Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cc(CO)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(CO)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(hydroxymethyl)-2-nitrophenol (2.20 g, 13.01 mmol) in DMF (60 mL) was added cesium carbonate (8.48 g, 26.0 mmol) followed by the portionwise addition of 4-methoxybenzyl chloride (3.06 g, 19.51 mmol). After stirring at rt for 45 mins additional 4-methoxybenzyl chloride (2.037 g, 13.01 mmol) was added followed by tetrabutylammonium iodide (2.402 g, 6.50 mmol). The reaction mixture was stirred at rt for 18 hr and then diluted with EtOAc (200 mL) and washed successively with water, 10% aq. K2CO3, water and finally brine, dried (MgSO4), filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with 10-50% EtOAc in isohexane to afford the title compound as a cream solid, 2.17 g, 57.7%.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]([OH:24])=O)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([NH2:39])[C:33]=1[NH2:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([NH:39][C:22]([C:17]2[C:18]([F:21])=[C:19]([F:20])[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([CH3:28])([CH3:27])[O:6][SiH2:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:13][CH:12]=3)=[C:15]([F:26])[C:16]=2[F:25])=[O:24])[C:33]=1[NH2:40]
Reactant: COC(=O)c1cc(C)cc(N)c1N
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(-c2c(F)c(F)c(C(=O)O)c(F)c2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)cc(NC(=O)c2c(F)c(F)c(-c3ccc(C(C)(C)O[SiH2]C(C)(C)C)cc3)c(F)c2F)c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.5 %

Procedure:
To a solution of 4′-(tert-butyl-dimethyl-silanyloxymethyl)-2,3,5,6-tetrafluoro-biphenyl-4-carboxylic acid (2.2 g, 5.3 mmol) in dry DMF (50 mL) was added 2,3-diamino-5-methyl-benzoic acid methyl ester (0.95 g, 5.3 mmol) and HATU (3.03 g, 7.9 mmol) followed by N,N-diisopropylethylamine (1 mL). The reaction mixture was stirred for 14 h at room temperature under nitrogen atmosphere. TLC shows completion of the reaction. The reaction mixture was quenched to crushed ice and the precipitate was filtered, washed with water and dried to get an off white solid (2.4 g, 80.80%) which was directly taken to the next step.
Reaction SMILES: [C:1]([C:5]1[C:6]([Cl:34])=[C:7]([C:11]2[NH:33][C:14]3[C:15]([O:29][CH2:30][CH:31]=[O:32])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([OH:39])(C)(C)C.CC(=CC)C.O.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[Na+].[OH-].[Na+]>>[C:1]([C:5]1[C:6]([Cl:34])=[C:7]([C:11]2[NH:33][C:14]3[C:15]([O:29][CH2:30][C:31]([OH:39])=[O:32])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCC=O)c2[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCC(=O)O)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of [2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy]-acetaldehyde (30.0 mg, 0.0610 mmol, prepared as described in the previous step) in 5:5:2 tert-BuOH/2-methyl-2-butene/H2O (1.2 mL) was added sodium chlorite (11.6 mg, 0.128 mmol) followed by sodium dihydrogen phosphate (17.8 mg, 0.183 mmol). After stirring at room temperature for 16 h, the resulting mixture was treated with 1N NaOH (2 mL) and concentrated in vacuo. The resulting residue was treated with H2O (20 mL) and washed with EtOAc (2×10 mL). The aqueous phase was acidified to pH 5 by adding HOAc and then extracted with EtOAc (3×15 mL). The combined organic layers were washed with H2O (15 mL), brine (15 mL) and then dried with Na2SO4. Removal of the solvent in vacuo yielded [2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy]-acetic acid as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 7.13-8.04 (m, 5H), 5.10 (s, 2H), 4.06 (s, 3H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C23H21ClF3N5O3: 508.1 (M+H), Measured: 508.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:31]=[C:18]4[C:19]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:32][O-:33].[Na+]>CO>[F:30][C:25]1[CH:24]=[C:23]([C:19]2[C:18]3[N:17]([N:16]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([O:33][CH3:32])[N:7]=5)[CH2:9][CH2:10]4)[N:31]=3)[CH:22]=[CH:21][CH:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)n5)CC4)nc23)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)n1
Temperature: 120 °C
Yield: 104.7 %

