Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:19]([Cl:34])=[CH:18][N:17]=1>>[Cl:34][C:19]1[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: CC1(C)CCCOc2c(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cccc21

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 179. Product was isolated as a tan foam (51 mg, 50%). LCMS (m/e) 494 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.22 (d, 1H, J=7.8 Hz), 7.96 (s, 1H), 7.72 (s, 1H), 7.01 (dd, 1H, J=7.8, 7.58 Hz), 6.93 (d, 1H, J=8 Hz), 5.42 (m, 1H), 5.24 (m, 1H), 4.02 (m, 2H), 3.93 (m, 1H), 3.27 (m, 1H), 2.80 (s, 3H), 2.24 (m, 2H), 2.08 (m, 2H), 1.84 (m, 2H), 1.69 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][OH:10])=[O:6])[CH2:3][OH:4].[H][H].[ClH:27]>CO.[Pd]>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][OH:10])=[O:6])[CH2:3][OH:4].[ClH:27]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CO)NC(=O)[C@@H](N)CO

Procedure:
2.5 Grams of Z-Ser-Ser-OMe was dissolved in 50 ml of methanol with 7.34 ml of 1N-hydrochloric acid, then in the presence of 500 mg of palladium balck, catalytic reduction was carried out at 20° C., under 1 atmospheric pressure of hydrogen gas, to obtain H-Ser-Ser-OMe.HCl.
Reaction SMILES: C[O:2][C:3]1(OC)[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:15]([C:17]1[C:18]([CH:23]([F:25])[F:24])=[N:19][N:20]([CH3:22])[CH:21]=1)=[O:16].Cl.O>CC(C)=O>[O:2]=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:15]([C:17]1[C:18]([CH:23]([F:25])[F:24])=[N:19][N:20]([CH3:22])[CH:21]=1)=[O:16]
Reactant: COC1(OC)C2CCC1c1c(NC(=O)c3cn(C)nc3C(F)F)cccc12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cn1cc(C(=O)Nc2cccc3c2C2CCC3C2=O)c(C(F)F)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
An oven-dried Schlenk was charged with compound 4 (100 mg, 0.26 mmol) and dissolved in acetone (1 mL). Hydrochloric acid was added (37%, 2 drops) and the mixture was stirred under nitrogen for 30 minutes at 50° C. GCMS analysis indicated compete conversion of starting material and water was added to mixture (5 mL). Extraction into ethyl acetate (3×5 mL) followed by concentration in vacuo affords compound 5 (quantitative conversion).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[CH2:8]1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 4-trifluoromethoxybenzoyl chloride.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]([O:9]C)=O.O.[NH2:12][NH2:13]>CC(O)C>[OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: COC(=O)[C@H]1CCC[C@@H]1O
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)[C@H]1CCC[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a 50-mL four-necked flask were added 2.33 g (16.2 mmol) of methyl (S,S)-2-hydroxycyclopentanecarboxylate and 9.3 ml of 2-propanol and stirring was started. Hydrazine monohydrate (1.62 g; (32.3 mmol) was dropped thereinto at 23° C. taking 30 minutes. After the dropping, the mixture was stirred at 85° C. for 15 hours. Followed by, heating was stopped and the mixture was cooled down to room temperature to precipitate the crystals. The crystals were filtered and washed with a small amount of 2-propanol. The resulting crystals were dried to give 1.50 g of the title compound. The yield was 63%. Ratio of anti-form to syn-form of the compound was measured by the same manner as in Example 4 and found that the anti/syn ratio was more than 99/1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:22]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (2 g, 9.99 mmol, 1.20 equip), dichloromethane (20 mL) and triethylamine (2.53 g, 25.00 mmol, 3.00 equip). To the resulting mixture was then slowly added benzoyl chloride (1.17 g, 8.32 mmol, 1.00 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to yield tert-butyl N-(1-benzoylpiperidin-4-yl)carbamate as a white solid. (ES, m/z) 305 [M+H]+
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH2:14][CH3:15])[CH3:13])[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[N:3]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1.[H-].[Na+]>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:11]=[C:10]([N:12]([CH2:14][CH3:15])[CH3:13])[C:9]4[CH2:8][CH2:7][CH2:6][CH:5]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:4]=4[N:3]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1
Reactant: CCN(C)c1nc(Cl)nc2c1CCCC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCCC2c1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 33.8 %

