Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2](=[O:13])[N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=12>C(O)CCCC>[N:1]1[C:2](=[O:13])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:5][CH2:6][CH2:7][CH2:8][C:10]([O-:12])=[O:11]
Reactant: O=C1N=c2ccc(C(=O)O)cc2=N1
Solvent: CCCCCO
Product: CCCCC(=O)[O-]
Product: O=C1N=c2ccccc2=N1
Yield: 293.1 %

Procedure:
Benzimidazol-2-one-5-carboxylic acid (4) (250 mg, 0.9070 mmol) and Dowex 50 W-X8(H+) resin (250 mg) were suspended in pentan-1-ol (40 mL) and the mixture heated to reflux for 42 hours. The solid was filtered off and washed with methanol (3×20 mL) and the combined filtrates evaporated to dryness to give benzimidazol-2-one-5-n-pentanoate (5) (310 mg, 43% yield) as an off-white powder;
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:29])([CH3:28])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[S:17]([NH:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[CH3:27])(=[O:19])=[O:18].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:6][Si:7]([CH3:28])([CH3:29])[CH2:8][CH2:9][O:10][CH2:11][C:12]1([CH:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]([S:17]([NH:20][C:21]2[O:25][N:24]=[C:23]([CH3:26])[C:22]=2[CH3:27])(=[O:18])=[O:19])[CH:15]=[CH:14][S:13]1
Reactant: O=Cc1ccccc1
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2COCC[Si](C)(C)C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)C2C=CSC2(COCC[Si](C)(C)C)C(O)c2ccccc2)c1C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
n-BuLi (2.39 M, 177 μl) was slowly added to a solution of (2-trimethylsilylethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (156 mg, 0.38 mmol) in THF at −78° C. under nitrogen. The reaction was stirred at −78° C. for 45 min., then benzaldehyde (45 μl, 0.42 mmol) was added in one lot at −78° C. and the solution was allowed to come to room temperature. Stirring was continued for 1 hr. Purification was achieved by column chromatography using 10% ethyl acetate/hexanes to give 179 mg 2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(α-hydroxybenzyl)thiophene-3-sulfonamide as a yellow viscous oil (90% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:9][C:8]=1[CH3:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.O>CN(C=O)C>[CH3:29][C:8]1[CH:9]=[C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:11]=[C:12]([CH3:13])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(4-bromo-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (494 mg, 1.07 mmol) in DMF (10 mL) was added pyrrolidine (609 mg, 8.57 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 278 mg (57%). MP 180-181° C. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 2H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.83 (t, J=6.4 Hz, 2H), 2.56 (m, 6H), 2.36 (s, 6H), 1.88 (m, 2H), 1.79 (m, 6H). MS (ES) m/z: 452.21 (M+1).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](=O)[CH3:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[CH2:21](OCC)C>>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15]([CH3:21])=[CH2:16])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCOCC
Reactant: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Product: C=C(C)c1cccc2c1CC(N(CCC)CCC)CO2

Procedure:
3-Dipropylamino-5-acetylchroman (Example 7; 0.40 g, 1.45 mmol) was dissolved in dry diethyl ether (2.0 ml) and this solution was added to the previously formed Wittig-reagent.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.CN(C=O)C.[CH3:21][S-:22].[Na+].O>[Cl-].[Na+].O>[CH3:21][S:22][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: C[S-]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 90 °C
Yield: 95.3 %

Procedure:
To a solution of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (2.02 g, 8.40 mmol) and DMF (40 mL) was added sodium thiomethoxide (0.618 g, 8.82 mmol). The mixture was heated to 90° C. for 50 min, then poured into brine. Water was added to bring the total volume to 300 mL and the orange precipitate was collected to yield the titled compound (2.02 g, 95%). 1H NMR (400 MHz, CDCl3): 8.42 (s, 1H), 6.51 (s, 1H), 6.39 (br s, 2H), 2.53 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:8]=1.[CH2:26]([N:28](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>ClCCl.O.CN(C=O)C>[C:26]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:8]=1)#[N:28]
Reactant: CCN(CC)CC
Reactant: COc1ccc(CO)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC#N)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.7 %