Procedure:
To a solution of N-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 195) (88 mg, 0.155 mmol) in MeOH (2.0 mL) was added sodium methoxide solution (30% in MeOH, 41 μL, 0.22 mmol) and the reaction mixture was heated in the microwave at 120° C. for 2 h. The mixture was then evaporated. Purification by chromatography (silica gel, 20 g, 0 to 100% methanol in dichloromethane) afforded the title compound (71 mg, 81%) as a white foam.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([Cl:22])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:23][C:24]1[CH:35]=[CH:34][CH:33]=[CH:32][C:25]=1[O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:22][C:14]1[CH:13]=[C:12]([O:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH:3]=2)[O:23][C:24]2[CH:35]=[CH:34][CH:33]=[CH:32][C:25]=2[O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:17]=[CH:16][C:15]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1F
Reactant: COC(=O)COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccccc1Oc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 20.1 %

Procedure:
A mixture of 2-chloro-α,α,α-trifluoro-p-tolyl 3-fluoro-4-nitrophenyl ether (1.0 g, 3.0 mmol), methyl (o-hydroxyphenoxy)acetate (0.81 g, 4.5 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in N,N-dimethylformamide is heated at 50° C. for 18 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a white oil. Column chromatography of the oil using silica gel and a 15% ethyl acetate in hexanes solution gives the title product as a clear liquid (0.3 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][CH:22]=[O:23])[C:3]=1[CH3:24].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.COCCOC>C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][CH:22]=[O:23])[C:3]([CH3:24])=[C:2]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Br)c2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1c(NC=O)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1

Procedure:
A mixture of (7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 59 (1.0 g, 2.58 mmol), phenylboronic acid (345 mg, 2.83 mmol) and tetrakis(triphenylphosphine)palladium (99 mg, 0.086 mmol) in 2 N sodium carbonate aqueous solution (30 mL)-1,2-dimethoxyethane (15 mL) was heated under reflux under nitrogen atmosphere for 16 hours. The reaction solution was diluted with ethyl acetate, the insolubles were taken by filtration, and the filtrate was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the crude product of (3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)formamide. This compound was dissolved in methanol (18 mL), to which concentrated hydrochloric acid (6 mL) was added, and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the obtained residue was neutralized with a 12 N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 642 mg (yield 70%) of the title compound. Melting point: 101-102° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].[NH2:27]/[C:28](/[CH3:37])=[CH:29]\[C:30]([O:32][CH2:33][CH2:34][C:35]#[N:36])=[O:31]>CC(O)C>[CH3:37][C:28]1[NH:27][C:1]([CH3:2])=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:29]=1[C:30]([O:32][CH2:33][CH2:34][C:35]#[N:36])=[O:31]
Reactant: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)NCC=Cc1ccccc1
Reactant: C/C(N)=C/C(=O)OCCC#N
Solvent: CC(C)O
Product: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
424 mg (1.21 mmol) of 2-acetyl-3-(4-nitrophenyl)-N-(3-phenyl-2-propene-1-yl)acrylamide and 187 mg (1.21 mmol) of 2-cyanoethyl 3-aminocrotonate were heated at 70° C. under stirring in 10 ml of 2-propanol for 2 days. 2-Propanol was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:15][CH2:14][C:13]2[C:16]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:38])[NH:30][CH:31]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)=[C:17]([Cl:20])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)=O)(C)(C)C>CCOC(C)=O.CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:12]2[CH2:11][CH2:10][NH:9][CH2:15][CH2:14][C:13]=2[C:16]=1[CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:38])[NH:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CNc3ccc(C(=O)NC4CCCCCC4)cc3)c2CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCCC1)c1ccc(NCc2c(Cl)ccc3c2CCNCC3)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Add hydrogen chloride into a mixture of 3-tert-butoxycarbonyl-7-chloro-6-[(4-cycloheptylcarbamoyl-phenylamino)-methyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (590 mg, 1.12 mmol) in EtOAc/methanol (1:1, 60 mL) until the mixture is saturated. Stir for 1 h at 40° C. and concentrate in vacuo. Purify the residue by SCX chromatography to obtain 7-chloro-6-[(4-cycloheptylcarbamoyl-phenylamino)-methyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (450 mg, 1.06 mmol). Use a method similar to the General Procedure 2-1 to obtain the title compound as an off-white solid (560 mg, 92%). MS (ES+) m/z: 426 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cc(C)cc(C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)cc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3,5-dimethylphenyl)-2-naphthalenyl)ethynyl]-benzoate (Compound 4) 90.0 mg (0.207 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2-ylSO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.45 (2H, s), 7.00 (1H, s), 6.97 (1H, s), 5.97 (1H t, J=4.5 Hz), 2.31 (2H d, J=4.5 Hz), 2.30 (6H, s), 1.29 (6H, s).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH:4]3[C:11](Cl)=[O:12])[CH2:2]1)[CH2:8]2.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:16]1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([NH:14][C:11]([CH:4]3[CH:5]4[CH2:10][N:1]5[CH2:8][CH:7]([CH2:9][C@@H:3]3[CH2:2]5)[CH2:6]4)=[O:12])[CH2:16]2)=[CH:23][CH:24]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)C1C2CC3CC1CN(C3)C2
Product: O=C(NC1CCN(CCc2ccc(F)cc2)C1)C1C2CC3C[C@@H]1CN(C3)C2

