Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH2:41])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH:41][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([F:23])([F:22])[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([F:21])=[CH:13][CH:12]=2)=[C:4]([F:25])[C:3]=1[CH2:26][CH2:27][OH:28].B.C1COCC1.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:23][C:10]([F:22])([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([F:21])=[CH:13][CH:12]=1)[CH2:9][NH:8][C:5]1[C:4]([F:25])=[C:3]([CH2:26][CH2:27][OH:28])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccc(F)c2ccccc12
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of N- [4-chloro-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl)acetamide (1.9 g, 4.6 mmol), as prepared in the preceding step, in THF (19 mL) at 0° C. was added dropwise a solution of BH3.THF complex (19.4 mL, 19.4 mmol, 1.0 M in THF) over a period of 20 minutes, and the reaction mixture continued to stir until the ice bath expired. The mixture was then heated at reflux in an oil bath at 75° to 80° C. for 3 hours, and continued to stir at ambient temperature overnight. A solution of NaHCO3 (1.63 g, 19.4 mmol) in H2O (20 mL) was added, the THF was evaporated, and the resulting mixture was extracted with DCM twice. The extracts were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 1, 1.5%) to give the title compound (805 mg, 44% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.24-8.19 (m, 2H), 7.70-7.61 (m, 3H), 7.14 (t, J=9.3 Hz, 1H), 6.90 (dd, J=8.7, 1.6 Hz, 1H), 6.42 (t, J=8.9 Hz, 1H), 4.22-4.16 (m, 1H), 4.00 (dt,J=13.4, 6.8 Hz, 2H), 3.82 (dd, J=12.1, 6.4 Hz, 2H), 3.02 (dt, J=6.8, 2.3 Hz, 2H), 1.39 (br s, 1H). Mass spectrum (LCMS, ESI) calc'd for C20H17ClF4NO (M+H): 398.1. Found: 398.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]([O:43][CH2:44][C:45]([Cl:46])([Cl:48])[Cl:47])=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Yield: 79.6 %

Procedure:
A solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.5 g) in trifluoroacetic acid (7.5 ml) and anisole (2.5 ml) was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into diisopropyl ether, and the precipitates were collected by filtration, followed by dissolving them in a saturated aqueous sodium bicarbonate (50 ml). The aqueous solution was washed with ethyl acetate, adjusted to pH 2.0 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.55 g).
Reaction SMILES: CN(C=O)C.Cl[N:7]([C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1)[C:8]([CH3:10])=[O:9].O.O.[S:19]1([C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[NH:22]1)(=[O:21])=[O:20].[Na]>O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([NH:7][C:8](=[O:9])[CH2:10][N:22]2[C:23](=[O:24])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[S:19]2(=[O:20])=[O:21])[CH:15]=1
Reactant: CC(=O)N(Cl)c1cc(C)on1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CN2C(=O)c3ccccc3S2(=O)=O)no1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
To 2.31 liters of DMF is added 479 grams (2.75 moles) of 3-(chloroacetamino)-5-methylisoxazole followed by 699 grams (2.9 moles) of sodium saccharin dihydrate. The mixture is heated to 100° C. and this temperature is maintained for 2 hours. The cooled reaction mixture is poured into 8 liters of water, filtered and the wet cake is recrystallized from 15 liters of ethanol to give 658 grams (74.8%) of 2,3,dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide, mp 218°-220° C.; I.R. and NMR spectra are consistant with the structure.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)c2cc(Br)c3c(c2)CCO3)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)c2cc(Br)c3occc3c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 7-bromo-5-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1-benzofuran (353 mg, 1 mmol; Intermediate 78), NBS (178 mg, 1 mmol) and dibenzoylperoxide (24 mg, 0.1 mmol) in carbon tetrachloride (20 mL) was heated to 80° C. for 2 h. TEA (2 mL) was added and the mixture was heated for another 2 h. Flash chromatography using EtOAc/hexane 10:90→25:75 as eluent gave the title product as a white crystalline material. Yield: 130 mg (37%). 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 6.93 (d, 1H), 7.30 (d, 2H), 7.78 (d, 1H), 7.84 (d, 2H), 8.02 (d, 1H), 8.19 (d, 1H).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2C=O)=[CH:12][CH:11]=1.[C:23](=O)([O-])[O-:24].[K+].[K+]>ClC(Cl)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:17]=[CH:18][C:19]([CH:23]=[O:24])=[CH:20]2)=[CH:14][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccn1-c1ccc(F)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC(Cl)Cl
Product: O=Cc1ccn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoromethanesulfonic acid (127 ml) was added dropwise to a dichloroethane solution (680 ml) containing 1-(4-fluorophenyl)-2-formylpyrrole (68 g) at room temperature, and the mixture was stirred at a refluxing temperature for 5 h. After cooling to room temperature, the reaction mixture was poured into aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (mobile phase:methylene chloride) to give 1-(4-fluorophenyl)-3-formylpyrrole (13 g).
Reaction SMILES: [OH:1][C@H:2]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:20]=[CH:21][C:14]=12.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:19]1[C:15]2=[N:16][CH:17]=[N:18][C:13]([O:1][C@H:2]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4])=[C:14]2[CH:21]=[N:20]1
Reactant: COC(=O)[C@H](O)COC(C)C
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H](COC(C)C)Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 130 °C

