Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5](/[CH:7]=[N:8]/[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH:4]=[N:3][CH:2]=1.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O>[Cl-].[Zn+2].[Cl-]>[CH2:28]([O:27][C:21]([C:22]1[C:7]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[N:8][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:18])([F:19])[F:20])[CH:11]=2)[C:23]=1[CH3:25])=[O:26])[CH3:29]
Reactant: FC(F)(F)Oc1cccc(N/N=C/c2cncnc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CCOC(=O)c1c(-c2cncnc2)nn(-c2cccc(OC(F)(F)F)c2)c1C
Temperature: 170 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
A mixture of N-[1-pyrimidin-5-yl-meth-(E)-ylidene]-N′-(3-trifluoromethoxy-phenyl)-hydrazine (215 mg, 0.76 mmol) and zinc chloride (208 mg, 1.52 mmol) in 2 ml ethyl acetoacetate was heated at 170° C. for 3 h and stirring was continued for 20 h at room temperature. Ethyl acetoacetate was distilled (Kugelrohr distillation, 90° C., 10-40 mbar) and the residue was purified by column chromatography (EtOAc:n-heptane 4:1) to afford the title compound as a yellow oil (89 mg, 30%). MS: 393.0 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([OH:22])[C:11]=2[C:23]([F:26])([F:25])[F:24])=[CH:6][CH:5]=1.[CH3:29][N:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[N:32]=[CH:31]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[OH:22][C:12]1[C:11]([C:23]([F:24])([F:25])[F:26])=[C:10]([CH:15]=[CH:14][C:13]=1[C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:35]([C:33]2[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=2)=[O:36])=[CH:28][CH:27]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)CC(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C)cn3)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Mix 1-[4-(4-aminomethyl-benzyloxy)-2-hydroxy-3-trifluoromethyl-phenyl]-3-methyl-butan-1-one hydrochloride (120 mg, 287.2 μmol), 1-methyl-1-H-imidazole-4-carboxylic acid (43.5 mg, 344.6 μmol), 1-hydroxybenzotriazole hydrate (52.8 mg, 344.6 μmol) in anhydrous tetrahydrofuran (4.5 mL). Add triethylamine (72.7 mg, 718 μmol, 100 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66.1 mg, 344.6 μmol) to the mixture. Stir the reaction mixture at room temperature overnight. Dilute the reaction mixture with water. Extract the mixture with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate under reduced pressure. Purify the crude residue by flash chromatography (silica gel) eluting with 5% methanol/ethyl acetate followed by reverse phase chromatography using 90/10 to 20/80 (water/0.1% trifluoroacetic acid)/acetonitrile to provide the product as a white solid (75 mg, 153 μmol, 53.4% yield). MS (m/z): 490 (M+1).
Reaction SMILES: [C:1]([CH:4]([CH:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[CH3:11][N:12]1[CH2:19][C@@H:18]2[C@@H:14]([N:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[C:37](=[O:38])[CH:36]=[CH:35][CH:34]=[N:33]5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)[CH2:13]1.ClCCl>O>[OH2:2].[C:1]([C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[CH3:11][N:12]1[CH2:19][C@@H:18]2[C@@H:14]([N:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[C:37](=[O:38])[CH:36]=[CH:35][CH:34]=[N:33]5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)[CH2:13]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Solvent: O
Solvent: ClCCl
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Temperature: 48 °C

Procedure:
2-{4′-[(3aR,6aR)-5-Methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one tartrate (Form A) was suspended in 1 mL of solution mixture, which was prepared by mixing 5.0 mL of dichloromethane with 5.0 mL of 20% water (in methanol). The suspension was vortexed and heated to about 48° C. yielding a clear solution. The solution was then filtered and the supernatant cooled to ambient temperatures naturally overnight. The solids precipitated over the night were dissolved again the next day by heating the suspension to about 90° C. The solution was cooled slowly by progressively lowering the temperature of the water bath to ambient temperatures. Single crystals were offered.