Procedure:
To a solution of 1,1-dimethylethyl 4-({[5-(hydroxymethyl)-2-(methyloxy) phenyl]oxy}methyl)piperidine-1-carboxylate (1.88 g, 5.4 mmol) in dichloromethane (14 mL) was added triethylamine (2.3 mL, 16.2 mmol). The resulting mixture was cooled with an ice bath, and methanesulfonyl chloride (0.84 mL, 10.8 mmol) was added dropwise. The mixture was allowed to warm to room temperature and a white precipitate formed. After 2.5 h, the solvent was removed and the residue was dissolved in water, which was subsequently extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to provide a yellow oil. To the oil was added DMF (10 mL) and potassium cyanide (703 mg, 10.8 mmol). The resulting mixture was stirred at rt for 15 h. Water was then added, and the aqueous mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (60% hexanes, 40% ethyl acetate) to provide 800 mg of 1,1-dimethylethyl 4-({[5-(cyanomethyl)-2-(methyloxy)phenyl]oxy}methyl)piperidine-1-carboxylate (2.2 mmol, 41% yield). 1H NMR (400 MHz, CDCl3): δ6.89-6.81 (m, 3H), 4.15 (br m, 2H), 3.86 (s, 3H), 3.86-3.83 (m, 2H), 3.69 (s, 2H), 2.76 (br m, 2H), 2.10-2.00 (m, 1H), 1.87 (br d, 2H), 1.47 (s, 9H), 1.31-1.20 (m, 2H); MS (EI) for C20H28N2O4: 383 (MNa+).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([Cu])#[N:11]>>[Cl:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: Fc1cc(Cl)cnc1Br
Reactant: N#C[Cu]
Product: N#Cc1ncc(Cl)cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 66434.6 %

Procedure:
2-Bromo-5-chloro-3-fluoropyridine (107 g, 0.5 mmol) and CuCN (55 g, 0.62 mmol) were added to a round bottom flask with a magnetic stirbar. The flask was fitted with a septum and purged with nitrogen for 10 minutes. DMSO (430 mL) was then added by syringe and the resulting mixture stirred at 120° C. for 3 h. The reaction was cooled to room temperature and then poured into a vigorously stirred mixture of EtOAc (1 L) and brine (1 L). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (15% ethyl ether, 85% hexanes) provided the title compound as an off-white solid (52 g, 67%). The product was characterized by 1H NMR.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([OH:25])=O)[CH2:12]1.[ClH:26].[C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)#[N:28]>CN(C=O)C>[ClH:26].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[C:27]#[N:28])=[O:25])[CH2:12]1
Reactant: N#C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2nc3ccccc3o2)C[C@H]1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@@H](Nc2nc3ccccc3o2)CN1

Procedure:
(2S,4R)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (title compound of Reference Example 6, 1.0 g) and (S)-2-cyanopyrrolidine hydrochloride (0.38 g) were dissolved in DMF (10 mL), and triethylamine (0.81 mL), HOBT (0.49 g) and EDC hydrochloride (0.61 g) were successively added thereto. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and mixture was extracted with ethyl acetate. The extract was dried and the residue was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-[(2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (0.91 g) as amorphous.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[S:11][C:12]([Br:15])=[CH:13][CH:14]=2)[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:15][C:12]1[S:11][C:10]([CH:8]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (18.9 g, 47.3 mmol) prepared in Step 3 and a solution of potassium hydroxide (5.3 g, 94.6 mmol) in distilled water (200.0 mL) were added to methanol (200.0 mL). The reaction mixture was stirred at 80° C. for 12 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 18.1 g of the titled compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH2:20][C:21]1[N:25]=[CH:24][O:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH2:20][C:21]1[N:25]=[CH:24][O:23][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccccc1SCc1ncon1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1SCc1ncon1)OCc1ccccc1

