Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]([CH2:19][CH3:20])=[CH2:18]>C(Cl)Cl>[CH2:19]([C:17]1([CH2:16][O:15][CH2:14][O:13][CH3:12])[CH2:18][O:9]1)[CH3:20]
Reactant: C=C(CC)COCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC1(COCOC)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
m-Chloroperbenzoic acid (143.7 g, 833 mmol) was gradually added to a solution of 2-methoxymethoxymethyl-1-butene (98 g, 757 mmol) prepared in Reference Example 206 in methylene chloride (8800 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water, 10% sodium sulfide aqueous solution and sodium hydrogencarbonate aqueous solution, dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-ethyl-2-methoxymethoxymethyloxirane (111 g, quantitative) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][NH2:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][NH:12][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1CN
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])ccc1CNS(C)(=O)=O
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a stirred solution of (2-methyl-4-nitrophenyl)methanamine (178 mg, 1.071 mmol) in pyridine, cooled to 0° C., were added methane sulfonylchloride (0.16 mL, 2.0349 mmol). The resulting reaction mixture was stirred for 2 h. The mixture dissolved in dichloromethane and washed with 1N HCl. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain N-(2-methyl-4-nitrobenzyl)methanesulfonamide (100 mg, 38%).
Reaction SMILES: [C:1]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]([NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: O=C(Nc1cccc2ccccc12)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1C(=O)Nc1cccc2ccccc12
Reaction time: 16 h

Procedure:
To a solution of N-naphthyl(2-nitrophenyl)carboxamide in ethanol was added Pd/C and the mixture was stirred under an atmosphere of hydrogen for 16 hours. Pd/C was removed by filtration and the solvent was evaporated. The resulting oil was dissolved in ethyl acetate and extracted with aqueous HCl. The aqueous layer was neutralized and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give (2-aminophenyl)-N-naphthylcarboxamide, a compound of Formula I.
Reaction SMILES: CC(C)([O-])C.[Na+].C([Li])CCC.[C:12]1([CH:18]2[S:23][CH2:22][CH2:21][CH2:20][S:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:25][C:26]1[CH:30]=[CH:29][O:28][CH:27]=1>CCCCCC.C1COCC1>[C:12]1([C:18]2([CH2:25][C:26]3[CH:30]=[CH:29][O:28][CH:27]=3)[S:19][CH2:20][CH2:21][CH2:22][S:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1ccoc1
Reactant: c1ccc(C2SCCCS2)cc1
Agent: CC(C)(C)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(C2(Cc3ccoc3)SCCCS2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred suspension of sodium tert-butoxide (5.16 g, 54 mmol) in dry hexane (120 mL) was added n-butyl lithium (34 mL, 51 mmol) at 0° C. and stirred for 1 h at 0° C., and then for 1 h at room temperature. The mixture was cooled to −78° C., and transferred to a preformed mixture of 2-phenyl-[1,3]dithiane (10.0 g, 51 mmol) dissolved in dry THF (120 mL) at −78° C., and n-butyl lithium (34 mL, 51 mmol) and kept for 15 min. A dark brown colored solution was observed. After stirring for 1 h at −78° C., 3-bromomethyl-furan (Danso-Danquah R. E. and Scott A. I. Tetrahedron, 1993, 49, 8195-8210; New D. G. et al, J. Org. Chem., 1996, 61, 1578-1598) (10.7 g, 66 mmol) was added via canula. After 30 min., the reaction mixture was quenched with water and warmed to ambient temperature. The reaction mixture was extracted with diethyl ether, and the organic extracts were dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography using 0.2-0.5% ethyl acetate in hexane as eluent. Yield: 5.6 g, 32%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:9]=[CH:10][C:11]=2[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:6](=O)[CH:7]=1.CCN(C1C=CC=CC=1)CC.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:6]1[N:5]2[N:9]=[CH:10][C:11]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-c2cnn3c(=O)cc(C)[nH]c23)c(C)c1
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc(C)c(-c2cnn3c(Cl)cc(C)nc23)c(C)c1
Yield: 94 %

Procedure:
A suspension of 5-methyl-3-(2,4,6-trimethyl-phenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (590 mg, 2.2 mmol) in 9 ml of POCl3 was treated with diethylaniline (0.7 ml) and the resulting mixture was stirred at reflux for 15 hours. The reaction mixture was concentrated to dryness. The residue was treated with ice water and stirred for 20 min, then extracted with chloroform. The organic layer was dried and concentrated to yield an orange oil which crystallized upon standing. The material was purified through silica gel column chromatography using chloroform as eluent to give 590 mg (94%) of the title compound as a yellow solid; 1H NMR (CDCl3) ä 8.08(s, 1H), 6.98(s, 2H), 6.86(s, 1H), 2.56(s, 3H), 2.33(s, 3H), 2.09(s, 6H) ppm.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].[CH:12]([Mg]Br)([CH3:14])[CH3:13].C(OCC)C.[Cl-].[NH4+]>O1CCCC1.O>[CH3:13][CH:12]([CH3:14])[CH:10]([C:2]1[NH:1][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)[OH:11]
Reactant: CC(C)[Mg]Br
Reactant: O=Cc1cc2ccncc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
1H-Pyrrolo[2,3-c]pyridine-2-carboxaldehyde (125 mg, 0.86 mmol) was suspended in tetrahydrofuran (5 mL) at −30° C. under a nitrogen atmosphere. Isopropylmagnesium bromide in diethyl ether (0.87 mL, 1.74 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature. After stirring for ca. 3 h, the reaction mixture was cooled to −30° C. and additional 2.0 M isopropylmagnesium bromide in diethyl ether (0.22 mL, 0.44 mmol) was added. The reaction mixture was stirred for another 1 h, while warming to room temperature. The reaction mixture was poured into a 2:1 solution of saturated ammonium chloride and water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was purified by Biotage chromatography (2 to 10% methanol in methylene chloride) to provide 2-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1-propanol (86 mg, 53%) as a white solid: mp 140-144° C.; 1H NMR (500 MHz, CD3OD) δ0.99 (6H, m), 2.01-2.25 (1H, m), 4.57-4.65 (1H, m), 6.38 (1H, s), 7.51 (1H, s), 8.00 (1H, s), 8.63 (1H, s); ESI MS m/z 191 [C11H14N2O+H]+; HPLC (Method A) >99% (AUC), tR=13.1 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:15]2[C:16]3[C:8]([CH2:9][CH2:10][C:11]=3[CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)(=O)[CH3:2].IC1C=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O.[OH-].[K+]>O.[Cu].C(O)CC(C)C>[C:21]1([CH3:24])[CH:20]=[CH:19][C:1]([NH:4][C:5]2[C:15]3[C:16]4[C:8]([CH2:9][CH2:10][C:11]=4[CH:12]=[CH:13][CH:14]=3)=[CH:7][CH:6]=2)=[CH:2][CH:22]=1
Reactant: Cc1ccc(I)cc1
Reactant: CC(=O)Nc1ccc2c3c(cccc13)CC2
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Solvent: CC(C)CCO
Product: Cc1ccc(Nc2ccc3c4c(cccc24)CC3)cc1
Temperature: 200 °C
Reaction time: 6 h
Yield: 72.3 %

Procedure:
7.39 g (0.035 mol) of the above prepared 5-(N-acetylamino)acenaphthene was mixed with 10.91 g (0.05 mol) of p-iodo toluene, 0.32 g (0.005 mol) of copper powder, 5.52 g (0.04 mol) of anhydrous potassium carbonate and 10 ml of nitrobenzene, and the mixture was stirred at 200° C. for 6 hours. The reaction was determined to be finished when disappearance of 5-(N-acetylamino)acenaphthene was identified. To the resultant reaction mixture, was added an aqueous solution having 10 ml of isoamyl alcohol and 9.8 g (0.15 mol) of 85% potassium hydroxide dissolved in 10 ml of water, and the resultant mixture was subjected to hydrolysis reaction at 130°-140° C. for 4 hours. After identifying the end of the hydrolysis reaction, 100 ml of water was added thereto, and isoamyl alcohol and nitrobenzene were distilled off by azeotropic distillation. 100 ml of toluene was then added to the remaining material to dissolve the reaction product, and the toluene layer was separated. The toluene layer was washed with 100 ml of water, and was concentrated. An oily product thus obtained was purified by column chromatography (carrier: silica gel, eluent: toluene/hexane=1/4). As this result, 6.56 g (yield: 72.3%, melting point: 96.2°-96.8° C.) of 5-[N-(4-tolyl)amino]acenaphthene was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C:6]3[CH:16]=[CH:15][C:9]4[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=4[CH:7]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-acetamide (Example 153a) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 209-211° C. (diethylether)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(O)(=[O:17])C>[O-2].[O-2].[O-2].[Cr+6]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=[O:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Nc1cc2c(cc1Br)CCC2