Procedure:
1-Azaadamantane-4-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-azaadamantane-4-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[NH:5][C:4](=O)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl-].[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19]>CC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])[CH:3]=1
Reactant: CC(=O)OCCCCBr
Reactant: COc1nc(N)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc(N)cc(CCCCOC(C)=O)n1
Temperature: 25 °C
Yield: 42 %

Procedure:
Alternative Method B. A mixture of 6-amino-2-methoxy-4-pyrimidone (30 g, 212.6 mmol), K2CO3 (44 g, 318 mmol), benzyltriethylammionium chloride (20 g, 88 mmol) and 4-bromobutyl acetate (60 g, 308 mmol) in acetone (800 ml) was heated at reflux overnight. After cooling to room temperature, the insoluble salts were filtered off and the solvent was removed. The residue was purified by chromatography on silica gel with CHCl3/MeOH (100:2-100:5) as eluent. After separation of 6-amino-2-methoxy-4-(4-acetoxybutyl)pyrimidine (22.8, yield 42%), 18.7 g (yield 34.5%) of 6-amino-2-methoxy-3-(4-acetoxybutyl)-4-pyrimidone was isolated as a white solid.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][O:12][CH2:11][C@H:10]1[CH3:15])C1C=CC=CC=1.[ClH:16]>[OH-].[OH-].[Pd+2].CCO>[ClH:16].[CH3:15][C@H:10]1[C@@H:9]([NH2:8])[CH2:14][CH2:13][O:12][CH2:11]1
Reactant: C[C@@H]1COCC[C@@H]1NCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1COCC[C@@H]1N
Yield: 43 %

