Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:16])[C:12]([O:14][CH3:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.CO.[NH4+].[Cl-]>C1COCC1.[Zn]>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:16])[C:12]([O:14][CH3:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: COc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cn2ncnc(Oc3ccc(N)cc3F)c2c1C
Temperature: 60 °C
Yield: 47.3 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazine (35 mg, 0.11 mmol) in THF (1.0 mL) was added MeOH (1.0 mL) followed by Zn (100 mg, 1.5 mmol) and NH4Cl (43 mg, 0.80 mmol). The reaction was heated at 60° C. for 3 h. The solution was filtered through Celite® and concentrated in vacuo. The product mixture was purified by a SCX cartridge (eluted with ammonia in methanol (2 M) to give the title compound (15 mg, 50%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:43][CH2:44][CH2:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][Cl:43])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCCl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester from Route J step 7 (0.958 g, 1.88 mmol), in anhydrous methylene chloride (20 mL) at 0° C. was added triethylamine (1.32 mL, 9.42 mmol) followed by 4-chlorobutyryl chloride (0.32 ml, 2.83 mmol) dropwise. The reaction was allowed to stir at 0° C. for 1 h and then allowed to slowly warm to room temperature overnight. The methylene chloride was evaporated and the reaction mixture was dissolved in ethyl acetate and water. The organic layer was collected and washed with 10% sulfuric acid, brine, dried over magnesium sulfate, and concentrated to yield (S)-3-[2-benzyloxy-4-(4-chloro-butanoylamino)-benzenesulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester (1.32 g) as a crude brown oil. MS (APCI) m/z 611.3 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].C[O:18][C:19]([C:21]1C(N[C:25](=[O:27])[CH:26]=1)=O)=O.S(=O)(=O)(O)O>O>[C:25]1(=[O:27])[N:1]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[C:19](=[O:18])[CH:21]=[CH:26]1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: COC(=O)C1=CC(=O)NC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(CN2C(=O)C=CC2=O)cc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
A 3.02 g (20 mmols) portion of 4-aminomethylbenzoic acid was admixed with 100 ml of saturated aqueous solution of NaHCO3, and 3.1 g (20 mmols) of methoxycarbonylmaleimide was added to the mixture at 0° C. After stirring the mixture at 0° for 10 minutes, 200 ml of water was added thereto. The mixture was then stirred at 30° C. for 1 hour and thereafter adjusted to a pH of 2 with concentrated sulfuric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over Na2SO4 and concentrated, affording 3.18 g (yield 87%) of crude 4-maleimidomethylbenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:18][CH:19]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: Cc1cc(=O)cc(C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2ccc(-c3ccccc3C#N)cc2)cc(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
369 mg of 2,6-dimethyl-4(1H)-pyridone was dissolved in 5 ml of N,N-dimethylformamide. To this solution was added 144 mg of 60% sodium hydride, followed by stirring at room temperature for 15 minutes. Subsequently, 900 mg of 4-bromomethyl-2'-cyanobiphenyl was added to the mixture, and the mixture was stirred at room temperature for two hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, to which was added ethyl acetate. The precipitated crystals were collected by filtration and then dried, and, on the other hand, the filtrate was purified by a silica gel column chromatography (80 g, chloroform:ethyl acetate=3:1 to 2:3), whereby 296 mg and 329 mg of 2,6-dimethyl-4-(2'-cyanobiphenyl-4-yl)methoxypyridine were obtained, respectively (total amount: 625 mg, yield: 66%).