Procedure:
A solution of benzylchloroformate (3.79 g) and 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole (3.1 g) in dioxan (75 ml) containing potassium carbonate (3.15 g) was refluxed for 1 hour. Solvent was then removed by evaporation under reduced pressure to give a colourless solid which was re-crystallised from hexane to give 3-(2-benzyloxycarbonylaminophenylthiomethyl)-1,2,4-oxadiazole, m.p. 41°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH:17][C:22]([C:21]2[C:20]([CH3:19])=[N:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])[CH:10]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[3-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently-saponified to yield the title compound as colorless solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4](=O)[NH:5][N:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.P(Br)(Br)([Br:24])=O.CN(C=O)C>>[Br:24][C:4]1[N:5]=[N:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:8][C:3]=1[C:2]([F:21])([F:20])[F:1]
Reactant: O=c1[nH]nc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(Br)nn2)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-2H-pyridazin-3-one (example C.26 step 6) (9.61 g, 31 mmol), POBr3 (26.8 g, 94 mmol) and DMF (0.72 mL, 9 mmol) was stirred for 3 h at 105° C. under nitrogen atmosphere. The reaction mixture was poured (the mixture was nearly solid) onto water (300 mL) and stirred for 2 h at 23° C., the precipitated solid was filtered off and applied onto silica gel for silica gel column chromatography with heptane/EtOAc 4:1->2:1 to give the title compound as a light brown solid (11.22 g, 97%). MS (ISP) 371 [(M+H)+], 373 [(M+2+H)+]; mp 123–125° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[CH:7]=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.[OH-].[K+]>CO.C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[CH:7]=[C:8]([CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1.[CH:1]1([C:4]2[CH:5]=[C:6]([CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=2)[C:14]([OH:16])=[O:15])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(C(=O)OC)cc(C2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)cc(C2CC2)c1
Product: O=C(O)c1cc(C(=O)O)cc(C2CC2)c1
Temperature: 78 °C
Yield: 56 %
Yield: 12 %

Procedure:
To a solution of dimethyl 5-cyclopropylisophthalate (0.8 g, 3.42 mmol) in MeOH (10 mL) and THF (10 mL) was added potassium hydroxide (0.23 g, 4.1 mmol) with stirring. The reaction mixture was heated at 78° C. for 7 h. It was cooled to rt and concentrated in vacuo. To the residue was added a small amount of acetic acid. The mixture was purified by preparative HPLC. The fractions containing the desired product were combined, concentrated and lyophilized to afford 5-cyclopropylisophthalic acid as a white solid (89 mg, 12%) and 3-cyclopropyl-5-(methoxycarbonyl)benzoic acid as a white solid (0.43 g, 56%). 1H NMR (DMSO-d6): δ 13.21 (s, 2H), 8.25 (t, J=1.2 Hz, 1H), 7.85 (d, J=1.2 Hz, 2H), 2.13 (m, 1H), 1.03 (m, 2H), 0.76 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])[CH:11]=1>CN(C)C=O>[ClH:16].[CH3:9][C:10]1[N:15]=[C:14]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[N:13]=[C:12]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])[CH:11]=1
Reactant: Cc1cc(N2CCc3ccsc3C2C)nc(Cl)n1
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccsc3C2C)nc(N(C)c2ccccc2)n1
Product: Cl
Yield: 49.8 %

Procedure:
After N-methylaniline(0.45 ml, 4.05 mmol) was added to a mixture solution of 6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-2-chloropyrimidine(0.75 g, 2.7 mmol) and dimethylformamide(10 ml), 0.52 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])=[CH:9][C:8]=1F)(=O)[CH3:5].CO>C(Cl)(Cl)Cl>[CH3:5][C:4]1[C:7]2[C:8](=[CH:9][C:10]([N:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:14]3=[O:25])=[CH:11][CH:12]=2)[NH:3][N:2]=1
Reactant: NN
Reactant: CC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3c(C)n[nH]c3c2)C1=O
Temperature: 120 °C
Reaction time: 12 h
Yield: 64.5 %

Procedure:
Hydrazine hydrate (10 mL) was added to 1-(4-acetyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (380 mg, 1.2128 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 120° C. for 12 hours, cooled to room temperature and continued stirring for the next 12 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and ice water. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% MeOH in CHCl3) afforded 240 mg of the product (64.5% yield).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH:25]=[CH2:26])=[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].[H][H]>O1CCCC1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH2:26][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:23])=[CH:27][CH:28]=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: [H][H]
Reactant: C=COC(=O)c1ccc(NCCCCCCCCCCCCCCCC)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCC(=O)OCC)cc1

