Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[OH-].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:25]([OH:26])[CH:24]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:27]=1[O:28][CH3:29])[CH:22]=[O:21])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)cc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18--Crown-6 ether (0.14 g, 0.00052 mols) and potassium hydroxide (1.35 g, 0.024 mols) is added to a stirred solution of isovanillin (201) (2.0 g, 0.013 mols) in THF (20 ml) at 0° C. The reacton becomes cloudy and turns bright yellow. Benzyl bromide (1.69 ml, 0.0143 mols) is added dropwise to the reaction at 0° C. After one hour, the ice bath is removed and the reaction is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with water and 10% HCl followed by brine solution. The organic extract is dried over sodium sulfate, filtered, concentrated and dried in vacuo no a yellow crystalline solid (3.0471 g, 96.9%).
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1.C(N(CC)CC)C>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCn1nnnc1S
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCCn1nnnc1S
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 74.1 %

Procedure:
A solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (12.3 g) in dioxane (30 ml) was added under ice-cooling to a stirred solution of 1-(3-aminopropyl)-1H-tetrazole-5-thiol hydrochloride (9.78 g) and triethylamine (11.1 g) in a mixture of dioxane (25 ml) and water (25 ml), and then the resulting mixture was stirred for 1.75 hours at ambient temperature. Dioxane was distilled off and to the residue were added diethyl ether and a small amount of water. After shaking, the aqueous layer was separated and the organic layer was extracted twice with 10% potassium carbonate. The extracts combined with the separated aqueous layer were washed three times with diethyl ether, adjusted to pH 1 with hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and evaporated in vacuo. The residual oil (10.92 g) was pulverized with diisopropyl ether to give 1-[3-(N-t-butoxycarbonylamino)propyl]-1H-tetrazole-5-thiol (9.6 g), mp. 75° to 77° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([Si:9]([CH3:12])([CH3:11])Cl)[CH3:8].C(N(CC)CC)C.[OH2:20]>CCOCC>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([Si:9]([CH3:12])([CH3:11])[OH:20])[CH3:8]
Reactant: C=CCCCCC(C)[Si](C)(C)Cl
Reactant: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCCCCC(C)[Si](C)(C)O
Temperature: 0 °C

Procedure:
A solution of 7-oct-1-enyl dimethylchlorosilane (2.56 mL) in ether (2 mL) was added dropwise over 1 hour to a stirring mixture of triethylamine (1.5 mL), water (0.18 mL) and ether (15 mL) in an ice/water bath. The resultant was stirred a further 1 hour in the ice/water bath and filtered washing the filtered solid with ether (10 mL). The filtrate was evaporated with a rotary evaporator and the residue partitioned between hexane (30 mL) and water (30 mL). The organic layer was separated, dried (MgSO4) and filtered through silica gel (70-230 mesh, 60 Å), washing with hexane (100 mL). The filtrate was evaporated with a rotary evaporator to afford a colorless oil which was vacuum dried and weighed (1.06 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([CH3:22])[CH3:21])=[N:7][CH:6]1[CH3:31])=[O:4].C([O-])([O-])=O.[K+].[K+].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:20]([CH3:22])[CH3:21])=[N:7][C:6]=1[CH3:31])=[O:4]
Reactant: COC(=O)C1C(=O)N(Cc2ccccc2)C(C(NC(=O)OC(C)(C)C)C(C)C)=NC1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)nc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 40.3 %

Procedure:
To a stirred solution of 1-Benzyl-2-(1-t-butoxycarbonylamino-2-methyl-propyl)-4-methyl-6-oxo-1,4,5,6-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (6.37 g, 14.8 mMol) in CCl4 (150 mL) was added K2CO3 (4.0 g, 29 mMol), N-Bromosuccinimde (2.63 g, 14.8 mMol) and Benzoyl peroxide (0.18 g, 0.74 mMol). The reaction was refluxed for 0.5 h, cooled to RT, filtered through a pad of Celite®, and rinsed with CH2Cl2. The filtrate was concentrated under vacuum and purified by flash chromatography (step gradient of 0 to 5% EtOAc in CH2Cl2). The semi-purified product obtained was taken up in a solution of 20% EtOAc in hexane (10 mL) at which point the product began to crystallize out. The mixture was diluted with a solution of 10% Et2O in pet. Et2O (50 mL), triturated, filtered and dried under vacuum to give the title compound (2.56 g, 40%) as a white solid: MS (ES) m/e 432.2 and 430.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])[C:30](=[O:31])[CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Clc1cc(Br)ccc1CNCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)N(Cc1ccccc1)Cc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
580 mg of benzyl-(4-bromo-2-chlorobenzyl)amine are dissolved in 10 ml of CH2Cl2 (anhydrous) and treated first with 300 μl of pyridine, then with 330 mg of 2-thiophen-2-ylacetyl chloride. The mixture is stirred at RT for 4 h, then diluted with 100 ml of CH2Cl2 and washed with 50 ml of a saturated aqueous Na2CO3 solution. It is dried over MgSO4 and the solvent is removed in vacuo. It is chromatographed on silica gel using DIP and 490 mg of a colorless oil are obtained.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[N:5][C:6](=O)[NH:7][CH:8]=1.P(Cl)(Cl)([Cl:12])=O>>[ClH:12].[Br:2][C:3]1[C:4]([Cl:12])=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ncc(Br)c[nH]1
Agent: Br
Product: Cl
Product: Clc1ncncc1Br
Temperature: 90 °C