Reaction SMILES: [NH2-:1].[Li+].Cl[SiH:4]1[N:8]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:6][N:5]1[C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].CCCCCC>COCCOC>[NH2:1][SiH:4]1[N:8]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:6][N:5]1[C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1Cl
Reactant: [NH2-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
In an argon atmosphere, 439 mg (purity: 95%, 18.2 mmol) of lithium amide was suspended in 20 mL of 1,2-dimethoxyethane and after adding 6.07 g (17.6 mmol) of Si(tOctNCHCHNtOct)(H)Cl, the mixture was stirred at room temperature for 4 hours. To the reaction mixture, 20 mL of hexane was added, and the mixture was stirred at room temperature for 10 minutes. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 116° C./1.3×102 Pa) to obtain 2-amino-1,3-bis(1,1,3,3-tetramethylbutyl)-1,3-diaza-2-silacyclopent-4-ene (Si(tOctNCHCHNtOct)(H)NH2) as a pale yellow liquid (yielded amount: 4.99 g, yield: 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=1.[C:39]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=3)=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:7](=[O:14])[O:8]2)=[CH:3][C:2]=1[CH3:39]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1C
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 4-(6-bromo-7-methoxy-2-oxo-3-(4-trifluoromethyl-phenyl)-2H-chromen-4-ylmethyl)-phenyl ester (100 mg, 0.17 mmol), K2CO3 (70 mg, 0.51 mmol), trimethylboroxine (24 μL, 0.17 mmol) and Pd(Ph3P)4 (20 mg, 0.017 mmol) in anhydrous dioxane (2 mL) was stirred at reflux temperature for 2 h. After cooling to room temperature, the resultant suspension was filtered over Celite, and the solvent was removed in vacuo. The residue was recrystallized from CH2Cl2/hexane to afford the desired compound as a beige solid (72 mg, 82%) displaying. 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.22 (d, J=0.9 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (s, 1H), 4.02 (s, 2H), 3.91 (s, 3H), 2.16 (s, 3H), 1.35 (s, 9H); MS (ESI) m/z 524.9 (M+H)+, HPLC tR 7.81 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=1.CCOCC.O.[Cl:27]CCl>Cl>[Cl:27][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[CH:11][C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:14][CH:15]=1
Reactant: ClCCl
Reactant: COc1ccc(OC)c(C=Cc2ccc(CO)cc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1ccc(OC)c(C=Cc2ccc(CCl)cc2)c1
Yield: 68 %

Procedure:
2,5-Dimethoxystilbene-4'-methanol (1.18 g, 4.36 mmol) in dichloromethane (3 ml) and hydrochloric acid (10M, 100 ml) was stirred for 1 h at room temperature. Ether (100 ml) and water (100 ml) were added and the organic layer separated, washed with water (2×125 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane) to give 4'-chloromethyl-2,5-dimethoxystilbene (856 mg, 68%); δH ; (CDCl3) 3.83 (3 H, s, OCH3), 3.85 (3 H, s, OCH3), 4.59 (2 H, s, CH2Cl), 6.81 (1H, dd, J=8.8, 2.7 Hz), 6.85 (1 H, d, J=8.8 Hz), 7.10 and 7.49 (2 H, d, J=16.5 Hz, vinylic H), 7.17 (1 H, d, J=2.7 Hz), 7.37 and 7.53 (4 H, AA'BB'); δc (CDCl3) 46.1, 55.7, 56.0, 111.5, 112.2, 113.6, 123.9, 126.8, 128.4, 128.7, 136.4, 137.9, 151.4 and 153.6.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].N1C=CC=CC=1>O1CCCC1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C(N)=O)c(N)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C(=O)OC(C)(C)C)ccc1C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 157.2 %

Procedure:
Acetyl chloride (50 uL, 0.32 mmol) was added to a solution of 1,1-dimethylethyl 3-amino-4-(aminocarbonyl)benzoate (126 mg, 0.53 mmol) and pyridine (52 uL, 0.64 mmol) in tetrahydrofuran (3 mL) at 0° C., and the resulting mixture was stirred at 0° C. for one hour. The mixture was quenched with ice-water (10 mL) and extracted ethyl acetate (3×10 mL). The combined extract was washed with 15 mL, each of 5% aqueous citric acid, saturated aqueous sodium bicarbonate, and brine solutions then dried over sodium sulfate, filtered and concentrated to give the 1,1-dimethylethyl 3-(acetylamino)-4-(aminocarbonyl)benzoate (140 mg, 94% yield). MS (EI) for C14H18N2O4: 279 (MH+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][C:11]([OH:13])=O.O[N:15]1[C:36](=[O:37])[NH:35][C@H:34]2[C@@H:16]1[CH2:17][S:18][C@H:19]2[CH2:20][CH2:21][CH2:22][CH:23](N1C(=O)CCC1=O)[C:24](=[O:26])[OH:25]>CN(C=O)C>[CH3:8][NH:9][CH2:10][C:11]([CH:23]([CH2:22][CH2:21][CH2:20][C@H:19]1[C@@H:34]2[C@@H:16]([NH:15][C:36]([NH:35]2)=[O:37])[CH2:17][S:18]1)[C:24](=[O:25])[OH:26])=[O:13]
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Reactant: CNCC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 85 °C
Yield: 83.2 %

Procedure:
DMF (8.0 ml) and triethylamine (0.61 ml, 4.35 mmol) were added to solids N-methyl glycine (182 mg, 2.05 mmol) and N-hydroxy-succinimidyl biotin (500 mg, 1.46 mmol). The mixture was heated for 1 hour in an oil bath at 85° C. during which time the solids dissolved producing a clear and colorless solution. The solvents were then evaporated. The yellow oil residue was acidified with glacial acetic acid, evaporated and chromatographed on a 27 mm column packed with 50 g silica, eluting with 30% MeOH/EtOAc 1% HOAc to give the product as a white solid (383 mg) in 66% yield.
