185 mg, 48%), as a pale yellow solid. 1H n.m.r. (400 MHz, CDCl3) δ 12.18, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.49, d, J=2.4 Hz, 1H; 7.31, dd, J=2.4 and 8.8 Hz, 1H; 4.80, m, 1H; 2.30, s, 3H; 1.89, m, 4H; 1.74, m, 2H; 1.64, m, 2H. HRMS (M+) 384.0518.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:11][CH3:10])[CH:21]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: COC(=O)c1ccc(-c2nc(Cl)ncc2C)cc1OC
Temperature: 110 °C
Yield: 56.4 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (244 mg, 1.5 mmol) and methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (210 mg, 1.0 mmol) in toluene (3 mL) were added n-propanol (1 mL), aqueous sodium bicarbonate (2 M, 1.5 μL) and tetrakis(triphenylphosphine)palladium[0] (116 mg, 0.1 mmol). The reaction was heated at 110° C. for 40 h, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions were washed with water, brine then dried (sodium sulfate), filtered and concentrated. Silica gel chromatography using 30-60% ethyl acetate/petroleum spirit as eluent provided methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate as a cream solid (165 mg, 56%); LC-ESI-MS (method B): rt 6.2 min.; m/z 293.3/295.3 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH3:9]I>C1COCC1>[CH3:9][O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CI
Reactant: CC(C)C[C@H](N)CO
Solvent: C1CCOC1
Product: COC[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-amino-4-methylpentan-1-ol (0.276 ml, 2.133 mmol) was added to a stirred, ice-bath cooled suspension of KH (267 mg, 2.327 mmol) in THF (10 ml) under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for ˜10 minutes and then treated with MeI (0.121 ml, 1.939 mmol). After stirring for 30 minutes the reaction mixture was quenched by addition of saturated NH4Cl(aq) (˜20 ml) and extracted with EtOAc (25 ml×2). The combined organic phases were dried over MgSO4, filtered under vacuum and the filtrate was evaporated to afford an orange oil. The oil was purified by chromatography on silica eluting with 10% (2M NH3 in MeOH)/DCM to afford the title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-3-methyl-5-nitro-pyridine (5.0 g, 28.73 mmol) in toluene (50 mL) is added palladium tetrakis triphenylphosphine (1.66 g, 1.44 mmol), 4-trifluoromethyl phenyl boronic acid (10.92 g, 57.46 mmol), and potassium fluoride (3.34 g, 57.46 mmol). The reaction is purged with nitrogen three times and heated to reflux under nitrogen. At reflux, water (25 mL) is added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl acetate and Celite is added, followed by water. This mixture is then filtered through a pad of Celite. The solution is poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The product is purified by flash column chromatography (5.6 g, 19.71 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH3:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[OH:14]S(O)(=O)=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]([CH3:13])[CH2:10][C:11]([NH2:12])=[O:14])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: C[C@@H](CC#N)Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](CC(N)=O)Nc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(3S)-3-[(4-bromophenyl)amino]butanenitrile (for a preparation see Intermediate 32) (17.3 g, 72.4 mmol) was taken up in Toluene (500 ml) and H2SO4 (19.28 ml, 362 mmol) added. The biphasic mixture was stirred at 60° C. After two hours, only a small amount of SM remained by LCMS so the reaction was diluted with water (500 ml) and the phases separated. The aqueous phase was basified with 10N NaOH and extracted with EtOAc (2×750 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield the product as a cream solid (17.5 g). LCMS (Method B): Rt=0.77, MH+=257
