Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1COCC1.C(OCC)(=O)C.[Zn].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[N:27]1[CH:28]=[CH:29][CH:30]=[N:31][C:26]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCCC(CI)C1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Cc2ncccn2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 1 L, 3-neck round bottom flask, equipped with magnetic stirring bar, thermometer, nitrogen gas inlet, and addition funnel was charged with Zn dust (66 g, 1.01 mol, 3 eq). The flask was evacuated and filled with nitrogen three times. On the third evacuation the flask was thoroughly heated with a heat gun, and then allowed to cool to room temperature. Anhydrous THF (120 mL) and 1,2-dibromoethane (19.7 g, 104.8 mmol, 0.3 eq) were charged and the mixture stirred under nitrogen at 65° C. for 10 min. The reaction was cooled to room temperature, and chlorotrimethylsilane (2.6 g, 23.7 mmol, 0.07 eq) was added and the reaction stirred at room temperature for 45 min. A solution of tert-butyl 3-(iodomethyl)piperidine-1-carboxylate (Preparation 69, 110 g, 338.2 mmol, 1 eq) in THF (60 mL and 20 mL to wash the flask) was added through an addition funnel and the mixture was stirred at room temperature for 45 min (NOTE: fast exothermic reaction which, if necessary, can be controlled by means of an ice/water bath). Then a solution of 2-chloropyrimidine (32.5 g, 284 mmol, 0.84 eq) in THF (80 mL+20 mL to wash the flask) was added followed by bis(dibenzylidene acetone) palladium (0) (9.3 g, 10 mmol, 0.03 eq), and tri-o-tolylphosphine (4.1 g, 13.5 mmol, 0.04 eq) and the reaction mixture was heated at 65° C. for 2 h then allowed to cool to room temperature and stirring was continued at room temperature for 17 h. The reaction mixture was diluted with ethyl acetate (1.2 L) and filtered through Celite. The Celite cake was thoroughly washed with ethyl acetate until the filtrate was no longer ultra-violet absorbent, the organic filtrates were combined and washed with a 10% solution of ammonium chloride (2×250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a brown residue that was purified through flash chromatography (Biotage). The fractions eluted with ethyl acetate:hexanes (40:60 v/v) were combined and concentrated in vacuo to title compound as a slightly yellow solid (27.3 g, 98.4 mmol, 34.6%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O>C(O)C.Cl>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:5]1[C:16]([CH3:17])=[CH:15][CH:11]=[C:12]1[CH3:14]
Reactant: NCc1ccc(F)cc1F
Reactant: CC(=O)CCC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)n1Cc1ccc(F)cc1F
Temperature: 80 °C

Procedure:
42.9 g (0.30 mol) of 2,4-difluorobenzylamine are dissolved in 300 ml of ethanol. 5 drops of concentrated hydrochloric acid (36%) are added to this solution. 36.0 g (0.315 mol) of acetonylacetone are then added dropwise, and the mixture is warmed to reflux. The reaction is complete (GC check) after refluxing for 4.5 hours at about 80° C. The brown solution is cooled to -30° C. and the crystals which have precipitated are filtered off and dried. 56.2 g (85% of theory) of white crystals which melt at 41°-42° C. are obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][Cl:8])C.Cl.[NH2:13][CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1>C(O)(C)C>[ClH:8].[Cl:8][CH2:7][CH2:6][CH2:5][CH:4]1[C:17]2[NH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]=2[CH2:15][CH2:14][NH:13]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CCOC(CCCCl)OCC
Agent: Cl
Solvent: CC(C)O
Product: ClCCCC1NCCc2c1[nH]c1ccccc21
Yield: 49.5 %

Procedure:
7 parts of γ-chlorobutyraldehyde diethyl acetal, 50 parts of isopropanol and 7.6 parts of 3-(β-aminoethyl)-indole hydrochloride were stirred for 7 hours at 83° C., and the mixture was cooled and then filtered under suction to give 5.5 parts (49.5%) of 1-(γ-chloropropyl)-1,2,3,4-tetrahydro-β-carboline hydrochloride of melting point 219°-221° C. The substance was identical to the product of Example 1.
Reaction SMILES: ClC1C(Cl)=C(C=O)C=CC=1OCCCC(O)=O.[N+](CCC)([O-])=O.[Cl:24][C:25]1[C:38]([Cl:39])=[C:37]([CH:40]=O)[CH:36]=[CH:35][C:26]=1[O:27][C:28]1([C:32]([OH:34])=[O:33])[CH2:31][CH2:30][CH2:29]1.[N+:42]([CH2:45][CH2:46][CH2:47][CH3:48])([O-:44])=[O:43]>>[Cl:24][C:25]1[C:38]([Cl:39])=[C:37](/[CH:40]=[C:45](/[N+:42]([O-:44])=[O:43])\[CH2:46][CH2:47][CH3:48])[CH:36]=[CH:35][C:26]=1[O:27][C:28]1([C:32]([OH:34])=[O:33])[CH2:29][CH2:30][CH2:31]1
Reactant: O=Cc1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Reactant: CCCC[N+](=O)[O-]
Agent: O=Cc1ccc(OCCCC(=O)O)c(Cl)c1Cl
Solvent: CCC[N+](=O)[O-]
Product: CCC/C(=C\c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl)[N+](=O)[O-]