Procedure:
A suspension of 5-bromopyrimidone hydrobromide (1.0 g, 3.9 mmol) in phosphorous oxychloride (4 mL) was heated at 90° C. for 1 h then cooled 0° C. The mixture was filtered, washed with POCl3 (2×2 mL) to furnish the title compound as a cream solid (388 mg). This compound was unstable to air and was used immediately in the next step.
Reaction SMILES: [C-:1]#[N:2].[Na+].[N+:4]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22]Cl)=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].O>CS(C)=O>[N+:4]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:1]#[N:2])=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: [C-]#N
Reactant: O=C(NCCc1ccccc1CCl)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccccc1CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 74.5 %

Procedure:
Sodium cyanide (2.9 g) was dissolved in 100 ml of dimethylsulfoxide, and with stirring at room temperature, 15.5 g of 1-(4-nitrobenzoyl)amino-2-(2-chloromethylphenyl)ethane was gradually added. The reaction was performed at room temperature for 10 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from ethanol to afford 11.2 g of 1-(4-nitrobenzoyl)amino-2-(2-cyanomethylphenyl)ethane having a melting point of 118.6° to 119.1° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:10]=[CH:9]/[C:8]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cccnc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
3-Bromopyridine (4 g, 25 mmol), methyl acrylate (2.6 g, 31 mmol), palladium(II) acetate (0.26 g, 1.2 mmol), tri-o-tolylphosphine (0.74 g, 2.4 mmol) and triethylamine (10 ml) were placed in a thick walled glass tube. The tube was sealed under argon and the mixture heated at 80° C. After 12 h the reaction mixture was allowed to cool to room temperature and chloroform (100 ml) was added. The mixture was washed with water (2×100 ml), the organics dried over anhydrous magnesium sulphate, and the solvent removed under reduced pressure. Column chromatography (flash silica gel; 1:1 ethyl acetate/hexane) yielded methyl E-3-(3-pyridyl)acrylate as a colourless oil (0.5 g, 12%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[S:7][C:8]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[S:7][C:8]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1
Reactant: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2sc(C(=O)Nc3ccc(C(=O)O)cc3)c(OC(C)C)c2c1
Yield: 64.8 %

Procedure:
A mixture of 4.0 g of methyl 4-[[[5-methoxy-3-(1-methylethoxy)benzo[b]thien-2-yl]carbonyl]amino]benzoate and 2 g of 50% NaOH in 100 mL of 10% aqueous methanol is heated on a steam bath for 15 minutes, then poured onto ice and acidified with 10% HCl. The resulting gum is extracted into 500 mL of diethyl ether. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude solid is triturated with t-butyl methyl ether to provide 2.5 g of product; mp 236°-239° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([O:18]C)=[O:17])=[CH:10]1.[OH-].[Na+]>CCO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]1
Reactant: COC(=O)c1ccc(=O)n(-c2c(F)cccc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(=O)n(-c2c(F)cccc2F)c1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of methyl 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (5.41 g) in a mixture of EtOH (108 mL) and THF (54 mL) was added 1 M aqueous NaOH (82 mL) at 0° C., and the mixture was stirred at the same temperature for 2 hr. The mixture was concentrated under reduced pressure and the residue was treated with 1 M HCl (160 mL). The precipitates produced were collected by filtration and dried under reduced pressure at 60° C. to give 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (4.73 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O1C(C2C=C(N[C:28]3[N:33]=[C:32]([C:34]4[C:35]([C:43]5[CH:44]=[C:45]([NH:49][C:50](=[O:57])[CH2:51][C:52]6[S:53][CH:54]=[CH:55][CH:56]=6)[CH:46]=[CH:47][CH:48]=5)=[N:36][N:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=45)[CH:31]=[CH:30][N:29]=3)C=CC=2)=CN=C1>CC(O)C.Cl.C(Cl)Cl>[F:14][C:11]([F:12])([F:13])[C:10]([NH:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:28]2[N:33]=[C:32]([C:34]3[C:35]([C:43]4[CH:48]=[CH:47][CH:46]=[C:45]([NH:49][C:50](=[O:57])[CH2:51][C:52]5[S:53][CH:54]=[CH:55][CH:56]=5)[CH:44]=4)=[N:36][N:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=34)[CH:31]=[CH:30][N:29]=2)[CH:3]=1)=[O:15]
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: Nc1cccc(CNC(=O)C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CNC(=O)C(F)(F)F)c3)n2)c1
Temperature: 180 °C
Yield: 67 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoroacetamide (46 mg, 0.21 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (75 mg, 0.17 mmol) (see Example 2, Step B) in i-PrOH (3 mL) was acidified with 2 drops of 12 N HCl and heated in a microwave for 15 min. at 180° C. The reaction mixture was then diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 67% yield. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=6.8 Hz, 1H), 8.31 (d, J=9.1 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.72-7.75 (m, 2H), 7.63 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.26-7.38 (m, 7H), 7.04 (s, 1H), 6.94 (m, 1H), 6.63 (d, J=5.4 Hz, 1H), 4.48 (d, J=5.7 Hz, 2H), 3.96 (s, 2H). ES-LC/MS m/z=628 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:24]O>>[CH3:24][O:13][C:12](=[O:14])[C:11]([CH3:15])([CH3:16])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([NH2:1])[CH2:17][CH3:18]
Reactant: CCC(N)CCCCCCCCC(C)(C)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCC(N)CCCCCCCCC(C)(C)C(=O)OC
Yield: 89.5 %