Procedure:
(R)-methyl 2-hydroxy-3-isopropoxypropanoate D1a (500 mg, 3.08 mmol), 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine B1 (817 mg, 3.08 mmol) and potassium carbonate (0.186 mL, 3.08 mmol) were suspended in acetonitrile (15 mL). The reaction was heated to 130° C. for 4 hours in the microwave reactor and cooled to ambient temperature. The reaction mixture was evaporated to dryness and the resulting residue was dissolved in EtOAc (25 mL), and washed sequentially with saturated NH4Cl (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. Purification by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane afforded (2R)-methyl 2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate D1b (965 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](O)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:14][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Temperature: 47 °C

Procedure:
A 150 mL flask is charged with 2,4-dihydroxy-3-nitropyridine (Compound XII) (10.0 g, 0.064 mole), and toluene (30 mL). The mixture is stirred at moderate speed and warmed to 47° C. Phosphorus oxychloride (POCl3) (4.4 g, 0.0289 moles) is added over 10 minutes, via a syringe pump, giving an exotherm to 49° C. N,N-diisopropylethylamine (DIPEA )(2.22 g, 0.017 moles) is added over 10 minutes, giving an exotherm to 51° C. Another portion of POCl3 (4.4 g, 0.0289 moles) is added over 10 minutes, followed by another portion of DIPEA (2.22 g, 0.017 moles) over 10 minutes. A third portion of POCl3 (4.4 g, 0.0289 moles) is added over 10 minutes, followed by a third portion of DIPEA (2.22 g, 0.017 moles) over 10 minutes, followed by a final portion of POCl3 (4.4g, 0.0289 moles) over 10 minutes (total POCl3 added is 17.7 g), then by a final portion of DIPEA (2.22 g, 0.017 moles) over 10 min.(total DIPEA added is 8.9 g). The reaction is then stirred at 50° C. for 5 hr until IPC indicates complete consumption of Compound XII. The reaction is allowed to cool to 20° C. over 30 minutes and 50 mL of water is added over 1.5 hr allowing the temperature to rise to 47° C. This mixture is stirred for four hours while cooling to 25° C. The batch is filtered washing twice with 15 mL of water, then twice with 15 mL of toluene. The product is dried to give Compound II.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:18][CH3:19])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16])=O.CC1(C)C2C(=C(OC)C=C(C)C=2)C(C)(C)CC1.C(O)(=O)C.P(=O)(O)(O)O.[ClH:46].C=O>C1C=CC=CC=1>[Cl:46][CH2:1][C:3]1[C:4]([O:18][CH3:19])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16]
Reactant: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Reactant: Cl
Agent: C=O
Agent: COc1cc(C)cc2c1C(C)(C)CCC2(C)C
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1c(CCl)c(C)cc2c1C(C)(C)CCC2(C)C
Temperature: 95 °C

Procedure:
To prepare the corresponding 6-carboxaldehyde, 6-formyl-1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene, 1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (23.2 g, 0.1 mol) is added to a stirred solution of acetic acid (18.2 g, 0.3 mol), 85% phosphoric acid (17.6 g, 0.15 mol), hydrochloric acid (28.7 g, 0.3 mol) and paraformaldehyde (7.3 g, 0.24 mol). The mixture is stirred and heated at 95° C. for 16 hr. The reaction mixture is then cooled to 25° C., benzene (50 ml) added, and stirred vigorously. The organic layer is separated, washed with water (2×25 ml), neutralized with 5% sodium bicarbonate solution, and dried (Na2SO4). The solvent is removed by distillation to provide 6-chloromethyl-1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[N:9][CH:8]=[C:7]([N:11]2[CH:15]=[C:14]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:13]=[C:12]2[CH3:25])[N:6]=1)C=C.C1([SiH3])C=CC=CC=1.O>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([C:17]#[C:16][C:14]2[N:13]=[C:12]([CH3:25])[N:11]([C:7]3[NH:6][C:5](=[O:4])[CH:10]=[N:9][CH:8]=3)[CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: C=CCOc1cncc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)n1
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A solution of 75 mg (0.214 mmol) 2-Allyloxy-6-[4-(3-chloro-phenylethynyl)-2-methyl imidazol-1-yl]-pyrazine in 5 ml of methylene chloride was degassed with argon. Then 0.052 ml (0.428 mmol) of phenyl silane and 2.5 mg (0.002 mmol) of tetrakis(triphenyl-phosphine)palladium were added and the mixture was stirred for 1 h at room temperature. Then water (1 ml) was added and the mixture was vigourously stirred for 5 min., diluted with 10 ml of methylene chloride and the organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The obtained solid was triturated with benzene to remove impurities (triphenylphosphine oxide), filtered and dried to yield 30 mg (0.097 mmol, 45%) of the title compound as a white crystalline solid, MS: m/e=311.1, 313.1 (M+H+)
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:56])([CH3:55])[CH2:11][N:12]1[CH:21]=[C:20]([S:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33]C(C)(C)C)=[O:32])[C@@H:27]([CH2:38]O)[CH2:26]2)(=[O:24])=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:40]3[CH:45]=[C:44]([C:46](=[O:51])[NH:47][CH:48]4[CH2:50][CH2:49]4)[CH:43]=[C:42]([F:52])[C:41]=3[CH3:53])[CH:18]=2)[C:13]1=[O:54])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:48]1([NH:47][C:46](=[O:51])[C:44]2[CH:45]=[C:40]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:54])[N:12]([CH2:11][C:10]([CH3:56])([CH3:55])[CH2:9][OH:8])[CH:21]=[C:20]4[S:22]([N:25]3[CH2:30][CH2:29][N:28]4[C:31](=[O:32])[O:33][CH2:38][C@H:27]4[CH2:26]3)(=[O:24])=[O:23])[C:41]([CH3:53])=[C:42]([F:52])[CH:43]=2)[CH2:49][CH2:50]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)[C@@H](CO)C3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)N3CCN4C(=O)OC[C@H]4C3)c2c1