Procedure:
By following substantially the same procedure described in Example 1, Step B except that the 4-(2,3-dichloro-4-formylphenoxy)butyric acid and 1-nitropropane are replaced by equimolar quantities of 1-(2,3-dichloro-4-formylphenoxy)cyclobutane-1-carboxylic acid (See Example 6, Step A) and 1-nitrobutane and there is obtained (E)-1-[2,3-dichloro-4-(2-nitro-l-pentenyl)phenoxy]cyclobutane-1-carboxylic acid
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cc1cnc(-c2cc(C=O)ccn2)s1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccnc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with synthesized 2-(5-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 424.03 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])[CH:5]=1.CO[CH:27](OC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCCC>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:11]([S:12]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[O:22][CH3:23])(=[O:13])=[O:14])[C:6]=2[CH:5]=1)=[O:24]
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: COC(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: O
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)C(c1ccccc1)O2
Temperature: 100 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A mixture of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1; 200 mg, 0.537 mmol), benzaldehyde dimethyl acetal (0.5 mL) and toluene-4 sulfonic acid monohydrate (10 mg, 54 μmol) was stirred at 100° C. for 48 h. After cooling, heptane was added, and the precipitate was collected by filtration to afford 3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carboxylic acid methyl ester (208 mg, 84%). Light yellow solid, MS (ISP)=460.2 (M+H)+.
Reaction SMILES: O[C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1.P(Cl)(Cl)([Cl:18])=O.CN(C)C1C=CC=CC=1>>[Cl:18][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1
Reactant: COC(=O)c1c(O)cc(=O)n2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1c(Cl)cc(=O)n2c1CCC2
Reaction time: 16 h
Yield: 69 %

Procedure:
Compound 1a (8.0 g, 38.3 mmol) was stirred in phosphorous oxychloride (20 mL, 218 mmol) at RT. Dimethylaniline (1 mL, 7.9 mmol) was added, and the reaction stirred for 16 h. The solution was concentrated in vacuo, quenched with ice, and made basic with sat. NaHCO3 solution. The aqueous solution was concentrated in vacuo. The residue was taken up in a 20% MeOH/CH2Cl2 and insoluble inorganic salts were removed by filtration. Organics were concentrated and purified by silica gel chromatography (75% EtOAc/CH2Cl2) to give 6.02 g (69%) of compound 1b as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.46 (s, 1H), 3.99 (t, 2H, J=7.6 Hz), 3.78 (s, 3H), 3.30 (t, 2H, J=7.6 Hz), 2.04-2.14 (m, 2H). MS (ES) [m⇄H] calc'd for C10H10ClNO3, 228, 230. found 228, 230.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](O)(=O)[CH2:14][CH3:15]>>[CH2:14]([C:15]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:13]
Reactant: CCC(=O)O
Reactant: Nc1cnc2ccccc2c1S
Product: CCc1nc2cnc3ccccc3c2s1