Procedure:
51.4 g (0.2 mole) of 11-amino-2,2-dimethyl-tridecanoic acid and 200 ml of methanol and 22 g (0.224 mole) of sulfuric acid are refluxed for 3 hours. Excess methanol is then distilled off, the residue is diluted with about 200 ml of water and the reaction solution is made weakly alkaline (pH 8-10) with aqueous sodium hydroxide, whereupon the aminoacid ester separates as upper organic phase. Subsequent distillation yields 48.5 g (0.179 mole) of 11-amino-2-,2-dimethyl-tridecanoic acid methyl ester, corresponding to a yield of 89.5% of theory.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[F:23].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].C[Si]([C:53]#[N:54])(C)C>C1COCC1>[C:53]([CH:4]([NH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[F:23])[C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[F:1])#[N:54]
Reactant: COc1cc(F)c(C=O)cc1OC
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C#N)Nc2ccc(C#N)cc2F)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 20 ml of a THF solution containing 1.9 g of 2-fluoro-4,5-dimethoxybenzaldehyde, 1.47 g of 4-amino-3-fluorobenzonitrile [CAS No. 63069-50-1], 6 g of MS3A, 640 mg of Yb(OTf)3, and 4 ml of trimethylsilyl cyanide were added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and then filtered through celite. The filtrate was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) and then filtered through NH silica gel to give the title compound (1.0 g) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCCl)cc1
Yield: 66.7 %

Procedure:
6.0 g (29.6 millimoles) of 6-(p-aminophenyl)-5-methyl-4,5-dihydropyridaz-3-one and 4.1 g (32.3 millimoles) of 3-chloropropionyl chloride are stirred with 100 ml of absolute toluene for 4 hours at 80° C. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 5.8 g (67% of theory) of 6-[p-(3-chloropropionylamino)-phenyl]-5-methyl-4,5-dihydropyridaz-3-one are obtained as beige crystals which, after recrystallization from methanol, melt, with decomposition, at 221°-223° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH3:20][O:21][C:22](=[O:43])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:25][C:24]=1[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>C(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:43])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:25][C:24]=1[N:35]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C)c(OC(F)(F)F)cc1NC(=O)OC(C)(C)C
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCN(C(=O)OC(C)(C)C)c1cc(OC(F)(F)F)c(C)cc1C(=O)OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 61.2 %

