Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]1[CH:14]=O)[CH3:2].Br.[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[N:28]=[N:27][C:26]([CH2:29]P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:25]2)[CH:21]=[CH:22][CH:23]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[N:28]=[N:27][C:26]([CH:29]=[CH:14][C:4]3[N:3]([CH2:1][CH3:2])[C:7]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)=[N:6][N:5]=3)=[N:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(-n2nnc(C[PH](c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCn1c(C=O)nnc1-c1ccncc1
Agent: Br
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1c(C=Cc2nnn(-c3cccc(Cl)c3)n2)nnc1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (56.4 mg, 0.279 mmol) was dissolved in dimethylformamide (2 mL) and added to a vial containing 2-(3-chloro-phenyl)-5-[(triphenyl-λ5-phosphanyl)-methyl]-2H-tetrazole hydrobromide (165.1 mg, 0.307 mmol) dissolved in dimethylformamide (2 mL). After addition of DBU (84.9 mg, 0.558 mmol), the vial was capped and the reaction was allowed to stir at room temperature for two hours. It was then heated at 80° C. for 1.5 hours. After cooling, water was added and an aqueous workup was done extracting with ethyl acetate three times. The combined organic layers were washed with water twice, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by an SPE tube (5% MeOH/CH2Cl2) to yield the title compound as a white solid. 1H NMR (CDCl3) δ (ppm): 8.84 (d, 2H), 8.22 (m, 1H), 8.10 (d oft, 1H), 8.04 (d, 1H), 7.67 (d, 1H), 7.64 (m, 2H), 7.51 (m, 2H), 4.27 (q, 2H), 1.51 (t, 3H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[N:7]1)(=[O:5])=[O:4])[CH3:2].CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([S:3]([N:6]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: [H][H]
Reactant: CCS(=O)(=O)n1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)n1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
Ethanesulfonyl-3-nitro-1H-pyrazole (139 mg, 0.68 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on carbon, wet (˜50 mg) was added to the mixture. The vial was charged with hydrogen gas (via balloon) and the mixture was stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo followed by purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% ethyl acetate/hexanes to 90% ethyl acetate/hexanes) afforded 1-ethanesulfonyl-1H-pyrazol-3-ylamine (88 mg, 74%) as a faintly yellow wax: ESI-LRMS m/e calcd for C5H9N3O2S [M+] 175.04, found 176.3 [M+H+], 351.2 [2M+H+].
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].Br[CH2:11][CH2:12][CH3:13]>C(O)CC>[CH3:8][C:3]1[C:2]([O:1][CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ncccc1O
Reactant: CCCBr
Agent: [Na]
Solvent: CCCO
Product: CCCOc1cccnc1C