Procedure:
tert-Butyl (2R)-4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfonyl)-2-(hydroxymethyl)piperazine-1-carboxylate (Example 49c, 0.537 g) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (3 mL). The reaction mixture was diluted with toluene (5 mL) and evaporated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:25]([Cl:32])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:23]C)=[C:9]([CH:22]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:25]([Cl:32])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11]
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-N-nonyl-benzamide (173 mg, 0.36 mmol) in CH2Cl2 (3 ml) was added a solution of BBr3 (0.72 ml of a 1 M solution in CH2Cl2). The resulting mixture was stirred at RT for 1.5 h then quenched by addition of MeOH (1 ml) and water (10 ml). The resulting mixture was stirred at RT for 30 min then further diluted with 1 M HCl (10 ml) and extracted with CH2Cl2 (3×5 ml). The combined CH2Cl2 extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound of Step D (168 mg) as a viscous oil. The title product of Step D was used in the next step without further purification. MS (APCI−) Calc.: 468.1, Found: 467.2 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O.CO.N.[H][H]>[Pd].O>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: COc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Product: COc1ccc(NC(C)=O)cc1N
Reaction time: 2 h

Procedure:
104 parts of 2-nitro-4-acetamidoanisole, 200 parts of methanol, 1.2 parts of a 30% aqueous solution of ammonia and 2 parts of a 50% suspension of palladium on charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 5 bar and a temperature of 100° C., hydrogenation is carried out for 2 hours. 2-Methoxy-5-acetamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:43][CH2:42]C[CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:43][CH2:42]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC4CCCCCC4)cc3C)c2cc1OC
Yield: 95 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cycloheptanol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 91%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[C:31]([CH3:32])=[C:30]([C:33]([O:35]CC)=[CH2:34])[C:29](=[O:38])[N:28]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>C(Cl)(Cl)Cl>[ClH:44].[C:33]([C:30]1[C:29](=[O:38])[N:28]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:26]2[N:27]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]4)=[CH:16][N:17]=3)[N:23]=[CH:24][C:25]=2[C:31]=1[CH3:32])(=[O:35])[CH3:34]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (116 mg, 0.20 mmol) in chloroform (5 mL) was added hydrogen chloride (2 M ethereal solution, 5.0 mL, 10.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-2-(5-[1,4]diazepan-1-yl-pyridin-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt (47 mg, 0.10 mmol). MS (APCI+) 432, 462 (M+1, 100);
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCCC.[Cu]>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: C1COCCN1
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: CSc1ccc(N2CCOCC2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
A mixture of 2-Chloro-5-(methylthio)-benzoic acid (1 g, 4.7 mmol), morpholine (620 ul, 7.1 mmol), potassium carbonate (1.05 g, 7.6 mmol) and Copper (24 mg, 0.38 mmol) in pentanol (6 ml) was stirred for 1 h at room temperature. The mixture was heated to 100° C. and stirred for 40 minutes. The solvent was evaporated. The residue was taken up in water and acidified to pH 2. The aqueous layer was extracted twice with ethylacetate. The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over silicagel: eluent: heptane/ethylacetate 0-20% over 15 minutes to provide the title compound as a brown solid (120 mg, 10%), MS (m/e): 252.1 (M−H, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)Cc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)Cc2ccccc2O)cc1
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
2-hydroxyphenylacetic acid (10 g, 66 mmol) was dissolved in N,N-dimethylformamide (100 ml) and cooled on ice-bath. Potassium tert-butoxide (8.85 g, 78 mmol) was added. The mixture was left for 30 min and allowed to reach room temperature. 4-Methoxy-benzylchloride (11.7 g, 72 mmol) in N,N-dimethylformamide (30 ml) was then added dropwise, under nitrogen atmosphere and left over-night. The solvent was evaporated under reduced pressure and the crude mixture was dissolved in ether (100 ml) and washed with water (25 ml), brine and dried over sodium sulphate. Chromatography (hexane-ethyl acetate, 2:1) followed by recrystallization (hexane-ethyl acetate) gave the title compound (7.6 g, 42%).