Procedure:
Racemic cis benzyl-(3-methyl-tetrahydro-pyran-4-yl)-amine (1.8 g, 8.768 mmol) was dissolved in 3M HCl (4.4 mL, 13.2 mmol). Pd(OH)2 20 wt % (0.6 g) and EtOH (50 mL) were added and the reaction mixture was hydrogenated in a Parr shaker at 55 psi H2 over the weekend. The palladium was filtered off. HCl 4M in dioxane was added and the solvent was evaporated. The remaining green oil was adsorbed onto SiO2 and purified by SiO2 chromatography (100 g SiO2, DCM/(DCM:MeOH:NH4OH 60:10:1) 100-55% DCM). The fractions containing the product were combined and HCl 4M in dioxane was added. NH4Cl crashed out. The solvent was evaporated. The remaining white semi-solid was taken up in MeOH/Et2O and the salt was filtered off and washed with Et2O. The filtrate was evaporated. The remaining oil was taken up in DCM and was evaporated again to obtain 0.58 of racemic cis 3-methyl-tetrahydro-pyran-4-ylamine hydrochloride as a light yellow solid (43% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[F:31].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([S:32]([N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[CH2:5][C:4]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:3]=2[O:2][CH3:1])(=[O:33])=[O:34])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(CNCc2ccc(OC)cc2OC)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2OC)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of bis(2,4-dimethoxybenzyl)amine (12 g) and 3-chloro-4-fluorobenzene-1-sulfonyl chloride (8.66 g) in dichloromethane (120 mL) was added N,N-diisopropylethylamine (13.5 mL) and catalytic amount of 4-dimethylaminopyridine. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (600 mL) and washed with 5% aqueous HCl, water and brine. After drying over Na2SO4, the mixture was filtered and the filtrate was concentrated under vacuum to give crude product which was loaded on a 400 g silica gel column and eluted with 30% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([C:21]([OH:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.Cl[CH2:30]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:30][O:22][C:21]([C@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:23]
Reactant: ClCCl
Reactant: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (CAS RN: 907184-53-6) (35.7 g, 0.102 mol) were dissolved in methanol (350 mL) and at ambient temperature treated with sulfuric acid 97% (10.9 mL). The reaction mixture was stirred at 60° C. for 18 h. At 0° C. dichloro methane (500 mL) was added followed by aqueous sodium carbonate 10% (500 mL) (final pH 11) under vigorous stirring. The phases were separated. The aqueous phase was washed with dichloro methane, the combined organic phases with water and brine and then dried on sodium sulfate. After filtration and evaporation of the solvent the title product was obtained as a yellow oil (36.3 g, 98%) which was directly used in the next step. ES-MS m/e: 365.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19]C)(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(S(Cl)(=O)=O)CCCC.N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH2:19])(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCCS(=O)(=O)Cl
Agent: N
Product: C[C@H](CCCS(N)(=O)=O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 41 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-(aminosulfonyl)-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]amino]pentylsulfonyl chloride with ammonia. Yield=41%; MS (ESI+), 485 (M+H)+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:45][C:46]([O:48][CH2:49][C:50]1[CH2:59][S:58][C@@H:53]2[C@H:54]([NH2:57])[C:55](=[O:56])[N:52]2[C:51]=1[C:60]([OH:62])=[O:61])=[O:47]>O1CCCC1.O>[C:46]([O:48][CH2:49][C:50]1[CH2:59][S:58][C@@H:53]2[C@H:54]([NH:57][C:27](=[O:28])[CH2:26][C:24]3[N:25]=[C:21]([NH:20][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:22][CH:23]=3)[C:55](=[O:56])[N:52]2[C:51]=1[C:60]([OH:62])=[O:61])(=[O:47])[CH3:45]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: -20 °C
Yield: 88.7 %

Procedure:
A mixture of 801 mg of 2-tritylamino-4-thiazolylacetic acid, 10 ml of dry tetrahydrofuran and 2 ml of a molar solution of N-methyl-morpholine in tetrahydrofuran was stirred at -20° C. and 2 ml of a molar solution of isobutyl chloroformate in tetrahydrofuran were slowly added thereto. The mixture was stirred and a solution of 544 mg of 7-amino-cephalosporanic acid in 10 ml of water and 2.4 ml of a molar solution of N-methyl-morpholine in tetrahydrofuran was added thereto. The mixture was stirred with reheating and the solvent was evaporated. The residue was diluted with water and 2 ml of 2 N hydrochloric acid were added. The mixture was vacuum filtered and the product was dried to obtain 1.16 g of 3-acetoxymethyl-7β-[2-(2-tritylamino-4-thiazolyl)-acetamido]-ceph-3-eme-4-carboxylic acid.