Procedure:
3-Hydroxy-2-methylpyridine (50 g) was added to a solution of sodium (11.6 g) in propan-1-ol (250 ml) and the mixture treated with 1-bromopropane (51 ml) in propan-1-ol (50 ml) to give 2-methyl-3-propoxypyridine, b.p. 96°-104° C. (30 mmHg).
Reaction SMILES: C1O[C:4]([CH2:6][CH2:7][CH2:8][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(C)OC1.Cl.[CH2:26]([OH:28])[CH3:27]>>[CH2:17]([N:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:27][C:26]([CH2:4][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(CCCN(Cc2ccccc2)Cc2ccccc2)OCCO1
Reactant: CCO
Agent: Cl
Product: O=C(CCCCN(Cc1ccccc1)Cc1ccccc1)CCCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of N,N-dibenzyl-5-amino-pentan-2-one ethylene acetal (90 g) in ethanol (500 ml) containing dilute hydrochloric acid (200 ml) was refluxed for 1 hour. The solution was allowed to cool and the ethanol was evaporated in vacuo. The residue was dissolved in water and extracted with ether. The aqueous layer was made alkaline with dilute sodium hydroxide solution and was extracted twice with ether. The combined ethereal extracts were washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo, to give a brown oil. The product was purified by chromatography to give N,N-dibenzyl-3-aminopropylmethyl ketone as a red-brown oil (60 g).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH3:24])[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1cc(F)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1cc(F)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-fluoro-2-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s), 5.17 (2H, s), 5.78 (1H, d, J=1.6 Hz), 6.89-6.95 (2H, m), 7.34-7.39 (2H, m), 7.58 (1H, d, J=2.4 Hz), 7.98 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13FN4O, 309; Found, 309.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.[N:10]([O-])=O.[Na+]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:10])=[C:5]([CH3:9])[CH:4]=1
Reactant: O=N[O-]
Reactant: CNc1cccc(C)c1
Agent: [Na+]
Product: CNc1ccc(N)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A mixture of 12.1 g N-methyl-m-toluidine (I) 14.5 g conc. HCl and 40 g of ice were stirred while 7 g NaNO2 were added over a period of 5 minutes. The mixture was cooled externally and small portions of ice were added when needed to keep the temperature below 10°C. The mixture was allowed to stand at 0°C for 1 hour after the addition was complete and the oily top layer formed was separated. The lower aqueous layer was then extracted twice with 10 ml portions of benzene and the combined organic layers were distilled under reduced pressure. The material which boiled at 132°-138°C/8mm Hg was collected and dissolved in ethanol. Dry HCl gas was passed through this solution which heated up and deposited a precipitate of N,2-dimethyl-4-nitrosaniline (III) as the hydrochloride salt. The 16 g of product were suspended in isopropanol and reduced over Pt/C on a Parr hydrogenator. The reduction mixture was filtered and the catalyst was extracted with water. The combined filtrates were evaporated to dryness to yield 8 g of the product N,3-dimethyl-p-phenylenediamine hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][O:38][CH2:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[CH2:39][O:38][CH3:37])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCc1ccccc1C=O
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCc1ccccc1CNCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (323 mg, 0.66 mmol), 2-(methoxymethyl)benzaldehyde (109 mg, 0.73 mmol) (Tetrahedron 4739, 47, 1991) and 1 drop of acetic acid in tetrahydrofuran (15 ml) was stirred at room temperature for 24 hr. Sodium triacetoxyborohydride (310 mg, 1.45 mmol) was then added and the reaction mixture stirred for 1 hr. At this point the solvent was partially removed under reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The solvent was removed from the organic layer under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (97:3) increasing in polarity to dichloromethane:methanol:ammonia (95:5:0.5). This gave the title compound (250 mg) as a foam. MS: 625 (MH+).
Reaction SMILES: Br.[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2.[OH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=O.Cl>>[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][OH:25])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=CCCCCO
Reactant: CC1CCC(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Br
Agent: Cl
Product: CC1CCC(C)c2cc(-c3csc(C4CCN(CCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 100 mg (0.25 mmol) of 4-[4-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide and 50 mg (0.49 mmol) of 5-hydroxypentanal. The product is in the form of the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Cl)s1

Procedure:
8.2 g (50.4 mmol) 5-chloro-thiophene-2-carboxylic acid were suspended in 26 ml (7 equiv.) thionyl chloride and the resulting mixture was refluxed for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was co-distilled three times with 150 ml toluene to give crude 9.64 g 5-chloro-thiophene-2-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=O)[NH:13][CH:14]=2)=[CH:5][CH:4]=1.P(Br)(Br)([Br:18])=O>O>[Br:18][C:12]1[CH:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1ccc(-c2c[nH]c(=O)cn2)cc1
Solvent: O
Product: COc1ccc(-c2cnc(Br)cn2)cc1
Reaction time: 18 h