Agent: [Cr+6]
Agent: [O-2]
Product: CC(=O)Nc1cc2c(cc1Br)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 5-acetylamino-6-bromoindane (43.0 g, 0.17 mol) in glacial acetic acid (400 mL) at 50°-55° C. was added dropwise a solution of chromium trioxide (70.0 g, 0,7 mol) in 50% aqueous acetic acid (400 mL) over a period of 30 min. After further stirring for 15 min, the mixture was cooled to 0° C. and quenched with 2-propanol (100 mL). Solvent was removed in vacuo. The residue was diluted with water (1 L) and extracted with ethyl acetate (2×500 mL). The combined ethyl acetate layer was washed with 0.5M aqueous NaOH (1 L), brine, dried over anhydrous MgSO4 and concentrated to give 36 g (80%) of the title compound as a light brown solid which was contaminated with about 10% of 5-bromo-6-acetylamino- 1-indanone. 1H NMR (CDCl3): δ8.60 (1H, s), 7.98 (1H, s), 7.90 (1H, s), 3.10 (2H, t), 2.70 (2H, t), 2.30 (3H, s).
Reaction SMILES: Br[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COC(OC)C.O.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>[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[N:6]1[CH:2]=[C:3]([N+:8]([O-:10])=[O:9])[N:4]=[C:5]1[CH3:7]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: Cc1nc([N+](=O)[O-])c(Br)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(C)OC
Agent: [Ba+2]
Solvent: O
Product: Cc1cc(C)c(-n2cc([N+](=O)[O-])nc2C)c(C)c1
Yield: 70.8 %

Procedure:
A solution of 5-bromo-2-methyl-4-nitroimidazole (5.0 g, 24 mmol), mesitylboric acid (3.96 g, 24 mmol), Pd(PPh3)4 (1.4 g, 1.2 mmol) and barium hydroxide octahydrate (19.1 g, 61 mmol) in 2,2-dimethoxyethane (150 mL) and water (25 mL) was heated at reflux for four hours. After filtered through Celite, the filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crystals were washed with ethyl acetate, to give the title compound (4.17 g) as white crystals.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([O:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.7 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.7 mg, 23.6% yield) as a thick oil: 1H NMR δ 7.46 (s, 2H), 7.40-7.30 (m, 4H), 7.25 (m, 3H), 7.20 (m, 2H), 6.97 (apparent d, 1H, J=7.4 Hz), 6.89 (apparent tt, 1H, J=0.8, 7.6 Hz), 6.84 (apparent dt, 1H, J=0.8, 8.0 Hz), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.35 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 457.4 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH:16]=[O:17].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][C:16]([OH:20])=[O:17]
Reactant: CC(C)=O
Reactant: COc1ccccc1C1CCCCC1CC=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccccc1C1CCCCC1CC(=O)O
Yield: 84 %

Procedure:
Combine [2-(2-methoxy-phenyl)-cyclohexyl]-acetaldehyde (0.336 g, 1.45 mmol), and acetone (10.0 mL). Add dropwise Jones reagent until color goes from green to orange and persists for several minutes (approximately 1.0 mL). Then concentrate on rotovap then add ethyl acetate and wash excess chromium away with brine washes. Dry over anhydrous sodium sulfate, concentrate to yield the titled compound (0.301 g, 84%). TLC Rf=0.13 in 20% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.2 (m, 1H), 7.0 (m, 1H), 6.8 (m, 2H), 3.8 (s, 3H), 3.3 (m, 1H), 2.6 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.6 (m, 8H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:23][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNCCc1ccccn1
Product: CN(CCc1ccccn1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with N-methyl-2-(pyridine-2-yl)ethanamine (1.2 equiv) to give 169 (14.4 mg, M+1 432.1)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1.[N-:14]=[N+]=[N-].[Na+]>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH3:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[O:5][CH2:4][CH2:3][CH2:2][NH2:14]
Reactant: Cc1ccc(OCCCCl)cc1C
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(OCCCN)cc1C
Yield: 97 %

Procedure:
9.05 (45.6 mnol) of 1-chloro-3-(3,4-dimethylphenoxy)- propane obtained in step 1 was dissolved in 200 ml of toluene. To the resulting solution were added 14.8 g of NaN3, 2.9 g of n-Bu4NBr and 15.2 g of KI and the mixture was refluxed For 24 hours. The reaction mixture was washed with water and concentrated under a reduced pressure. The resulting residue was purified by chromatography (ethyl acetate: hexane=1:10) to obtain 9.04 g (yield 97%) of the title compound as a brown oil.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])=[CH:14][CH:13]=1)=O.C([O-])(O)=O.[Na+].[C:41]([NH:48][CH2:49][CH2:50][NH2:51])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>O.CC#N>[C:44]([O:43][C:41]([NH:48][CH2:49][CH2:50][NH:51][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][CH2:22][CH:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:14][CH:13]=1)=[O:8])=[O:42])([CH3:45])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A solution of N-{4-[(2,5-dioxoazolidinyloxy)carbonylamino]phenyl}(fluoren-9-ylmethoxy)carboxamide (16.10 g, 34.15 mmol, 1.0 eq) in H2O/CH3CN (1/1, v/v, 360 mL) is reacted at room temperature with NaHCO3 (2.86 g, 34.15 mmol, 1.0 eq) and N—BOC-ethylenediamine (5.47 g, 34.15 mmol, 1.0 eq). After stirring overnight at room temperature, the reaction mixture is filtered to afford 16.36 g of the expected crude product as a white solid.
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[N:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1.C1(N2C3C(O[C@@H]([C@@H]4CC(=O)NC4)C)=NC(C4C=CC(N5CCN(C(OC(C)(C)C)=O)CC5)=C(F)C=4)=CC=3N=C2)CC1>>[CH:9]1([N:6]2[C:5]3[C:12]([O:14][C@@H:15]([C@@H:17]4[CH2:18][C:19](=[O:22])[NH:20][CH2:21]4)[CH3:16])=[CH:13][C:2]([C:28]4[CH:27]=[CH:26][C:25]([N:39]5[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:41][CH2:40]5)=[C:24]([F:23])[CH:29]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Reactant: C[C@@H](Oc1cc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
Following the procedure described for intermediate from Step-3 in Example 3.100, starting from combined (R)-4-((R)-1-((5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one (250 mg, 0.69 mmol) and tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (348.59 mg, 0.86 mmol) (B11), 250 mg tert-butyl 4-(4-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-2-fluorophenyl)piperazine-1-carboxylate was synthesized.
Reaction SMILES: C(N1C[C@H](OCC)[C@H](NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)C1)(=O)C.[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:40]1[N:41]=[C:42]([CH2:58][CH3:59])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH2:56][F:57])[CH2:52][NH:51][CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47].Cl[C:61]([O:63][CH3:64])=[O:62]>>[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:40]1[N:41]=[C:42]([CH2:58][CH3:59])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH2:56][F:57])[CH2:52][N:51]([C:61]([O:63][CH3:64])=[O:62])[CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47]
Reactant: COC(=O)Cl
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CNC[C@@H]1OCCF
Agent: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OC)C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrolidin-3-yl]pyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (DMSO-d6) δ 1.08, 1.15, 2.37, 2.65, 3.54, 3.60, 3.71, 3.82, 4.25, 4.43, 4.54, 5.93, 6.98, 7.10, 7.26; IR (liq.) 2972, 2068 (w), 1996 (w), 1707 (s), 1607, 1566, 1484 (s), 1454 (s), 1393 (s), 1287, 1230, 1197, 1175, 1128, 1104, cm−1
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:27][CH2:26]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:31][S:28]([CH:25]1[CH2:27][CH2:26]1)(=[O:30])=[O:29])=[O:9]
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A mixture of 5-chloro-2,4-difluorobenzoic acid (10.0 g, 51.93 mmol) and 1,1′-carbonyldiimidazole (10.11 g, 62.32 mmol) was stirred at reflux for 2 hours, cooled to ambient temperature, and cyclopropanesulfonamide (7.55 g, 62.32 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours, diluted with ethyl acetate (300 mL), washed with 1M aqueous hydrochloric acid, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was re-crystallized from ethyl acetate/hexanes mixture (1:2) to afford the title compound as a colorless solid (7.7 g, 56%): MS (ES−) m/z 294.1 (M−1).