Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([OH:44])=O)([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:44])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)c3ccc(OC)c(C)c3n2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)c3ccc(OC)c(C)c3n2)cc1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
The acid (130) (70 mg, 0.111 mmol) was dissolved in DCM (2 ml). EDAC (26 mg, 0.133 mmol) was added and the mixture was stirred at room temperature over night. Cyclopropanesulfonic acid amide (15 mg, 0.122 mmol) and DBU (35 μl, 0.233 mmol) was added and the reaction mixture was stirred at room temperature over night. 5% Citric acid was added to the reaction mixture, and the mixture was extracted with brine, dried over Na2SO4 and purified by column chromatography (DCM/MeOH 20:1) to give the title compound (29 mg, 36%). MS (M+H)=733
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1>[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[CH:1]=[CH2:2])=[CH:8][C:7]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 280 mL (36.5 g, 0.28 mole) of a 1.0 M solution of vinylmagnesium bromide in tetrahydrofuran diluted with 250 mL of dry tetrahydrofuran under a nitrogen atmosphere was slowly added 60 g (0.28 mole) of 4-fluoro-3-phenoxybenzaldehyde. Upon completion of addition the reaction mixture was allowed to cool to room temperature and was stirred for three hours. Aqueous 10% hydrochloric acid was added, and the mixture was then extracted with diethyl ether. The ether extract was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, leaving 72.0 g of 1-(4-fluoro-3- phenoxyphenyl)-2-propen-1-ol as a brown liquid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:20]=2[N:19]=[CH:18]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=[O:27])=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: OCc1ccc2c(c1)ncn2C1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc2c(c1)ncn2C1CCCCO1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of oxalyl chloride (1.17 g, 9.23 mol) in DCM (10 mL) at −70° C. was added dropwise DMSO (1.41 g, 18.09 mmol). The reaction mixture was stirred at −70° C. for 30 min. To the resulting solution was added dropwise over 30 min a solution of 24 (1.4 g, 6.03 mmol) in DCM (20 mL). After the addition the reaction temperature was raised to −55° C. The reaction was stirred for 1 h while the temperature was maintained between −55° C. and −45° C., then DIPEA (6.0 mL) was added dropwise over 5 min. The reaction mixture was warmed to 0° C. over 10 min then quenched with 1 M HCl (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to afford 1.0 g (72%) of 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbaldehyde (64) as red oil: MS (ESI) m/z=231.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[CH:9][C:8]=2[C:20]2[N:24](C3CCCCO3)[N:23]=[CH:22][CH:21]=2)=[CH:4][C:3]=1[CH2:33][CH3:34]>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[O:12])=[CH:9][C:8]=2[C:20]2[NH:24][N:23]=[CH:22][CH:21]=2)=[CH:4][C:3]=1[CH2:33][CH3:34]
Reactant: CCc1cc(Oc2ccc(C(=O)NS(C)(=O)=O)cc2-c2ccnn2C2CCCCO2)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(Oc2ccc(C(=O)NS(C)(=O)=O)cc2-c2ccn[nH]2)ccc1Cl
Reaction time: 3 h
Yield: 87.7 %

