Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[CH3:7][NH:8][C:9]1([CH3:19])[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH3:5][O:4][C:2]([N:8]([CH3:7])[C:9]1([CH3:19])[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: CNC1(C)CC(C)(C)CC(C)(C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(C)C1(C)CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
Methyl chloroformate (0.97 g, 0.8 ml, 10.3 mmol) was added in one portion to a suspension of N,1,3,3,5,5-hexamethylcyclohexanamine hydrochloride (5-20) (1.13 g, 5.13 mmol) and Na2CO3 (1.63 g, 15.4 mmol) in THF (30 ml). The resulting mixture was stirred at room temperature for 6 h, and then it was diluted with water (50 ml) and extracted with ether (3*30ml). The combined organic phases were washed with 10% K2SO4, saline, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography, eluting with hexane-ethyl acetate mixture (6:1) to give 0.90 g (78%) of (15) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:11](=O)([O:14]C)[O:12][CH3:13].[H-].[Na+]>CO>[CH3:1][C:2]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:11]([O:12][CH3:13])=[O:14])[C:3]1=[O:9]
Reactant: COC(=O)OC
Reactant: CC1(C)CCCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCCC(C)(C)C1=O
Temperature: 25 °C

Procedure:
A mixture of Example 1A (2.104 g, 15.00 mmol) and 5 drops of MeOH in dimethyl carbonate (12.7 mL, 151 mmol) was treated with sodium hydride (60% dispersion, 1.200 g, 30.0 mmol). The reaction was then refluxed for 2 hours before being cooled back to room temperature. The reaction was quenched with 2M HCl and extracted with ether, then chromatographed on silica gel (3 to 12% EtOAc-hexane, eluant) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 4.15 (m, 1H), 3.58 (s, 3H), 2.02 (m, 1H), 1.61-1.77 (m, 5H), 1.30-1.44 (m, 2H), 1.11 (s, 3H), 1.01 (s, 3H). MS (DCI+) m/z 216 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:21]=[C:22]([CH2:26][NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:23]=[N:24][CH:25]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:27]([CH2:26][C:22]1[CH:23]=[N:24][CH:25]=[C:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][CH:12]=[CH:13]3)[CH:21]=1)[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C)CCNCc1cncc(-c2ccc3[nH]ccc3c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(Cc1cncc(-c2ccc3[nH]ccc3c2)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
4-Fluorobenzoyl chloride (111 mg, 0.7 mmol) was added to a solution of N′-[5-(1H-indol-5-yl)-pyridin-3-ylmethyl]-N,N-dimethyl-ethane-1,2-diamine (160 mg, 0.54 mmol) and triethyl amine (109 mg, 1.08 mmol) in 15 mL of dichloromethane at room temperature. The resulting mixture was stirred at ambient temperature overnight, and then a further 111 mg of 4-fluorobenzoyl chloride was added and the mixture stirred for an additional 2 h. The volatiles were removed in vacuo to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 231 mg of material. This was dissolved in dichloromethane and washed with 1M sodium hydroxide solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to leave material which was further purified by HPLC (elution with acetonitrile/water/TFA) to give 21 mg of product. LC/MS (long run): Retention time, 3.85 min; (M+H)=417.
Reaction SMILES: C(OC(N1CCN[C@@H](C)C1)=O)(C)(C)C.[ClH:15].[CH3:16][CH:17]1[CH2:22][NH:21][CH2:20][CH:19](C)[N:18]1[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[ClH:15].[CH3:16][C@@H:17]1[N:18]([C:24]2[N:25]=[CH:26][CH:27]=[CH:28][N:29]=2)[CH2:19][CH2:20][NH:21][CH2:22]1
Reactant: CC1CNCC(C)N1c1ncccn1
Agent: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Product: C[C@H]1CNCCN1c1ncccn1