Procedure:
To a solution of 2-chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (42.9 mg, 0.142 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (31.8 mg, 0.142 mmol) in THF (2 mL) was added 60% suspension of sodium hydride in mineral oil (6.82 mg, 0.284 mmol). The reaction mixture was heated with stirring in a capped vial at 80° C. for 1.5 h. The reaction mixture was carefully partitioned between an aqueous solution of ammonium chloride and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by reverse-phase preparative HPLC to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine (31.6 mg, 0.048 mmol, 33.5% yield) as brown oil. LC-MS (M+H)+=489.2. 1H NMR (500 MHz, CDCl3) δ ppm 11.50 (1H, br s), 7.74 (1H, d, J=1.2 Hz), 7.39 (1H, dd, J=8.5, 2.1 Hz), 7.29 (2H, dd, J=4.9, 2.7 Hz), 7.21-7.27 (2H, m), 7.12-7.19 (3H, m), 7.07 (1H, d, J=1.5 Hz), 4.20 (1H, t, J=7.0 Hz), 3.80 (3H, s), 3.68-3.78 (2H, m, J=13.8, 7.0, 7.0, 7.0, 7.0 Hz), 3.31 (3H, s), 2.64-2.82 (2H, m), 2.27 (1H, ddd, J=13.3, 7.5, 5.2 Hz), 1.88-1.99 (1H, m), 1.74-1.85 (1H, m), 1.54-1.67 (1H, m), 1.34 (3H, t, J=7.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][C:5]=1[O:12][CH3:13])([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12>C1COCC1>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:8][N:37]1[C:33](=[O:43])[C:34]2[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:36]1=[O:38]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a 250 mL round bottomed flask containing 10 g (55 mmol) of 4-nitro-3-methoxybenzyl alcohol in 150 mL THF was added, diethylazodiacarboxylate (8.03 g, 54.6 mmol, 1 eq.) and triphenylphosphine (15.0 g, 57.3 mmol) followed by 11.6 g of phthalimide (57.3 mmol) at 0° C. Reaction was then allowed to gradually warm to room temperature over night. A white precipitate formed and was collected by suction filtration. Recrystallization from acetonitrile gave 13.8 g (81%) of the desired product. 1H NMR (400 MHz, d6-DMSO): δ 7.79 (m, 5H), 7.19 (s, 1H), 7.08 (d, J=8.80 Hz, 1H), 4.91 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[CH:7][CH:6]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[C:43]([CH2:45][C:46](O)=[O:47])#[N:44]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:46](=[O:47])[CH2:45][C:43]#[N:44])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2[C@@H]1CCCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[4-(2-fluorophenoxy)-phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (10 mL), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (60 mg, 0.37 mmol, 1.50 equiv), and 2-cyanoacetic acid (110 m/z, 1.29 mmol, 5.23 equiv). The resulting solution was stirred for 60 min at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.06 g (51%) of 3-[(3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a light yellow solid.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18]>C1COCC1>[CH2:1]([S:8][C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: NC(=O)c1cc(Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)ccc1SCc1ccccc1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
Benzyl mercaptan (0.61 mL, 5.20 mmol) was added dropwise over 10 min to a stirred suspension of sodium hydride (60% in oil, 230 mg, 5.75 mmol) in THF (10 mL) at ambient temperature under a nitrogen atmosphere. The white suspension was stirred for a further 1 h and then added dropwise to a stirred solution of 5-chloro-2-fluorobenzamide (900 mg, 5.20 mmol) in THF (10 mL), under nitrogen, over 10 min. The mixture was stirred at ambient temperature for 1 h, at 50° C. for 1 h and at reflux for 3 h and then quenched with water (200 mL). The product mixture was extracted with EtOAc (3×30 mL) and the combined extracts washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel with EtOAc:heptane (3:2, v/v) as eluent to give the title compound as a white solid (523 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:49]([OH:55])[CH2:50][O:51][CH2:52][CH2:53]O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:53][CH2:52][O:51][CH2:50][CH2:49][OH:55])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OCCOCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCOCCO)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (165 mg), diethyleneglycol (0.20 mL) and diethyl azodicarboxylate (0.10 mL). The mixture is stirred at room temperature for 2 hrs. The reaction mixture is concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 10% to 40% methanol in ethyl acetate and then by recrystallization from ethyl acetate to afford 68 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([SH:10])=[S:9])([CH3:4])([CH3:3])[CH3:2].[CH2:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([S:10][CH:20]([CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[S:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccccc1
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(SC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1ccccc1

Procedure:
A solution of 14.1 g (0.05 mol) 3,5-di-t-butyl-4-hydroxydithiobenzoic acid and 10.4 g (0.1 mol) styrene in 100 ml toluene was heated at reflux for about 1 hour. The reaction mixture was filtered through silica gel and evaporated under reduced pressure to give the product, m.p. 70°-72° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH3:23])([O-:22])=[O:21]>>[CH2:11]([N:10]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:23][N+:20]([O-:22])=[O:21])=[CH:3][C:2]=1[CH3:1])[CH2:13][CH3:14])[CH3:12]
Reactant: CCN(CC)c1ccc(C=O)cc1C
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])cc1C
Temperature: 100 °C
Yield: 45 %

Procedure:
A solution was prepared by dissolving 30 grams (0.16 mol) of 3-methyl-4-(N,N-diethylamino)benzaldehyde in 150 ml of nitromethane, and added with 5 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 17 grams of red crystals was obtained. The yield was 45%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](O)=[C:7]([Br:12])[N:6]=1)=[O:4].O=P(Cl)(Cl)[Cl:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:15])=[C:7]([Br:12])[N:6]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cnc(O)c(Br)n1
Product: COC(=O)c1cnc(Cl)c(Br)n1
Yield: 29 %