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:19](=[O:20])[CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Ic1cnc2c(c1)NCCN2
Product: O=C(Cc1ccccc1)N1CCNc2ncc(I)cc21
Yield: 31 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with phenyl acetyl chloride as in General Procedure 2 to give the title compound as a pale yellow foam (31% yield). M.p. (foam), LCMS: m/z=379.86 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.32-3.45 (m, 2H), 3.75-3.85 (m, 2H), 3.87 (s, 2H), 5.25 (bs, 1H), 7.21-7.38 (m, 5H), 8.01 (s, 1H).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].O.[C:6]([O:10][CH3:11])(=[O:9])[CH2:7]O.[Na].[OH-].[Na+].[CH3:15][O:16][CH2:17][CH2:18][OH:19]>>[CH3:15][O:16][CH2:17][CH2:11][O:10][C:6](=[O:9])/[CH:7]=[CH:2]/[CH3:3].[CH3:15][O:16][CH2:17][CH2:18][O:19][C:6](=[O:10])[CH2:7][CH:1]=[CH2:2]
Reactant: C=CCCl
Reactant: COC(=O)CO
Reactant: COCCO
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: C/C=C/C(=O)OCCOC
Product: C=CCC(=O)OCCOC
Yield: 16 %
Yield: 75 %

Procedure:
76.5 g (1 mole) of allyl chloride is reacted as in Example 1, at 60° C., 1.8 atmospheres of CO pressure, and a pH of 10.2, in the presence of 5 ml of Ni(CO)4, but in 200 g of methyl glycol containing 0.16 wt.-% of H2O, with 1.1 moles of sodium methyl glycolate in a 28.5 wt.-% solution in methyl glycol containing 0.35 wt.-% of NaOH, over a period of 4 hours. At a Cl' transformation of 84.2%, 91 g of crotonic acid-2-methoxyethylester (yield 75%) and 19.5 g of vinyl acetic acid-2-methoxy-ethylester (yield 16%) are obtained by gas chromatography (Hewlett-Packard, DC 200 silicone oil column, length 4 m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH3:29].Cl>C(#N)C>[CH2:26]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:15]([F:16])([F:18])[F:17])[CH:4]=2)([OH:14])[CH2:13][CH2:12]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCBr
Reactant: Cc1ccc(C2(O)CCNCC2)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2ccc(C)c(C(F)(F)F)c2)CC1

Procedure:
Preparation according to Example 2: 4-[4-methyl-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.5 g, 1.93 mmol), acetonitrile (20 ml), potassium carbonate (0.53 g, 3.8 mmol), 1-bromobutane (0.20 ml, 2.1 mmol). Yield: 0.48 g, 79%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 197-198° C. MS m/z (relative intensity, 70 eV) 315 (M+, 7), 272 (bp), 254 (48), 181 (38), 169 (25).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][C:8]=1[F:16].CN(C)[CH:19]=[O:20]>>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:19]=[O:20])=[CH:12][NH:13]2)=[CH:9][C:8]=1[F:16]
Reactant: CN(C)C=O
Reactant: Fc1cc2cc[nH]c2cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Cl)c(F)cc12
Temperature: 35 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
POCl3 (2.43 mL, 26.53 mmol) was added dropwise to N,N-dimethylformamide (15.0 mL) at −20° C. and stirred below −5° C. for one hour. A solution of 6-chloro-5-fluoroindole (3.0 g, 17.69 mmol) in dimethylformamide (5.0 mL) was added dropwise to the above reaction mixture at −20° C. The salt-ice bath was removed and the reaction mixture was warmed to 35° C. After one hour, the reaction was poured onto ice and basified by solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed with water and then concentrated to give 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (3.4 g, 97%) as a light brown solid. 1H NMR (500 MHz, CDCl3): δ 10.02 (s, 1 H), 8.10 (d, 1H, J=9.5 Hz), 7.87 (s, 1 H), 7.49 (d, 1H, J=5.5 Hz).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=O.[C:10]1([C:16]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)O)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([N:28]=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:10]1([C:16]2[N:28]=[C:7]([C@@H:2]3[NH:1][C:5](=[O:6])[CH2:4][CH2:3]3)[O:9][C:18]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1CC[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of D-pyroglutamic acid (30 g) in CH2Cl2 (200 ml) were added benzoin (74 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (68 ml) and 4-dimethylaminopyridine (30 g) at room temperature under N2. After being stirred for 12 hours at room temperature, the solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The obtained compound and ammonium acetate (60 g) were dissolved in acetic acid (500 ml) and the mixture was stirred for 4 hours at 100° C. After the solvent was removed, the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (5R)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (21.2 g). MS (m/z): 305 (M+ +1) IR (Neat): 3200, 1680, 1640 cm-1NMR (CDCl3, δ): 2.3-2.8 (4H, m), 4.8-5.0 (1H, m), 6.24 (1H, br s), 7.2-7.7 (10H, m)
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.C1(C)C=CC=CC=1.[CH:23]12[CH2:29][CH:26]([CH:27]=[CH:28]1)[CH2:25][CH:24]2[C:30](Cl)=[O:31]>O>[CH:23]12[CH2:29][CH:26]([CH:27]=[CH:28]1)[CH2:25][CH:24]2[C:30]([O:6][CH2:5][CH2:4][CH2:3][C:2]([OH:8])([CH3:7])[CH3:1])=[O:31]
Reactant: CC(C)(O)CCCO
Reactant: O=C(Cl)C1CC2C=CC1C2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(O)CCCOC(=O)C1CC2C=CC1C2
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To a mixture of 118 g of 4-methyl-1,4-pentanediol, 111 g of triethylamine and 400 ml of toluene at 20° C., 157 g of 5-norbornene-2-carbonyl chloride was added over one hour. After 5 hours of stirring, 200 ml of water was added to the reaction solution to stop the reaction whereupon the mixture separated. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was purified by vacuum distillation, collecting 214 g of 4-hydroxy-4-methylpentyl 5-norbornene-2-carboxylate (boiling point: 111-113° C./27 Pa, yield: 90%).