Procedure:
4-(4-chloro-3-ethylphenoxy)-N-(methylsulfonyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzamide (Preparation 22, 335 mg, 0.53 mmol) was dissolved in 4M hydrogen chloride in dioxane (5 mL). The reaction mixture was stirred 3 hours then concentrated in vacuo. The crude residue was dissolved in methanol (5 mL) and 12N aqueous solution of hydrochloric acid (0.5 mL) was added. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated to dryness then the residue was azeotroped with methanol (25 mL). The crude solid was triturated with tert-butyl methyl ether (4 mL) and the suspension was filtered off. The filtrate was washed with tert-butyl methyl ether to afford the title compound as a cream coloured solid (HCl salt, 106 mg, 44%).
Reaction SMILES: I[CH:2]([C:32]1[O:33][CH:34]=[CH:35][N:36]=1)[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.CO.[BH4-].[Na+]>O1CCCC1>[CH3:31][N:23]([CH:20]1[CH2:21][CH2:22][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][CH2:2][C:32]5[O:33][CH:34]=[CH:35][N:36]=5)[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:18][CH2:19]1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(I)c2ncco2)CC4)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCc2ncco2)CC4)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
A 25-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-[2-iodo-2-(1,3-oxazol-2-yl)ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (150 mg, 0.24 mmol, 1.00 equiv) in a mixed methanol (5 mL) and tetrahydrofuran (5 mL) was added NaBH4 (40 mg, 1.08 mmol, 4.50 equiv) at 0° C. The resulting solution was stirred for 4 h at 0° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10 to 1:22) to afford the desired tert-butyl N-methyl-N-(4-[[(3S)-3-[2-(1,3-oxazol-2-yl)ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (110 mg, 92%) as a yellow solid. MS (ES, m/z): 499 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]1=[O:25].C(N(CC)CC)C.Cl[C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]([F:47])([F:46])[F:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1>CCO>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[C:41]([C:44]([F:46])([F:47])[F:45])[CH:42]=4)[N:37]=[CH:36][N:35]=3)[C:3]2=[O:25])[C@H:8]([CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:9]1)([CH3:17])[CH3:16]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 80 °C
Yield: 43.9 %

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (75 mg, 0.14 mmol) in EtOH (2 mL) was added triethylamine (0.12 mL, 0.84 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (39 mg, 0.16 mmol). The mixture was heated at 80° C. for 14 h and then concentrated in vacuo. The residue was pjurified by HPLC to provide the title compound, (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (35 mg, 44% yield). MS found: (M+H)+=570.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>CO.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Temperature: 3.5 °C
Reaction time: 0.5 h

Procedure:
In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 150-200° C. The jacket temperature was set to −5° C. and the reaction solution cooled to a temperature of ±3.5° C. A 21° C. solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°-15° C. When addition was complete, the jacket temperature was reset to 1° C. and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve most of the solid. The reaction mixture was filtered through canvas and then a 27R10SV Honeycomb filter. The filtered solution was metered into a 21° C. mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 26° C. The resulting product was centrifuged and washed until the wash pH rose to least 6 (by pH indication paper). The crude was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were dried over 1.32 kg magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 4° C. Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg (22%) of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[CH:23]1[CH2:28][C:27](=[O:29])[C:26]([C:30](=[N:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:32][CH3:33])=[C:25]([OH:38])[CH2:24]1>CC(C)=O>[C:1]([O:29][C:27]1[CH2:28][CH:23]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([CH3:22])=[CH:21][C:12]=2[CH3:11])[CH2:24][C:25](=[O:38])[C:26]=1[C:30](=[N:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:32][CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(C)cc(C)c3ccccc23)CC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na]
Solvent: CC(C)=O
Product: CCCC(=NOCC)C1=C(OC(=O)c2ccccc2)CC(c2c(C)cc(C)c3ccccc23)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A slight excess of benzoyl chloride was added to a suspension of the sodium salt of 5-(2,4-dimethylnaphth-1-yl)-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one (0.34 g) in acetone (20 ml) and the mixture was stirred at room temperature for 12 hr. The mixture was filtered, the filtrate was evaporated and the residue was purified by column chromatography overe silica with dichloromethane elution to give 3-benzoyloxy-5-(2,4-dimethylnaphth-1-yl)-2-[1-(ethoxyimino)butyl]cyclohex-2-en-1-one as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 4, Example 10.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH:17]1[CH:22]=[CH:21]C=CC=1>C(NCCC)CC>[N+:14]([C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[N:8]([CH2:17][CH2:22][CH3:21])[CH2:7][CH2:6][CH3:5])([O-:16])=[O:15]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: c1ccccc1
Solvent: CCCNCCC
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C(C)=O)cc1[N+](=O)[O-]