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[Cl:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:39][C:38]=1[Cl:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), (4-(benzyloxy)-3-chlorophenyl)boronic acid (1.31 g, 4.97 mmol), copper(II) acetate (0.903 g, 4.97 mmol), and triethylamine (2.00 mL, 14.4 mmol) in anhydrous DCM (25 mL) was treated with powdered 3 angstrom molecular sieves (2.00 g). The resulting mixture was stirred at RT under air using a drying tube to exclude moisture. After 18 hours the mixture was treated with an additional 1.00 g portion of (4-(benzyloxy)-3-chlorophenyl)boronic acid. After another 18 hours the mixture was diluted with 15 mL of DCM and treated with 1.30 g of (4-(benzyloxy)-3-chlorophenyl)boronic acid, 0.900 g of copper(II) acetate, 2.00 g of 3 angstrom molecular sieves and 2 mL of triethylamine. After 16 more hours the mixture was filtered through Celite to remove solids and the filtrate concentrated to dryness at reduced pressure. The residue was suspended in EtOAc and the undissolved solids removed by filtration through Celite. The filtrate was washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) followed by recrystallization from hexane/EtOAc to afford the title compound (0.83 g, 54%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40-8.47 (m, 1H) 8.20 (s, 1H) 7.93-8.00 (m, 2H) 7.69 (d, J=2.6 Hz, 1H) 7.52 (dd, J=8.9, 2.7 Hz, 1H) 7.30-7.48 (m, 7H) 7.25 (d, J=9.1 Hz, 1H) 7.14 (s, 1H) 5.21 (s, 2H) 3.33 (s, 3H) 2.82 (d, J=4.6 Hz, 3H) 2.17-2.33 (m, 1H) 0.75-1.09 (m, 3H) 0.42 (br. s., 1H). LCMS (m/z, ES+)=619, 621 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>CCOC(C)=O>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[O:28][C:27]([F:26])([F:37])[F:38])[N:17]=2)[CH2:12][CH2:13]1
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2F)CC1
Temperature: 180 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
{4-[(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (127 mg, 0.35 mmol) was dissolved in 2-trifluoromethoxybenzylamine (2.5 mL) and heated at 180° C. for 20 min. The reaction mixture was diluted with EtOAc and poured into 1N HCl. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (2.5 mL) and TFA (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc. The solution was poured into 10% NaHCO3 and the aqueous layer was re-extracted with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 9:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 22 mg (15%) of the title compound, m/z 414.6 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([NH:19][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCc1csc2c(Cl)nc(Cl)nc12
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Product: CCCc1csc2c(NC(C)(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
In 5 ml of DMF, 371 mg (1.5 mmol) of 2,4-dichloro-7-propylthieno[3,2-d]pyrimidine was dissolved, and then 241 mg (3.3 mmol) of t-butylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 173 mg (yield: 40.6%) of the title compound.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7]
Reactant: NCCC(=O)O
Reactant: CCCCOC(=O)c1ncc2ccc(Oc3ccccc3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCNC(=O)c1ncc2ccc(Oc3ccccc3)cc2c1O
Yield: 94.9 %

Procedure:
A mixture of 4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (200 mg, 0.59 mmol) (prepared according to U.S. Pat. No. 7,629,357) and beta-alanine (792 mg, 8.9 mmol) in 0.5 M NaOMe/MeOH solution was refluxed overnight. Reaction mixture was concentrated and residue was dissolved in water (150 mL). It was cidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 196 mg (0.56 mmol) in 94% yield. LC-MS ESI−: 351.05 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si](C)(C)C(C)(C)C(C)C)[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH2:33])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1.[F-].[NH4+]>CO>[CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH2:33])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1
Reactant: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1c(C)c(OC)cc(O)c1CSC[C@H](N)c1nc(C)no1

Procedure:
(R)-2-[2-Amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl-methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methyl-benzoic acid methyl ester was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl-methyl]-3-hydroxy-5-methoxy-6-methyl-benzoic acid methyl ester as an amorphous foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH3:24][CH:25]([N:27]1[C:31]([NH2:32])=[CH:30][CH:29]=[N:28]1)[CH3:26]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:30]3[CH:29]=[N:28][N:27]([CH:25]([CH3:26])[CH3:24])[C:31]=3[N:32]=2)=[CH:4][CH:3]=1