Procedure:
26.1 g of 5-(4-methoxyphenyl)-2(1H)pyrazinone and 140 g of phosphorusoxybromide are heated to 100° C. for 45 minutes. After cooling, the hardened mass is added in batches to ice and water, with stirring. After 30 minutes stirring the mixture is left to stand for 18 hours and the precipitate is suction filtered. The filtrate is extracted with methylene chloride and the precipitate is dissolved in methylene chloride extract. The methylene chloride solution is washed with sodium bicarbonate solution, dried, filtered over activated charcoal and evaporated down.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:6]=1)C.[OH-].[Na+]>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:19])=[O:3])=[CH:6][C:7]=1[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: CCOC(=O)c1ccc(OC)c(COCCOC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOCc1cc(C(=O)O)ccc1OC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 4-methoxy-3-(2-methoxy-ethoxymethyl)-benzoic acid ethyl ester (0.87 g, 3.24 mmol) in a 1:1 mixture of THF and 4N NaOH (10 mL) is stirred at 50° C. overnight. After cooling, the volatiles are removed at reduced pressure, the remaining aqueous phase is acidified to pH 1 by dropwise addition of HCl 37%, and the resulting suspension is filtered off. The precipitate is washed with water, dried overnight in vacuo to give the title compound. TLC, Rf (hexane/AcOEt 1:1)=0.07. MS: 239.0 [M−H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 2.71 min. 1H-NMR (DMSO-d6): δ 3.29 (s, 3H), 3.52 (m, 2H), 3.64 (m, 2H), 3.88 (s, 3H), 4.51 (s, 2H), 7.10 (m, 1H), 7.90 (m, 1H), 7.94 (m, 1H), 12.6 (s, br, 1H) ppm.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH:14]([CH3:17])[CH2:15][NH2:16]>>[OH:13][CH:14]([CH3:17])[CH2:15][NH:16][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(O)CN
Product: CC(O)CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and 2-hydroxypropylamine comparable as in Example A.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>C(OCC)C>[C:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[NH:20][C:14](=[O:16])[C:13]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:17])#[N:24]
Reactant: N#Cc1ccccc1N
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: N#Cc1ccccc1NC(=O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 2-amino-benzonitrile (Aldrich) according to the method described in Example 1c. Melting Point: 101-103° C. (diethylether)
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[CH:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(OCC)(=O)C>CCCCCC>[CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[CH:15]([NH:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCCCCCCCC(Br)C(=O)Nc1c(SC)ccc2ncccc12
Reactant: CCCCCCN
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCC(NCCCCCC)C(=O)Nc1c(SC)ccc2ncccc12
Temperature: 120 °C
Yield: 88 %

Procedure:
A mixture of N-(6-methylthioquinolin-5-yl)-2-bromodecanamide (200 mg, 0.47 mmol) and n-hexylamine (10 ml) was heated at 120° C. for 1 hour, cooled to room temperature, and chromatographed using 1:24:25/triethylamine:ethyl acetate:hexane as eluants to give the title compound as a pink oil (184 mg, 88% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:26])=O>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:26])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(I)c1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: O=C(Cl)c1cccc(I)c1
Reaction time: 1 h

Procedure:
A solution of 15 g (0.06 mol) of 3-iodobenzoic acid in 100 ml of anhydrous dichloromethane is introduced into a round-bottomed flask, 13 ml (0.063 mol) of dicyclohexylamine are added and the mixture is stirred for one hour. 4.6 ml (0.063 mol) of thionyl chloride are then added and the mixture is stirred for one hour. The mixture is evaporated to dryness, the residue is taken up in anhydrous ethyl ether, the dicyclohexylamine salt is filtered off and the filtrate is evaporated. 17 g (100%) of the crude acid chloride are collected, which product will be used without further purification for the rest of the synthesis.
Reaction SMILES: COC1[CH:13]=[CH:12][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:5]=2C=1.[F:14][C:15]([F:25])([F:24])[C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>[Cl-].[Zn+2].[Cl-].CCO>[F:14][C:15]([F:25])([F:24])[C:16]1[C:13]2[C:21](=[CH:22][C:5]3[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)[O:20][C:18](=[O:19])[CH:17]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)NCCCC2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: O=c1cc(C(F)(F)F)c2cc3c(cc2o1)NCCCC3
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Equimolar amounts of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine 1-4 (0.18 g, 1.12 mmol), ethyl 4,4,4-trifluoroacetoacetate (0.205 g, 1.12 mmol), and zinc chloride (1.12 mL, 1M solution in Et2O) were combined in a pressure bottle with 10 mL absolute EtOH. The bottle was sealed and allowed to stir at 100° C. for overnight. The reaction darkened from a clear and colorless solution to a dark green solution. After cooling to rt, the reaction solution was absorbed onto silica gel and purified on an ISCO automated system affixed with a BIOTAGE flash 40(S) cartridge eluting 5–25% EtOAc in hexane to provide the desired product 1-5. Data for 1-5: HRMS Calcd (M+1) 284.0893; found 284.0901.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[N:35]=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([CH:43]=O)=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[N:35]=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:39])([CH3:40])[CH3:41])[C:33]([CH:43]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)C(=O)Nc1nc(OCCCCOCc2ccccc2)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OCCCCOCc2ccccc2)nc1NC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 51.6 %