Reaction SMILES: [BH4-].[Na+].[S:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C@H:22]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[C:32](=[O:34])[CH3:33])[CH2:23]1)[C@@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6].C(O)(=O)C.C(Cl)(Cl)Cl>C(O)C>[S:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C@H:22]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[CH:32]([OH:34])[CH3:33])[CH2:23]1)[C@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium borohydride (60 mg) was added to a solution of 6-(pregn-5-en-20-one-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (250 mg) in absolute ethanol (7 ml). After stirring at room temperature for 4 hours, the solution was cooled and glacial acetic acid (10 ml) was slowly added. The solution was added to chloroform (100 ml) and successively washed with water (3 ×), 1N sodium bicarbonate (2 ×), and water (1 ×) and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the product as a fine white solid. The 200 MHz NMR spectrum of the peracetylated derivative was in accord with the desired structure. TLC data and Rf values are given in the above Table.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6](S(C)(=O)=O)[N:5]=1)([CH3:3])[CH3:2].O1CCOCC1.[CH2:25]1[CH:29]2[CH2:30][CH:31]([NH2:32])[CH:27]([CH2:28]2)[CH2:26]1>O>[C@H:27]12[CH2:28][C@H:29]([CH2:25][CH2:26]1)[CH2:30][C@H:31]2[NH:32][C:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=1
Reactant: NC1CC2CCC1C2
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(C)C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a mixture of ethyl 4-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (500 mg) and 1,4-dioxane (10 mL) was added exo-2-aminonorbornane (612 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain ethyl rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-isopropylpyrimidine-5-carboxylate (470 mg) as a white solid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:22])[CH3:21])[CH:12]=2)=[O:7])CCC.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:21])[CH3:22])[CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(OC(C)C)ccc2c1O
Reactant: COCCN
Product: COCCNC(=O)c1nc(Cl)c2cc(OC(C)C)ccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-methoxy-ethylamine in analogy to example B-5; MS-(−)-ion: M−1=337.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:8])=[O:6].[CH3:20][O:21][C:22](=[O:25])[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:20][O:21][C:22](=[O:25])[CH2:23][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:7]([C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Br:1])[CH:3]=1)[CH3:8]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A mixture of 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (442 mg, 1.3 mmol), methylbromoacetate (0.247 mL, 2.6 mmol) and K2CO3 (717 mg, 5.2 mmol) was heated in DMF (8 mL) at 80° C. for 5 hrs. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over Na2SO4, then purified by silica gel column chromatography eluted with ethyl acetate/hexane (1/4) to yield {2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}acetic acid methyl ester (495 mg). MS [M+H]+: 413.9; tR=2.75 min. (method 1)
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][C:4](=O)[CH:3]=1.O.[NH3:16].O.CCOCC>C1(C)C=CC=CC=1>[NH2:16][C:4]1[CH2:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:2](=[O:1])[CH:3]=1
Reactant: CCCCCCC1CC(=O)C=C(O)C1
Reactant: N
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCC1CC(=O)C=C(N)C1
Temperature: 130 °C
Reaction time: 3.5 h

Procedure:
A suspension of 3-hydroxy-5-n-hexyl-2-cyclohexene-1-one (29.7 g) in toluene (200 ml) was combined with conc. ammonia water (100 ml), and the mixture was stirred at 130° C. for 3.5 hours in an apparatus equipped with a water separator. After completion of the reaction, ether was added. The precipitate was collected by filtration, and was recrystallized from a solvent mixture of chloroform-ether. 17.0 g of 3-amino-5-n-hexyl-2-cyclohexene-1-one was obtained as pale yellow needles having a melting point of 113° C. (57.5%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.CO.[S:22]([O-:25])([O-:24])=[O:23].[Na+:26].[Na+]>O.C(O)C>[CH3:18][O:17][CH2:16][N:8]1[C:7]2[CH:19]=[C:3]([CH2:2][S:22]([O-:25])(=[O:24])=[O:23])[CH:4]=[CH:5][C:6]=2[S:11][C:10]2[N:12]=[CH:13][CH:14]=[N:15][C:9]1=2.[Na+:26]