Procedure:
A mixture of 6-bromo-5-hydroxy-pyrazine-2-carboxylic acid methyl ester and 9.75 mL (10.7 mmol) POCl3 was refluxed for 3 h and subsequently quenched with 200 g ice. The mixture was extracted with DCM, the combined organic phases were dried with MgSO4 and evaporated to dryness the residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product fractions were combined and evaporated to dryness to yield 0.95 g (29%) of the title compound as light yellow solid. 300-MHz-1H-NMR (DMSO): δ=9.00 (s, 1H, 3-H), d=4.04 (s, 3H, OMe).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:4]2=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[N:20]1([CH2:26][CH2:27][C:28]2[N:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]3=[C:30]([C:37](Cl)=[O:38])[N:29]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[C:10]1([NH:11][C:37]([C:30]2[N:29]=[C:28]([CH2:27][CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=23)=[O:38])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2ccccc12
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2ccccc12)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of 1-naphylamine (0.077 g, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (58 mg, 32%). 1H NMR (DMSO-d6) δ 10.0 (1H), 8.45 (1H), 8.10 (1H), 7.98 (3H), 7.78 (1H), 7.55 (3H), 7.18 (1H), 6.93 (1H), 3.59 (4H), 3.30 (2H), 2.85 (2H), 2.57 (4H); m/z (M+H)=401.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: CCCCCCO
Product: CCCCCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 71 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 1-hexanol (10.2 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 71% yield (18.3 mg). 1H NMR (500 MHz, CDCl3) δ ppm 0.87-0.93 (m, 3 H) 1.27-1.36 (m, 4 H) 1.35-1.43 (m, 2 H) 1.65-1.74 (m, 2 H) 2.45 (s, 3 H) 4.26 (t, J=6.71 Hz, 2 H) 6.85 (s, 1 H) 7.36 (dd, J=8.08, 7.68 Hz, 1 H) 7.42 (ddd, J=8.08, 2.35, 1.28 Hz, 1 H) 7.44 (dd, J=8.69, 1.95 Hz, 1 H) 7.71 (dd, J=8.69, 0.55 Hz, 1 H) 7.71-7.72 (m, 1 H) 7.71 (dd, J=1.95, 0.55 Hz, 1 H) 7.84 (ddd, J=7.68, 1.50, 1.28 Hz, 1 H). MS (ESI+) m/z 466 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Toluene (50 mL) was placed into a round bottom flask and 3-cyano-4-isobutoxybenzothioamide (5.0 g) was added, followed by addition of ethyl-2-chloroacetoacetate (4.25 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25° C. and maintained at that temperature for about 20 minutes. The reaction mass was then filtered and the solid was washed with toluene (10 mL). The wet solid was dried at about 75° C. to a constant weight to yield 4.0 g of the title compound. Purity by HPLC: 99.41%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2>CO.O.[Pt](=O)=O>[OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1
Reactant: OCc1cnc2ccccc2c1
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: OCC1CNc2ccccc2C1
Reaction time: 6 h
Yield: 83.2 %

Procedure:
3-Hydroxymethylquinoline (0.45 g, 2.83 mmoles) (prepared as described in: B. R. Brown, D. Ll. Hammick and B. H. Thewlis, J. Chem. Soc., 1951,1145-1149.) was dissolved in methanol (100 mL) and placed in a Parr bomb. Platinum (IV) oxide monohydrate (0.225 g. 0.918 mmoles) was added and the mixture was hydrogenated at 50 psi at 25° C. for 6 h. The catalyst was removed by decantation and washed with methanol. The methanol was evaporated to dryness and the product was chromatographed on silica gel using 3% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (0.3843 g, 83%): CIMS: m/z 164.35 (MH+); δH (CDCl3) 6.50 (1H, d, Ar—H8), 6.64 (1H, t, Ar—H6), 6.98 (1H, d, Ar—H5) and 6.99 ppm(1H, m, Ar—H7); δC (CDCl3) CH2: 29.5, 44.0, 65.2; CH: 34.9, 114.2, 117.4, 126.9, 129.8; C: 120.2, 144.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([C:23](OC)=[O:24])[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)=[O:16])[CH:7]=[C:8]([C:10](OC)=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH2:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33]>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([C:23]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])=[O:24])[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)=[O:16])[CH:7]=[C:8]([C:10]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(NC(=O)c2cc(C(=O)OC)cc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Reactant: NC(CO)CO
Product: O=C(Nc1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1)c1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
3-Nitro-5-methoxycarbonylphenylaminocarbonyl-(3'-nitro-5'-methoxycarbonylbenzene) (0.40 g, 1.0 mmol) and serinol (0.23 g, 2.5 mmol) were mixed and heated to 95° C. After 30 min, the pressure was reduced to 200 mm Hg and heating was continued for 3 h. The reaction mixture was purified by preparative HPLC. Yield: 0.27 g (52%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=1)=[O:19])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:30][C:26]3[C:25]([F:31])=[CH:24][C:23]([CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:28][C:27]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 77.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.033 g, 0.143 mmol) obtained in Step C of Preparation Example 27 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (0.033 g, 0.143 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 77%).