Procedure:
To a solution of 8.9 grams (0.0365 mole) of 4'-chloro-3',5'-dinitroacetophenone in 100 milliliters of benzene, 51 milliliters of di-n-propylamine was slowly added with stirring. The resulting mixture was refluxed for 3 hours. The precipitated dipropylamine hydrochloride was separated by filtration. Evaporation of the filtrate to dryness in vacuo yielded a brown solid weighing 11.5 grams (94.5 percent of the theory). Recrystallization from hexane yielded 8.5 grams of an orange colored crystalline compound, melting point 71°-72° C. Anal. calcd. for C14H19N3O5 : C, 54.36; H, 6.19; N, 13.58. Found: C, 54.47; H, 6.25; N, 13.37.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:33])[N:11]([CH:30]([CH3:32])[CH3:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([N:19](CC2C=CC(OC)=CC=2)[CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:33])[N:11]([CH:30]([CH3:31])[CH3:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2ccc(F)c(N)c2)c(=O)n3C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1ccc(F)c(N)c1)c(=O)n2C(C)C
Yield: 32.5 %

Procedure:
The above prepared 3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-[(4-methoxy-benzyl)-methyl-amino]-1H-[1,6]naphthyridin-2-one (5.3 g) was combined in DCM (150 mL) with TFA (50 mL) and the resultant mixture was heated at reflux overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in 10% HCl aqueous solution. The aqueous layer was washed with EtOAc (3×100 mL) and the aqueous layer was basified to pH 11, and extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated to give 3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-methylamino-1H-[1,6]naphthyridin-2-one (1.26 g, 32% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1 H), 7.70 (s, 1 H), 7.06 (dd, J=8.4, 2.0 Hz, 1 H), 6.94 (dd, J=11.6, 8.4 Hz, 1 H), 6.88 (m, 1 H), 6.72 (m, 1 H), 6.39 (s, 1 H), 5.07 (m, 1 H), 5.06 (s, 2 H), 2.83 (d, J=4.8 Hz, 1 H), 1.51 (d, J=6.8 Hz, 6 H); MS (ESI) m/z: 327.1 [M+H]+.
Reaction SMILES: C(O[C:4]1[S:5][C:6]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:7]=2[C:8](=[O:10])[N:9]=1)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C>[CH2:22]([NH:29][C:4]1[S:5][C:6]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([C:18]([F:19])([F:20])[F:21])=[CH:11][C:7]=2[C:8](=[O:10])[N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOc1nc(=O)c2cc(C(F)(F)F)cc([N+](=O)[O-])c2s1
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Product: O=c1nc(NCc2ccccc2)sc2c([N+](=O)[O-])cc(C(F)(F)F)cc12
Yield: 73 %

Procedure:
A solution of 0.7 g of 2-ethoxy-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one in 15 ml acetic acid was treated with 0.4 ml of benzylamine and refluxed for 14 h. The reaction mixture was evaporated and the residue was treated by 10 ml water, the yellow precipitate was filtered off and washed with 50 ml water. Pure final product was obtained after recrystallization twice from ethanol/DMF. 2-(Benzylamino)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one is a light yellow crystalline solid. Yield 73%. mp 192-194° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[C:8]2[C:14]([CH3:15])=[N:13][N:12]([CH2:16][CH3:17])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:21])=[C:8]2[C:14]([CH3:15])=[N:13][N:12]([CH2:16][CH3:17])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2CC)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c(C)nn2CC)c1Cl