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(Br)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-(4-bromophenyl)-2,4-dioxobutanoate (956 mg, 3.20 mmol), benzene (10 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 3.20 mmol), and acetic acid (4 mL). The crude product was purified using column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 1.1 g (89%) of product. LCMS E-S (M+H)=388.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49-1.57 (t, J=67.2 Hz, 3 H), 1.63-1.74 (d, J=6.8 Hz 6 H), 4.56 (q, J=7.2 Hz, 2 H), 5.46 (spt, J=6.7 Hz, 1 H), 7.65-7.71 (m, 2 H), 8.04-8.15 (m, 2 H), 8.21 (s, 1 H), 8.42 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]([CH3:16])([CH3:15])[C:12](=O)[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[C:18]1=O)[CH2:24]2.O.C(OCC)(=O)C>C1COCC1.[Cu].[Zn].[Cl-].[Cl-].[Cl-].[Ti+3]>[CH:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[C:18]1=[C:12]1[C:11]([CH3:16])([CH3:15])[O:10][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:13]1)[CH2:24]2
Reactant: COc1cccc(C2=NC(=O)C(C)(C)O2)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Cu]
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C2=NC(=C3C4CC5CC(C4)CC3C5)C(C)(C)O2)c1
Temperature: 25 °C

Procedure:
122 mmol zinc-copper couple is added to a suspension of 35 mmol titanium trichloride in 60 ml absolute THF while stirring carefully. After heating for one hour under reflux a mixture of 11.4 mmol 2-(3'-methoxyphenyl)-5,5-dimethyl-oxazolin-4-one and 8.1 mmol adamantanone is added after cooling to room temperature. It is heated for 4 h to boiling at reflux. After cooling to room temperature it is poured onto 200 ml water. The mixture is shaken out twice with 200 ml ethyl acetate. The combined organic phases are washed once with water and separated. After drying over sodium sulfate it is filtered and the solvent is removed by distillation. The oily residue is separated by column chromatography (silica gel: ethyl acetate/petroleum ether 1:9).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2O.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[C:7]([CH3:12])[C:6]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: Cc1nc2ccc(I)cc2c(O)c1S(C)(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reaction time: 9.5 h
Yield: 77.6 %

Procedure:
6-Iodo-3-methanesulfonyl-2-methyl-quinolin-4-ol (example C.2) (14.7 g, 40.5 mmol) and N,N-dimethyl-p-toluidine (11.7 mL, 81 mmol) were dissolved in toluene (150 mL) and heated under argon to reflux. Then phosphorous oxychloride (4.1 mL, 44.5 mmol) was added and heating at reflux continued for 9.5 h. The thick suspension became gradually a dark solution. The reaction mixture was allowed to cool and then extracted with dichloromethane (not soluble in toluene), cold 1 N HCl (2×), and sat. NaCl (2×). The product was crystallized from heptane/dichloromethane. One obtained 12 g (78%) of white crystals. MS: m/z=381 (M).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:15][CH3:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].NC1C=C(C(CC)=CC(OC)=O)C=CC=1Cl>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH3:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC=C(CC(=O)OC)c1ccc(Cl)c(N)c1
Agent: [Pd]
Agent: CCC(=CC(=O)OC)c1ccc(Cl)c(N)c1
Solvent: CCOC(C)=O
Product: CCC(CC(=O)OC)c1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
3.05 g (12.7 mmol) of methyl 3-(3-amino-4-chlorophenyl)pent-3-enoate and 0.85 g (3.55 mmol) of methyl 3-(3-amino-4-chlorophenyl)pent-2-enoate were dissolved together in 500 ml of ethyl acetate, 346 mg (0.325 mmol) of palladium on carbon (10%) were added and the mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure overnight. The reaction mixture was then filtered off through celite, the residue was washed with ethyl acetate and the filtrate was concentrated. Drying of the residue under high vacuum gave 3.73 g of the target product (94.8% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:41])=[C:5](/[C:7](=[N:31]/[O:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[S:3][C:4]([Cl:41])=[C:5](/[C:7](=[N:31]/[O:32][CH2:33][C:34]([OH:36])=[O:35])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)OC(C)(C)C)c3nc(N)sc3Cl)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)O)c3nc(N)sc3Cl)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Two grams of 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid is dissolved in 20 ml of trifluoroacetic acid. The solution is stirred at room temperature for 1 hour and then evaporated to dryness under reduced pressure to give crude 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)-(carboxymethoxyimino)acetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:31])[CH:9]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([O:21]N3C4C=CC=CC=4N=N3)[CH:16]=[N:15]2)[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:38]1[C:46]2[CH:45]=[CH:44][CH:43]=[C:42](O)[C:41]=2[CH:40]=[CH:39]1>C(#N)C.[Cl-].[NH4+]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:31])[CH:9]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([O:21][C:42]3[CH:43]=[CH:44][CH:45]=[C:46]4[C:41]=3[CH:40]=[CH:39][NH:38]4)[CH:16]=[N:15]2)[CH2:10][CH:11]([CH3:12])[CH3:13])=[N:3]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C)n1)n1ncc(On2nnc3ccccc32)cc1=O
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)CC(C(=O)Nc1ccn(C)n1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Temperature: 80 °C
Yield: 65.4 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (170.3 mg, 0.403 mmol) in acetonitrile (8.4 mL, 0.048M) was treated with cesium carbonate (0.26 g, 0.798 mmol) and 1H-indol-4-ol (64.3 mg, 0.483 mmol). The resulting reaction mixture was heated at 80° C. overnight. At this time, the reaction mixture was allowed to cool to 25° C. and was treated with a saturated aqueous ammonium chloride solution (5 drops). The reaction was then concentrated in vacuo onto silica gel. Silica gel column chromatography (AnaLogix 24 g, 1-10% methanol/methylene chloride) afforded impure 2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (110.9 mg, 65%) as a brown solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]([O:18]CC)=[O:17])[CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)=[O:4].[OH-].[Na+]>CC(C)=O>[OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]([OH:18])=[O:17])[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)=[O:4]
Reactant: CCOC(=O)c1cc(C(=O)NO)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(C(=O)O)cc(C(=O)NO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of diethyl 5-[(hydroxyamino)carbonyl]-1,3-benzenedicarboxylate (0.281 g, 1.0 mmol) in acetone (5 mL) was added 1.0 N NaOH (5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up with 1 N HCl (15 mL) to give white precipitate. This material was dried under vacuum to give 0.096 g of white solid: 1H NMR (D2O) δ 8.52 (s, 2H), 8.76 (s, 1H). Elemental analysis calculated for CH7NO6.H2O: C, 44.45; H, 3.73; N, 5.76. Found: C, 44.47; H, 3.78; N, 5.74.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH:11]([C:13]1[N:14]=[N:15][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([CH3:19])[N:18]=1)[NH2:12]>CO.[OH-].[NH4+]>[CH:1]([NH:12][NH:11][C:13]1[N:14]=[N:15][C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:17]([CH3:19])[N:18]=1)=[O:3]
Reactant: O=CO
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: Cc1nc(NNC=O)nnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Formic acid (5 ml) was added dropwise to acetic anhydride (10 ml) with stirring under ice cooling, and stirred at 50° C. for 15 minutes. To the solution was added 3-hydrazino-5-methyl-6 -phenyl-1,2,4-triazine (5g) with stirring under ice cooling, and the stirring was continued for 50 minutes under ice cooling. The reaction mixture was poured into ice water, and the resultant precipitates were collected by filtration and washed with water. The above obtained solid was dissolved in methanol (100 ml), the solution was treated with 28% ammonium hydroxide (14 drops) and evaporated to give white powder of 3-(2-formylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (4.505 g).