Reaction SMILES: [CH3:1][C:2]([C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)([CH3:6])[C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:40]([NH2:44])[CH:41]([CH3:43])[CH3:42]>C(Cl)Cl>[CH2:40]([NH:44][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:6])[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)(C(=O)O)c1nc(-c2ccccc2)no1
Reactant: CC(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)CNC(=O)C(C)(C)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
To a solution of 2-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propanoic acid (example 41a) (307 mg, 1.32 mmol) in CH2Cl2 (10 mL) were added HOBt (196 mg, 1.45 mmol), EDCI.HCl (278 mg, 1.45 mmol) and isobutylamine (146 μL, 1.45 mmol). The reaction was stirred at room temperature under N2 for 18 h. Upon completion, the reaction was concentrated and purified by flash-chromatography (0-75% EtOAc in Hexane) to yield N-isobutyl-2-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propanamide (198 mg, 52%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 0.81-0.83 (d, 6H, J=6.7 Hz), 1.66 (s, 6H), 1.70-1.80 (sept, 1H, J=6.7 Hz), 2.89-2.92 (t, 2H, J=6.4 Hz), 7.56-7.61 (m, 3H), 7.92-7.95 (t, 1H, J=5.6 Hz), 8.01-8.03 (m, 2H). MS(M+H, 288).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:48][C:49]12[CH2:56][CH:53]([NH:54][CH2:55]1)[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]2>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:54]2[CH2:55][C:49]3([CH3:48])[CH2:56][CH:53]2[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]3)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(OCc3ccccc3)cc2)C1
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
To a mixture of 4-benzyloxy-benzoic acid (0.5 g, 2.191 mmol) and HOBT (326 mg, 2.41 mmol) in dry THF (50 ml) was added EDAC (462 mg, 2.41 mmol). The resulting mixture was stirred for 10 min. followed by addition of a mixture of DIPEA (420 μl, 2.41 mmol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (410 μl, 2.41 mmol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. To the residue was added water (50 ml) and the resulting mixture was extracted with EtOAc (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:3) as eluent. Pure fractions were collected and evaporated to dryness affording 610 mg (77%) of the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:13])=[N:9][NH:10][C:11]=1[NH2:12].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH:23]=O)[CH:21]=O)=[CH:16][CH:15]=1>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([NH2:12])=[N:10][N:9]2[CH:23]=[C:20]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)[CH:21]=[N:13][C:8]=12
Reactant: O=CC(C=O)c1ccncc1
Reactant: Nc1n[nH]c(N)c1-c1ccccn1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nn2cc(-c3ccncc3)cnc2c1-c1ccccn1
Yield: 61.6 %

Procedure:
A mixture of 4-pyridin-2-yl-1H-pyrazole-3,5-diamine (290 mg, 1.66 mmol) and 2-pyridin-4-yl-malonaldehyde (247 mg, 1.66 mmol) were placed in ethanol (5 mL) with a catalytic amount of acetic acid (6 drops). The reaction mixture was submitted to microwave irradiations at 140° C. for 15 minutes. The crude mixture was cooled down to room temperature and the resulting precipitate was filtered and washed with more ethanol to provide the title as a golden yellow solid (295 mg, 62%). MS (ES+) 289, (ES−) 287. δH (DMSO-d6) 7.16 (1H, dd), 7.21 (2H, m), 7.84 (1H, m), 7.89 (2H, m), 8.57 (2H, br m), 8.65 (2H, d), 8.98 (1H, d), 9.44(1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].CNC(O)C.CC1C=C(NC2C3C(=CC=CC=3[O:44][CH2:45][CH2:46][NH:47][CH3:48])N=CN=2)C=CC=1O>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:44][CH2:45][CH2:46][NH:47][CH3:48])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20]
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Agent: CNC(C)O
Product: CNCCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 96 %

Procedure:
2-Chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol was reacted with N-methylaminoethanol using an analogous process to that described in Example 3 for the preparation of 2-methyl-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol, to give 2-Chloro-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol in 96% yield; NMR spectrum (DMSO-d6) 2.41 (s, 3H), 3.05 (t, 2H), 4.36 (t, 2H), 6.97 (d, 1H), 7.12 (d, 1H), 7.31 (d, 1H), 7.63 (1H, dd), 7.70 (t, 1H), 7.96 (s, 1H), 8.47 (s, 1H) 10.47 (bs, 1H); Mass spectrum MH+ 345.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:9][CH:10](OCC)[O:11][CH2:12][CH3:13])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:7]([O:9][CH:10]([O:11][CH2:12][CH3:13])[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH3:8]
Reactant: Cc1c[nH]cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(OCC)n1cnc(C)c1

Procedure:
4-Methylimidazole (16.4 g), triethylorthoformate (118.4 g), and p-toluene sulphonic acid (1 g) were mixed and heated at 130° until evolution of ethanol ceased (approximately 2 hours). Volatile material was removed in vacuo and the residue was distilled under vacuum from anhydrous sodium carbonate (1 g) to afford the title compound, b.p. 126°-130°/5 mm (22.06 g). The product was characterised spectroscopically and used without further purification (Preparation 26).