Procedure:
A mixture of 24.9 g. 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.1 mol.) and 150 ml. of phosphorus oxychloride is refluxed for 4 hours. The excess phosphorus oxychloride is removed by means of vacuum distillation. As soon as the phosphorus oxychloride has been removed, the oily residue solidifies on cooling. It is treated with water and filtered under suction (25 g., m.p. 70°-74°). The 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is recrystallized from cyclohexane, yield 22.8 g. (85%), m.p. 78°-79°.
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19](O)=[O:20])=[N:5]1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.N1C=CC=CC=1>C(COC)OC>[CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[N:7]2[C:19](=[O:20])[C:11]3[CH:12]=[C:13]4[CH:18]=[CH:17][O:16][C:14]4=[N:15][C:10]=3[C:6]2=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1(C)N=C2c3nc4occc4cc3C(=O)N2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
To a suspension of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-furo[2,3-b]-pyridine-5-carboxylic acid (11.7 g, 0.039 mol) in 100 mL dimethoxyethane (DME) is added 7.3 mL acetic anhydride and 3.9 mL pyridine. After stirring 24 hours at room temperature, the solids are filtered and washed with ether and the mother liquor is concentrated by adding xylene to aid removal of pyridine. The residue is triturated with ether to obtain solids which are combined with the first crop to give 11.1 g (100%) of product. Recrystallization from 2:1 ethyl acetatehexane gives an analytical sample mp 193°-205° C.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH2:37]([N:40]([CH2:45]CC)[CH2:41][C:42](=O)[CH3:43])[CH2:38][CH3:39].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([CH2:45][N:40]([CH2:41][CH2:42][CH3:43])[CH2:37][CH2:38][CH3:39])[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CCCN(CCC)CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)Cc1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 58 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-dipropylamino-propan-2-one (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (70 mg, 58% yield). MS: 485.34 (M+H+); HPLC Procedure A, retention time=9.20 min.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>N1C=CC=CC=1>[C:17]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 86 %

Procedure:
3-Lauroyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with lauroyl chloride in pyridine.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[CH2:12]1[CH:19]2[C:15]3([C:21]([NH:23][C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[S:25])=[O:22])[CH2:16][CH:17]([CH2:20][CH:13]1[CH2:14]3)[CH2:18]2>>[CH3:30][O:29][CH2:28][CH2:27][N:26]1[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][C:2]=2[S:25]/[C:24]/1=[N:23]\[C:21]([C:15]12[CH2:16][CH:17]3[CH2:20][CH:13]([CH2:12][CH:19]1[CH2:18]3)[CH2:14]2)=[O:22]
Reactant: COCCNC(=S)NC(=O)C12CC3CC(CC1C3)C2
Reactant: O=C1c2ccccc2CC1Br
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)Cc1ccccc1-2

Procedure:
Commercially available 2-bromo-indan-1-one and the product of Example 14B were processed according to the method of Example 14C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.70 (m, 4H), 1.70-1.86 (m, 4H), 2.09-2.20 (m, J=9.0, 2.5 Hz, 2H), 2.24-2.34 (m, 2H), 2.60 (t, J=6.6 Hz, 1H), 3.23 (s, 3H), 3.74-3.86 (m, 4H), 4.69 (t, J=5.4 Hz, 2H), 7.29 (td, J=7.4, 0.8 Hz, 1H), 7.39 (td, 1H), 7.58 (d, J=7.1 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H); MS (ESI+) m/z 395 (M+H)+; Anal. Calculated for C23H26N2O2S: C, 70.02; H, 6.64; N, 7.10. Found: C, 69.83; H, 6.57; N, 6.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][S-:11].[Na+].CCOC(C)=O>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (1.0 g, 6.1 mmol) in EtOH (15 ml) was added sodium thiomethoxide (0.43 g, 6.10 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The mixture was poured onto water and EtOAc. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the crude title compound (910 mg) as a yellow solid. LC-MS (ES) m/z=176 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.[Br:22][C:23]1[N:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1>>[Br:22][C:23]1[N:28]=[CH:27][C:26]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[CH:25][N:24]=1
Reactant: Brc1cnc(Br)nc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cnc(Br)nc2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2,5-dibromo-pyrimidine.