Procedure:
Using (3S)-1-tert-butyloxycarbonyl-3-methylpiperazine, reactions similar to those in Example 1 (2), (3) were successively performed to give (3S)-3-methyl-4-pyrimidin-2-ylpiperazine hydrochloride, then reactions similar to those in Example 1 (4) were successively performed to give the title compound (216 mg).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:6]1)=O.[BH4-].[Na+].[NH4+].[Cl-].CC(C)=O>CCO>[OH:2][CH2:3][CH:5]1[CH2:6][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8](=[O:10])[CH2:9]1
Reactant: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc(CN2CC(CO)CC2=O)cc1
Temperature: 12 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer and reflux condenser, under inert atmosphere, a solution of 8.48 g (32 mmol, 1 eq) of 1-(4-methoxy-benzyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester al in 120 ml of EtOH is cooled down to 0° C. Solid NaBH4 (3.6 g, 96 mol, 3 eq) is then added by portions over 1.5 h, all the while maintaining the temperature between 2 and 4° C. After 2 h, the temperature is raised to 12° C. for 1 h, and lowered again to 2–4° C. A saturated solution of NH4Cl (240 ml) is added dropwise over 1 h, followed by 120 ml of acetone, and the mixture is left overnight at room temperature. The mixture is extracted by CH2Cl2 (3 times), dried on MgSO4, filtered and concentrated in vacuo to afford the crude alcohol which is purified by chromatography on silicagel (CH2Cl2/MeOH: 95/05 (v/v)) to give the pure alcohol a2 (4.3 g, 57%).
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31](=O)[C:32]([CH3:43])([C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)[CH3:33]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:32]([CH3:43])([C:34]3[CH:35]=[C:36]([F:42])[C:37]([F:41])=[C:38]([F:40])[CH:39]=3)[CH3:33])[CH:30]=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: CN(C)C=CC(=O)C(C)(C)c1cc(F)c(F)c(F)c1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2nccc(C(C)(C)c3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(C)c1
Yield: 21 %

Procedure:
The title compound was prepared in analogous manner as described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate and 1-dimethylamino-4-methyl-4-(3,4,5-trifluoro-phenyl)-pent-1-en-3-one as a pale-brown solid in 21% yield.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([S:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(Sc2ccncc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Sc2ccncc2)c2ccccc2c1=O

Procedure:
The product from Example 191B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.44-8.35 (m, 3H), 8.05-7.92 (m, 3H), 7.44-7.35 (m, 4H), 7.29-7.22 (m, 2H), 3.71 (s, 2H); MS (DCI+) M/Z 423 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@H:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reaction time: 1 h

Procedure:
(S)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate (31 g, 127.95 mmol) was dissolved in MeOH (400 ml), and Pd/C (5%, 6 g) was added, followed by stirring under H2 (gas) for 1 hour. After the completion of the reaction, the reaction mixture was filtered through celite, followed by drying, and then the next reaction was advanced.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCCCl)cc1
Reaction time: 20 h

Procedure:
Combine 4-hydroxybenzophenone (8 kg, 57.6 mol), potassium carbonate (8 kg, 57.6 mol), and 1-bromo-4-chlorobutane (8.384 kg, 48.9 mol) in acetone (40 L). Heat to reflux. After 20 hours, cool the reaction mixture and filter. Rinse the filter cake with acetone and evaporate the filtrate in vacuo to obtain 4-(4-chlorobutoxy) benzophenone.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:23]([F:26])([F:25])[F:24])[NH:15]1.[N:27]1([C:33]2[N:34]=[C:35]([CH2:40][C:41]([O-])=[O:42])[NH:36][C:37](=[O:39])[CH:38]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+]>CN(C)C=O.N1C=CC=CC=1.O>[CH3:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:23]([F:24])([F:26])[F:25])[N:15]1[C:41](=[O:42])[CH2:40][C:35]1[NH:36][C:37](=[O:39])[CH:38]=[C:33]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:34]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2c(cccc2C(F)(F)F)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(cccc2C(F)(F)F)N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
225 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 196 mg of 2-methyl-4-trifluoromethyl-2,3-dihydro-1H-indole are added to a solution of 259 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 3 ml of N,N-dimethylformamide and 3 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours and then diluted with water and extracted with ethyl acetate. The extracts are washed successively with water, a hydrochloric acid solution (1M), water and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 144 mg of 2-[2-(2-methyl-4-trifluoromethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one in the form of a white solid.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=O.[CH2:9]([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O>[CH3:6][CH:4]1[N:15]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:1](=[O:8])[CH2:2][CH2:3]1
Reactant: CCCCCCN
Reactant: CC(=O)CCC(=O)O
Solvent: O
Product: CCCCCCN1C(=O)CCC1C