Procedure:
Propionyl anhydride (20 mL) was added to a suspension of 3-amino-quinoline-4-thiol (15 g) in propionic acid (100 mL). The reaction mixture was heated at reflux overnight and then filtered to remove a precipitate. The filtrate was concentrated under vacuum. The residue was taken up in dichloromethane (200 mL), washed with sodium bicarbonate then with water, and then dried over magnesium sulfate. The solution was filtered through a layer of silica gel eluting first with 1:1 ethyl acetate:hexane and then with ethyl acetate. The filtrate was evaporated to provide 2.6 g of 2-ethylthiazolo[4,5-c]quinoline as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].C(=O)([O-])[O-].[Ca+2].Cl[C:23]([O:25][CH2:26][CH2:27][Cl:28])=[O:24].Cl>O1CCOCC1.O>[Cl:28][CH2:27][CH2:26][O:25][C:23]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH3:16])=[O:24]
Reactant: O=C(Cl)OCCCl
Reactant: COc1cc(OC)c([N+](=O)[O-])c(OC)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)c([N+](=O)[O-])c(OC)c1NC(=O)OCCCl
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
0.26 moles (60 g) of 2-amino-4-nitro-1,3,5-trimethoxybenzene are dissolved in 270 ml of dioxane. 26.3 g of calcium carbonate are added and the temperature is then raised to about 90° C. 0.34 moles (48.6 g) of chloroethyl chloroformate are then added with stirring. When the addition is complete, stirring is continued for additional 30 minutes at 90° C. The reaction mixture is diluted with 600 ml of iced water and is then acidified by adding 25 ml of concentrated hydrochloric acid. The precipitate obtained is filtered off and washed with water. After drying, it melts at 133° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)CCN(C)C.[CH3:32][C:33]([CH3:39])([CH2:36][CH:37]=[CH2:38])[CH:34]=[O:35]>C1COCC1.O>[CH3:32][C:33]([CH3:39])([CH2:36][CH:37]=[CH2:38])[CH:34]([OH:35])[CH:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CCC(C)(C)C=O
Reactant: c1ccc(Cn2ccnc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=CCC(C)(C)C(O)C(c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
40 ml of 1.5 molar n-butyllithium/hexane solution were added dropwise to a solution of 4.75 g (30 mmol) of 1-benzylimidazole and 3.49 g (30 mmol) of N,N,N',N'-tetramethylethylenediamine (TMED(A) in 60 ml of absolute THF at -70° C. The mixture was stirred at -70° C. to -78° C. for a further 30 minutes, a solution of 3.74 g of 90% purity (30 mmol) 2,2-dimethyl-4-pentenaldehyde in 38 ml of absolute THF was then added dropwise at about -70° C. over 25 minutes, and the mixture was stirred at about -70° C. for a further 20 minutes and allowed to warm to room temperature over about 2 hours. 350 ml of water were then added at 0°-8° C., the mixture was stirred for a further 30 minutes while cooling in an ice bath, and the phases were subsequently separated and the aqueous solution was extracted repeatedly with ether. The combined organic solutions were further worked up as described in Example 1. The extract residue (8.4 g) was chromatographed, eluting with CH2Cl2 and CH2Cl2 /C2H5OH mixtures with an increasing C2H5OH content (to a maximum of 2% by volume) on a silica gel S/CH2Cl2 column (2.8 cm, height 48 cm). After elution of 4.8 g preliminary fractions, 3.5 g of product were eluted in which the compound desired was contained. This product (3.5 g) was again chromatographed in the same fashion as described above on a silica gel S/CH2Cl2 column (φ 2.0 cm, height 60 cm), during which the composition of the fractions eluted was checked by thinlayer chromatography (TLC). After elution of 0.35 g preliminary fractions, 4 fractions were eluted (with CH2Cl2 /C2H5OH 99.6:0.4- 99.5:0.5 ) which contained the compound desired in virtually pure form. These fractions were combined and evaporated in a high vacuum at a bath temperature of 65° C. until the weight remained constant. 0.62 g (≅7.6% yield) of 3,3-dimethyl-1-(1-imidazolyl)-1-phenyl-5-hexen-2-ol was thus obtained as a viscous, colorless oil; the 1H NMR spectrum confirmed the structure of this compound.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]3.Cl>>[F:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]3
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OCC(F)(F)c1cc(F)sc12
Agent: Cl
Product: Fc1cc2c(s1)C1(CCNCC1)OCC2(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
t-Butyl 2,4,4-trifluorospiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (2.00 g, 5.50 mmol) is dissolved in hydrochloric acid (4N in dioxane) (10 mL, 40 mmol). The mixture is stirred at room temperature for 1 h and then passed through a 50 g SCX cartridge (solid cation exchange) to yield 1.3 g of the title compound after evaporation of 2 N ammonia in methanol fraction. MS (m/z): 264 (M+1).
Reaction SMILES: CI.[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19](=[O:37])[NH:20][C@H:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:38](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19](=[O:37])[NH:20][C@H:21]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:38])=[CH:25][CH:24]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2C(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 49.6 %

Procedure:
Methyl iodide (4.00 mL, 64.2 mmoles) was added to a room temperature solution of (S)-2-[(S)-1-tert-Butoxycarbonyl-2-(4-hydroxy-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (1.39 g, 2.88 mmoles) and cesium carbonate (1.87 g, 5.75 mmoles) in DMF (10 mL) and the mixture stirred at room temperature for 4 days. The reaction mixture was diluted with EtOAc (200 mL) and washed with brine (3×200 mL). The aqueous layers were re-extracted with EtOAc (2×200 mL). The organic layers were dried (Na2SO4), combined, and concentrated in vacuo to give a yellow oil. Purification of the residue by flash chromatography, eluting with 0-10% EtOAc/CH2Cl2 afforded 0.71 g (50% yield) of (S)-2-[(S)-1-tert-Butoxycarbonyl-2-(4-methoxy-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester, as a colorless oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:27]=O)=[N:18][CH:19]=[C:20]([N:22]([CH3:26])[CH:23]([CH3:25])[CH3:24])[N:21]=1.[CH2:29]([NH:36][CH2:37][CH2:38][OH:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.C(O)(=O)C>[CH2:29]([N:36]([CH2:27][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH3:26])[CH:23]([CH3:24])[CH3:25])=[CH:19][N:18]=1)[CH2:37][CH2:38][OH:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(C)N(C)c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)N(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 107.5 %