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:26][CH:27]([F:30])[CH2:28]I>>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:28][CH:27]([F:30])[F:26])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1OCC(F)F
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 6-(tert-butylsulfonyl)-4-chloroquinolin-7-ol (100 mg, 0.334 mmol) was added K2CO3 (138 mg, 1.001 mmol) followed by 1,1-difluoro-2-iodoethane (44.1 μl, 0.500 mmol). This was heated to 60° C. overnight. LCMS showed incomplete conversion. Additional 1,1-difluoro-2-iodoethane (44.1 μl, 0.500 mmol) was added and the reaction was stirred at 60° C. for 5 hr. Reaction was still not complete by LCMS, so another aliquot of 1,1-difluoro-2-iodoethane (44.1 μl, 0.500 mmol) was added and the reaction was stirred at 60° C. overnight again. LCMS showed complete and clean conversion to the desired product. The crude sample was purified via Biotage normal phase chromatography (25 g SNAP column, 0% -50%, 50% hex/EtOAc). The pure product containing-fractions were combined and concentrated leading to the product as an off-white solid: 6-(tert-butylsulfonyl)-4-chloro-7-(2,2-difluoroethoxy)quinoline (88.8 mg, 0.244 mmol, 73.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9H) 4.66 (td, J=14.53, 3.54 Hz, 2H) 6.28-6.63 (m, 1H) 7.80 (d, J=4.80 Hz, 1H) 7.85 (s, 1H) 8.67 (s, 1H) 8.97 (d, J=4.80 Hz, 1H). MS: m/z: 364.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: BrCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCCCBr)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
3.3 g of 2-(3,3,3-trifluoropropyl)malononitrile and 8.6 g of 1,4-dibromobutane were dissolved in 20 ml of dimethyl sulfoxide, 3.0 g of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.2 g of 2-(4-bromobutyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (63)).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11](Cl)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[N:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[N:23]1([CH:29]2[CH2:34][CH2:33][N:32]([C:11]3[C:12]([F:17])=[CH:13][N:14]4[C:9]([C:10]=3[CH3:19])=[C:8]([CH:20]3[CH2:22][CH2:21]3)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]4=[O:16])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Solvent: CC#N
Product: Cc1c(N2CCC(N3CCCCC3)CC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A 70 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 4-(1-piperidyl)piperidine (70 mg, 0.4 mmol, Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the title product. MS 428 (M+H)+ ; 1H NMR (CDCl3) ∂: 0.69 (m, 2H), 1.02 (m, 2H), 1.18 (m, 4H), 2.27 (n, 1H), 2.78 (s, 3H), 2.72 (m, 1H), 3.35 (m, 3H), 3.55 (m, 1H), 3.75 (m, 1H), 8.36 (s, 1H), 9.20 (d, 1H). Anal. Calcd for C24H30 N3O3F.1.5 H2O: C, 63.42; H, 7.32; N, 9.24; Found: C, 62.99; H, 7.04; N, 8.78.
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].CC([O-])(C)C.[K+]>C1COCC1>[CH2:19]([O:18][C:14]([CH:15]1[C:3](=[O:13])[CH2:4][N:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[CH2:16]1)=[O:17])[CH3:20]
Reactant: C=CC(=O)OCC
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of BOC glycine methyl ester (J. Med. Chem. 2001, 44, 8, 1192-1201) (19.2 g, 101.5 mmol) in THF at 0° C. was added dropwise ethyl acrylate (11 mL, 101.5 mmol) over 10 minutes. The solution was stirred for 20 minutes, then KOtBu (111.65 mL, 111.65 mmol) was added over 45 minutes. The solution was allowed to warm to 25° C. overnight. The resulting solution concentrated in vacuo and portioned between ethyl acetate and water containing 5 mL of acetic acid. The ethyl acetate layer was removed and aqueous layer extracted with 2×200 mL of ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford an oil. MS (DCI/NH4) m/z=258 (M+H)+, 275 (M+NH4)+.