Procedure:
Under N2, an ice-cooled flask containing THF (100 mL) was charged with sodium hydride (5.7 g, 142.5 mmol) to which ethyl 2-(diethoxyphosphoryl)acetate (32 g, 142 mmol) was added. The ice bath was removed and a solution of intermediate 7 (21.8 g, 56.7 mmol) in THF (120 mL) was slowly added to the preformed anion. The reaction was heated to reflux overnight. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give ethyl 3-(6-(4-(benzyloxy)butoxy)-2-pivalamidopyridin-3-yl)acrylate (intermediate 8) (13.3 g, 52%) as a white solid. mp: 75-76° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1([N:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccccc1)N(CCCCCCO)C1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCCCCN(C(=O)c1ccccc1)C1CCCCC1
Reaction time: 4 h
Yield: 79.8 %

Procedure:
N-cyclohexyl-N-(6-hydroxyhexyl)benzamide (136 mg, 0.45 mmol) was dissolved in methylene chloride (6 mL) and treated with Dess-Martin reagent (247.0 mg, 0.58 mmol). The oxidation was finished in 4 hours. The mixture was diluted with methylene chloride and washed with saturated bicarbonate and sodium thiosulfate (5%). The organic phase was concentrated and purified on silica gel with ethyl acetate: hexanes from 0:1 to 2:8 gave the desired product as a clear oil (108.2 mg, 80%). 1H NMR (300 MHz, CDCl3): δ 9.80 (s, 1H), 7.46-7.28 (m, 5H), 3.60-2.98 (m, 3H), 2.60-2.15 (m, 2H), 1.95-0.80 (m, 16H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:5].N1C=CC=CC=1.[F:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[F:27][CH2:28][C:29]([NH:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:5])=[O:30]
Reactant: Cc1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
14.4 g(0.053 mol) of N-(2-amino-5-nitrobenzoyl)-o-toluidine and 6.3 g(0.08 mol) of pyridine are dissolved in 300 ml of tetrahydrofuran. 12.2 g(0.126 mol) of fluoroacetyl chloride are added to the solution for 10 minutes under ice-cooling. The solution is stirred at the same temperature for 30 minutes and then at room temperature for 2.5 hours. The reaction solution is allowed to stand at room temperature overnight. The crystalline precipitate is collected by filtration, washed with water and then dried. 16.4 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-o-toluidine are obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][CH2:20][C:21]3[CH:38]=[CH:37][C:24]4[N:25]([CH2:35][CH3:36])[C:26](=[O:34])[C:27]([CH3:33])([CH3:32])[C:28](=[O:31])[N:29]([CH3:30])[C:23]=4[CH:22]=3)[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:42]I.O>CN(C=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]([CH2:20][C:21]3[CH:38]=[CH:37][C:24]4[N:25]([CH2:35][CH3:36])[C:26](=[O:34])[C:27]([CH3:33])([CH3:32])[C:28](=[O:31])[N:29]([CH3:30])[C:23]=4[CH:22]=3)[CH3:42])[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(Cc3ccccc3)C(=O)CC4)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(C)Cc3ccc4c(c3)N(Cc3ccccc3)C(=O)CC4)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl) amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (247 mg) was dissolved in DMF (2 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 13.56 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (73.5 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (169 mg) as a white amorphous.