Procedure:
Sodium triacetoxyborohydride (12.8 g) was added to a solution of 3-chloro-5-[methyl(1-methylethyl)amino]pyrazine-2-carbaldehyde (8.6 g), N-benzylethanolamine (7.3 g) and acetic acid (6.9 mL) in acetonitrile (86 mL), and the mixture was stirred at room temperature for 5 hr. To the reaction mixture were added ethyl acetate and 2M aqueous potassium carbonate solution (86 mL), and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (solvent gradient: 10→30% ethyl acetate/hexane) to give the title compound (15.1 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:22])([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]([F:22])([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1
Reactant: CC(F)(F)COc1ccc(CCNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)COc1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(2,2-difluoropropoxyl)phenethylcarbamate (95 mg, 0.30 mmol) in DCM (2 mL) was added TFA (1 mL) at 0˜5° C. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to give the crude product, which was used directly for next step without further purification (70 mg crude). MS (ESI) m/z 216.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:42]=[CH:41][C:38]([C:39]3[NH:25][C:24]4[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]5[CH:14]=[CH:13][C:12]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][CH2:16]6)=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Product: CN1CCN(c2ccc(-c3nc4cc(NC(=O)c5ccc(N6CCOCC6)cc5)ccc4[nH]3)cc2)CC1

Procedure:
Compound 423 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 4-(4-methylpiperazino)benzaldehyde. [M+H]+ calcd for C29H32N6O2: 497.26; found: 496.98.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=O)[CH2:25][CH3:26])=[CH:23][C:18]=2[N:17]=[CH:16]1.O>CO>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=[N:2][OH:3])[CH2:25][CH3:26])=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 89.1 %

Procedure:
Hydroxylamine hydrochloride (54 mg, 0.78 mmol) and sodium acetate (100 mg, 1 mmol) were added to a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one (100 mg, 0.39 mmol) in MeOH (5 mL). The mixture was refluxed overnight. The mixture was poured into water and extracted with EtOAc. The organics were washed sequentially with water and brine, then (Na2SO4). Removal of solvent followed by SiO2 chromatography afforded 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one oxime (95 mg, 90% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:25][CH:24]=1.P(C#N)(OCC)(OCC)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:18]([C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:21][C:12]=3[CH:13]=2)=[O:19])=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: Nc1ccc(CNc2ccccn2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNc4ccccn4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of 7-(4-methylphenyl)-2,3-dihydrobenzoxepine-4-carboxylic acid (280 mg) and 2-[(4-aminophenyl)methylamino]pyridine (199 mg) in DMF (4 ml) was added, under ice-cooling, diethyl cyanophosphate (0.18 ml) and triethylamine (0.17 ml), and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. To the mixture was added DMAP (1 piece), and the mixture was stirred at room temperature for 18 hours. Under ice-cooling, to the mixture was added sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, washed with brine, dried (anhydrous magnesium sulfate) and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1/1) and recrystallized from ethyl acetate/hexane to give N-[4-[(pyrid-2-yl)aminomethyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 72) (97 mg) as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:5]([F:17])=[C:6]([CH:12]=[C:13]([F:16])[C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:19]=[N+:20]=[N-:21].[Na+].C(OCC)(=O)C.Cl>CS(C)=O>[N:19]([C:14]1[C:13]([F:16])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([F:17])[C:4]=1[O:3][CH:2]([F:18])[F:1])=[N+:20]=[N-:21]
Reactant: CCOC(=O)c1cc(F)c(F)c(OC(F)F)c1F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(N=[N+]=[N-])c(OC(F)F)c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 66 ml of dimethyl sulfoxide was dissolved 13.2 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoate, and to this solution was added 7.3 g of sodium azide, after which the resulting mixture was stirred at room temperature for five hours. The reaction mixture was added to a mixed solvent of 150 ml of ethyl acetate and 150 ml of ice water and the pH was adjusted to 2 with 6N hydrochloric acid, after which the organic layer formed was separated, then washed successively with water and a saturated saline solution, and thereafter dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=10:1), to obtain 13.9 g of colorless, oily ethyl 4-azido-2,5-difluoro-3-difluorome-thoxybenzoate.