Reactant: O=S([O-])[O-]
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: COCN1c2cc(CS(=O)(=O)[O-])ccc2Sc2nccnc21
Temperature: 90 °C
Yield: 58.7 %

Procedure:
To a solution of 900 mg of 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in a mixture of water (8 ml)/methanol (4 ml) was added 0.8 g of sodium sulfite and the resulting mixture was heated to 90° C. for 2 hours. Then the reaction mixture was brought back to room temperature and diluted with ethanol. After filtering off the inorganic salt, silica gel was added to the filtrate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/acetic acid) to thereby give 650 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[OH:26])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH4+].[Cl-].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[OH:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C@@H:16]1[CH2:15][CH2:14][C@H:13]([NH:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:31][N:30]=[N:29][N:2]=3)[CH:4]=2)(=[O:11])=[O:10])[CH2:18][CH2:17]1
Reactant: N#Cc1cccc(S(=O)(=O)N[C@H]2CC[C@@H](c3ccc(O)cc3O)CC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(N[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1)c1cccc(-c2nnn[nH]2)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
A solution of Example 9 (20 mg, 54 μmol) in DMF (2 ml) was treated with NH4Cl (17 mg, 323, ol) and NaN3 (21 mg, 323 μmol). The mixture was heated under reflux for 6 hr, then stirred for 18 hr at 20° C., before being partitioned between EtOAc (30 ml) and H2O (5 ml). The aqueous phase was extracted with EtOAc (3×15 ml) and the combined organic extracts were washed with brine (30 ml) and dried (MgSO4). Filtration, solvent evaporation under reduced pressure, and FCC (EtOH-EtOAc, 1:3) afforded the title compound (16 mg, 72%) as a pale yellow solid. δ((CD3)2CO) 1.30-1.88 (m, 8H), 2.60-2.71 (m, 1H), 3.62-3.69 (m, 1H), 4.23-4.30 (m, 1H), 6.20 (dd, 1H), 6.44 (d, 1H), 6.50 (d, 1H), 6.87 (d, 1H), 7.55 (t, 1H), 7.63-7.68 (m, 1H), 7.72-7.76 (m, 1H), 7.80 (d, 1H), 8.30 (d, 1H), 8.73 (s, 1H); m/z (ES−) 414 [M−H]−.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[C:37](O)=[O:38])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:37]([C:33]2[N:34]=[CH:35][O:36][C:32]=2[CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)=[O:38])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ocnc2C(=O)O)CC1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ocnc2C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.30 g, 1.03 mmol), 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-oxazole-4-carboxylic acid (Reference Example 16, 0.33 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 50:50) to give the title compound (0.47 g, 92%) as a white amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[N+](C)=CCl.[Cl-].[C:22]([O-])(=[O:24])C.[Na+]>ClCCCl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([CH:22]=[O:24])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Reactant: CC(=O)[O-]
Agent: C[N+](C)=CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)N1CCc2cc(C=O)sc2CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acid ethyl ester (1.50 g, 6.65 mmol) in 1,2-dichloroethane (20 ml) was added Vilsmeier reagent (1.49 g, 11.65 mmol). The reaction mixture was heated to 70° C. for 5 hours. The reaction mixture was allowed to cool to RT followed by addition of 1 M sodium acetate (20 ml). The mixture was vigorously stirred for 2 hours and then diluted with water (50 ml). The resulting solution was extracted with DCM (3×). The combined DCM extracts were washed with water, brine, and dried over MgSO4. The resulting mixture was filtered and solvent evaporated in vacuo to give the subtitled compound as a tan oil (1.56 g) that was used without further purification. MS: ESI (positive): 254 (M+H).