Procedure:
The feedstock used in examples 31 through 38 was 30% of the ammonium salt of levulinic acid, 26% hexylamine, and 24% water by weight. The temperature and pressure of the reactions were maintained at 150° and 6.9 MPa. Water was used as the solvent medium for the reactions. The results are set forth in the following table.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C[O-].[Na+].[C:12](O)(=[O:14])C>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:14][CH3:12]
Reactant: N#Cc1ccccn1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 6 h

Procedure:
2-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in methanol (50 ml). Sodium methoxide (0.26 g, 4.8 mmol) was added to the solution, and reaction was conducted for 6 hours at room temperature. After the reaction was completed, acetic acid (0.32 g, 5.3 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (50 ml) was added to the concentrated residue, and diethyl ether insoluble products were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 2-pyridinecarboximidate as a pale yellow oil in a yield of 7.5 g.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)=[O:5]>C(O)C.[Pd]>[CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)=[O:5]
Reactant: CON(C)C(=O)c1ccc2occc2c1
Agent: [Pd]
Solvent: CCO
Product: CON(C)C(=O)c1ccc2c(c1)CCO2
Reaction time: 6 h

Procedure:
A solution of benzofuran-5-carboxylic acid methoxy-methyl-amide (Intermediate P, 235 mg, 1.145 mmol) in ethanol (20 ml) is hydrogenated over 10% Pd on carbon (30×4 mm CatCart®) at 40° C. and 30 bar using the H-Cube Hydrogenator. After 6 hrs the reaction is complete and the reaction mixture is concentrated in vacuo to give an oil; MS m/z=208.1 [M+H]+; H NMR 400.13 MHz (CDCl3)-7.6 (1H, s), 7.55 (1H, d), 7.8 (1H, d), 4.6 (2H, t), 3.6 (3H, s), 3.35 (3H, s), 3.25 (2H, t).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([OH:30])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-5-nitropyridine (547 mg, 3.45 mmol) and 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methoxyphenyl)benzamide (1.03 g, 3.33 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.92 g, 13.9 mmol), and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate (75 mL)/hexane (75 mL). The obtained suspension was washed with water (50 mL×3), and the combined aqueous layer was extracted with ethyl acetate (75 mL)/hexane (75 mL). The organic layer were combined, washed with saturated aqueous ammonium chloride solution (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)-N-{4-methoxy-3-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide as a brown oil. This was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C@:8]2([CH3:22])[CH2:14][C@@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][CH2:11][C:10]([NH2:21])=[N:9]2)[CH:7]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:21][C:10]1[CH2:11][O:12][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:23])([CH3:22])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](c2ccccc2)OCC(N)=N1
Reactant: O=C(O)c1ccc(F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)C[C@@H](c2ccccc2)OCC(N)=N1