Procedure:
Add methyl 4-bromobutyrate (1.1 g, 6.0 mmol) and cesium carbonate (3.9 g, 12.0 mmol) to a DMF solution of 2-(tert-butoxycarbonylamino)-5-methyl-4-trifluoromethoxy-benzoic acid methyl ester (1.4 g, 4.0 mmol) under nitrogen. After stirring at 60° C. for 5 hours, the reaction mixture is cooled to room temperature and diluted with ethyl acetate (150 mL). Wash the organics with water (2×150 mL) followed by brine (100 mL), dry over sodium sulfate, and filter. Remove the solvent under vacuum and chromatograph the crude product over silica gel using ethyl acetate/hexane (5-30%) to elute. This provides the title compound (1.1 g, 61%) as an oil: H NMR (CDCl3, 400 MHz) δ 1.28 (s, 6H), 1.49 (s, 3H), 1.91 (m, 2H), 2.33 (m, 5H), 3.39 (m, 1H), 3.63 (s, 3H), 3.77 (m, 1H), 3.86 (bs, 3H), 7.06 (m, 1H), 7.80 (m, 1H). MS (ES+): 350 (M+H-100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]([F:22])[C:11]([F:21])=[C:12]3[O:17][CH2:16][CH:15]([CH2:18][OH:19])[N:14]([CH:20]=1)[C:13]=23)=[O:5])[CH3:2].N1C=CC=CC=1.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36](Cl)=[O:37])([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]([F:22])[C:11]([F:21])=[C:12]3[O:17][CH2:16][CH:15]([CH2:18][O:19][C:36](=[O:37])[C:35]4[CH:34]=[C:33]([N+:30]([O-:32])=[O:31])[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=4)[N:14]([CH:20]=1)[C:13]=23)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2CO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
One gram of (±)-9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (I) and 500 mg of pyridine were suspended in 100 ml of anhydrous tetrahydrofuran (THF), and 1.6 g of 3,5-dinitrobenzoyl chloride was added thereto, followed by refluxing at 90° C. The suspension was once dissolved, and a colorless precipitate was then formed. The reaction was continued for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with methanol and diethyl ether and dried to obtain 1.2 g of (±)-9,10-difluoro-3-(3,5-dinitrobenzoyloxy)methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (II) as a colorless powder having a melting point of 240°-242° C.
Reaction SMILES: ClC1C=C(N(C)C[C:11](=O)[CH2:12][C:13](OCC)=[O:14])C=C(Cl)C=1.[OH:20][CH2:21][CH2:22][NH:23][NH2:24].C(N(CC)CC)C.[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>CCO.C(OCC)(=O)C>[OH:20][CH2:21][CH2:22][N:23]1[CH:11]=[CH:12][C:13](=[O:14])[N:24]1[S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NNCCO
Reactant: CCOC(=O)CC(=O)CN(C)c1cc(Cl)cc(Cl)c1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2c(=O)ccn2CCO)cc1
Reaction time: 3 h
Yield: 141.7 %

Procedure:
To a solution of ethyl 4-((3,5-dichlorophenyl)(methyl)amino)-3-oxobutanoate (304 mg, 1.0 mmol) in EtOH (5 mL), was added 2-hydroxyethylhydrazine (85 uL, 1.1 mmol) and was stirred for 3 h. After the volatiles were evaporated, the residue was dissolved in dry acetonitrile (10 mL) and triethylamine (156 uL, 1.1 mmol) followed by the addition of tosyl chloride (190 mg, 1.0 mmol). The solution was stirred for 20 min, diluted in ethyl acetate (20 mL), washed with water (10 mL), dried over Na2SO4, and concentrated. The residue was purified on a silica gel column, eluting with a mixture of MeOH and dichloromethane (2% MeOH) to afford the product as a pale yellow liquid 35 (400 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH3:30].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:29][C:25]1[C:24]([CH3:30])=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:20]1[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: Cc1c(Cl)cccc1CBr
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(Cl)c1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (200 mg, 0.72 mmol), prepared as described in Example 3, step f, 1-(bromomethyl)-3-chloro-2-methylbenzene (237 mg, 1.08 mmol) and Na2CO3 (153 mg, 1.44 mmol) in DMF (10 mL) was stirred at 80° C. for 5 h. It was cooled to room temperature and poured into water (100 mL). It was extracted with EA (100 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with MeOH/DCM=1/60 to afford the desired product as a black solid (239 mg, 80%); LC/MS: MS (ES+) m/e 415 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.39 (s, 3H), 2.44 (s, 3H), 3.42 (t, J=4.8 Hz, 4H), 3.69 (t, J=4.8 Hz, 4H), 3.92 (s, 3H), 5.45 (s, 2H), 6.37 (d, J=7.8 Hz, 1H), 7.07-7.12 (m, 2H), 7.36 (d, 1H).
Reaction SMILES: [C:1]([S:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>>[Br-:16].[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][N+:12]2[CH:13]=[CH:14][CH:15]=[C:10]([S:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=2)[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: O=C(Sc1cccnc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C(Sc1ccc[n+](CCN2C(=O)c3ccccc3C2=O)c1)c1ccccc1
Product: [Br-]
Yield: 44.3 %

Procedure:
A mixture of 3-benzoylthiopyridine (8.6 g) and N-(2-bromoethyl)phthalimide (12.2 g) was heated for eight hours at 95°-100° C. and triturated in chloroform (100 ml) for 30 minutes at room temperature. The resulting precipitates were collected by filtration, washed with chloroform and dried to give 1-(2-phthalimidoethyl)-3-benzoylthiopyridinium bromide (8.3 g).