Procedure:
A solution of 4 g. (8.7 m moles) 2-ethoxycarbonyl)vinyl 4-(hexadecylamino)benzoate and 400 mg. 10% Pd(C) in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-(ethoxycarbonyl)ethyl 4-(hexadecylamino)benzoate.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][O:23][CH2:24][CH2:25][N:26]([CH2:34][CH2:35][O:36][CH3:37])[C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1>C1(C)C=CC=CC=1>[CH3:37][O:36][CH2:35][CH2:34][N:26]([CH2:25][CH2:24][O:23][CH3:22])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:7]2[N:8]=[CH:9][C:4]3[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:5]=3[N:6]=2)=[N:31][CH:32]=1
Reactant: COCCN(CCOC)c1ccc(N)nc1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: COCCN(CCOC)c1ccc(Nc2ncc3c(C)c(Br)c(=O)n(C4CCCC4)c3n2)nc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.4 g, 1.08 mmol) and N5,N5-Bis-(2-methoxy-ethyl)-pyridine-2,5-diamine (0.5 g, 2.2 mmol) were combined in toluene (3.5 mL) and heated to 110° C. After 5 h the reaction mixture was allowed to cool and the crude product was directly chromatographed on silica gel eluting with a gradient of 25% to 100% ethyl acetate in hexanes to provide 2-{5-[bis-(2-methoxy-ethyl)-amino]-pyridin-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.49 g, 85%) as an orange gum. mp 94-95° C. MS (APCI); M++1: Calc'd, 530.2. Found 530.1. Anal. Calc'd for C24H32N6O3Br, 0.13H2O: C, 54.00; H, 5.90; N, 15.74. Found; C, 53.61; H, 5.68; N, 15.60.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)(=[O:29])[CH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:27]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]=2[NH:7][C:8](=[O:12])[CH2:9]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(C)=O)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
To a slurry of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (100 mg, 0.42 mmol) in dichloromethane (10 mL) was syringed N,N-diisopropylethylamine (0.15 mL, 0.84 mmol). The mixture was cooled in an ice-water bath and acetyl chloride (0.04 mL, 0.55 mmol) was added via syringe. After 15 minutes LCMS indicated completion of the reaction. Dichloromethane (10 mL) and 10% aqueous citric acid (10 mL) were added and the mixture was stirred while being allowed to warm to room temperature. The mixture was filtered and the collected solid was washed with water and dried to constant weight to give 4-acetyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (70 mg, 60%) as a yellow solid. NMR analysis indicated a mixture of two conformational isomers, similar to that observed for the related trifluoroacetyl analog (see procedure 6c); NMR (400 MHz, DMSO-d6) δ 10.19/10.17 (2s, 1H), 7.69/7.66 (2s, 1H), 7.46/7.35 (2s, 1H), 4.78/4.67 (2s, 2H), 4.36/4.37 (2s, 2H), 3.90/3.92 (2s, 3H), 2.05 (s, 3H); MS (m/e) 278 (M−1); mp 266° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:39]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-])=O)=[CH:46][CH:45]=2)=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:37])[C:6]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])[CH3:9])=[O:7].[H][H].[ClH:55]>CO.C(O)C.[OH-].[Pd+2].[OH-]>[ClH:55].[ClH:55].[NH2:50][C:47]1[CH:48]=[CH:49][C:44]([C:39]2[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=4[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:24])[CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:45][CH:46]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3-methoxy-4-(4′-nitrobiphenyl-2-carboxamido)-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]-N-methylbenzamide (910 mg), 20% palladium hydroxide (200 mg) in methanol (30 ml) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 5 hours, the reaction mixture was filtered through a bed of Celite, and the solvent was removed by evaporation and the crude product was purified by silica gel column chromatography (SiO2; 30 g, 5% methanol in chloroform) to give free product. To a solution of this product (810 mg) in ethanol (20 ml) was added 1N hydrochloric acid (2.39 ml) and stirred at ambient temperature for 10 minutes. The solvent was removed to give 4-(4′-aminobiphenyl-2-carboxamido)-3-methoxy-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]-N-methylbenzamide dihydrochloride as amorphous.