Procedure:
The compound was prepared in an analogous manner as described for the preparation of the amides Ia from (5S ,7S)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-7-phenyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (intermediate A10G) and 5-fluoropyridine-2-carboxylic acid. The title compound was obtained as a white solid. MS (ISP): m/z=437.3 [(M+H)+].
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=O.N1CCCCC1>C(Cl)(Cl)Cl>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][C:26]([F:27])([F:28])[F:29])=[C:17]([Cl:16])[CH:18]=1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: O=C(C=Cc1ccc(OC(F)(F)F)c(Cl)c1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A mixture of 2.25 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 2.25 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 20 ml of chloroform and 0.7 ml of piperidine was heated under refluxing for 2 hours and 30 minutes. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography. Resulting crystals were washed with 40 ml of t-butyl methyl ether to obtain 1.49 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (1c-6)] was obtained as a yellow crystal.
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](=[O:19])([O:15][CH2:16][CH:17]=[CH2:18])OCC=C>[Cl-].[Zn+2].[Cl-]>[C:10]([O:15][CH2:16][CH:17]=[CH2:18])(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)OCC=C
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: C=CCOC(=O)c1ccccc1
Temperature: 60 °C
Yield: 82 %

Procedure:
In a glass reactor benzoyl chloride (7.03 g, 0.05 mole), diallyl carbonate (7.1 g, 0.05 mole) and zinc chloride (0.136 g, 0.001 mole) were combined. The reacinitiated at room temperature. After heating at 60° C. for 3 hours and heating at 80° C. for an additional 3 hours, the reaction was discontinued. Distillation gave 6.65 g (78 percent yield) of allyl benzoate which was identified by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[N+:17]([CH:20]=[CH:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)([O-:19])=[O:18]
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccc2cc[nH]c2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of indole-6-carboxaldehyde (2.8 g), nitromethane (30 mL) and ammonium acetate (0.560 g) was stirred at 100° C. for 30 minutes. The excess nitromethane was removed under reduced pressure and the residue washed with water, dissolved in ethyl acetate (500 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to a volume of about 50 mL. This solution was then diluted with petroleum ether and the resulting suspension filtered and dried to provide 3.3 g (91%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1.[ClH:52]>CCOCC>[ClH:52].[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 80.35 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (step 1, example 39) (370 mg, 0.52 mmol) was deprotected in ether (5 ml) and HCl in ether (3 ml). This afforded 270 mg (80.35% yield) of the titled compound. MS: m/z=607.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=1)[C:14]([O:16]C)=[O:15].[OH:36][Li].O>C1COCC1.O>[C:14]([CH:13]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][O:25][Si:26]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:34])[CH3:35])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1)[CH2:12][NH:3][C:2]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:4]([OH:11])=[O:36])=[O:1])([OH:16])=[O:15]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(C(CNC(=O)c2ccccc2C(=O)O)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
To methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoate (E134) in THF/H2O was added LiOH.H2O, and the solution was stirred for 1.5 h or until conversion to product was visible by LC-MS. The solution was then poured into EtOAc/NH4Cl(sat)/1 N HCl (3:1) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated to give crude 2-(2-carboxy-2-(4-((triisopropylsilyloxy)methyl)phenyl)ethylcarbamoyl)benzoic acid (E135).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[F:21][C:22]([F:28])([F:27])[CH:23]([OH:26])[CH2:24]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:24][CH:23]([OH:26])[C:22]([F:28])([F:27])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C#N)nn1
Reactant: OC(CBr)C(F)(F)F
Product: CCN(Cc1cc(Br)ccc1OCC(O)C(F)(F)F)c1ccc(C#N)nn1

Procedure:
The title compound was prepared by reacting 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-3-cyanopyridazine with 1,1,1-trifluoro-3-bromo-propan-2-ol using a method similar to that of reference example 4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.C1(C)C=CC=CC=1>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CNC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: -20 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
A toluene solution (33.0 ml) of N-acetylglycine ethyl ester (1.00 g, 6.89 mmol) and N-methylimidazole (679 mg, 8.27 mmol) was cooled to −20° C., and palmitoyl chloride (1.89 g, 6.89 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 30 minutes at the same temperature, titanium tetrachloride (4.57 mg, 24.12 mmol) and triethylamine (2.79 g, 27.56 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −20° C. Water (20 mL) was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 1.75 g of the title compound (yield: 66%).