Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:22])=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O)C.O.[NH2:25][NH2:26].Cl>O>[CH3:22][C:5]1[C:4](=[O:3])[NH:25][N:26]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=1
Reactant: NN
Reactant: CCOC(=O)C(C)=CC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Solvent: O
Product: Cc1cc(-c2ccc(-c3ccc(F)cc3)cc2)n[nH]c1=O
Reaction time: 1 h

Procedure:
A mixture of 31.2 g of 2-methyl-4-(4'-fluoro-4-biphenylyl)-4-oxo-2-butenoic acid ethyl ester, 60 ml of 24% aqueous hydrazine hydrate solution and 50 ml of water is boiled for one hour. When it has cooled, 25 ml of concentrated hydrochloric acid is added and the liquid is boiled for an additional 30 minutes. After again cooling the mixture, the 4-methyl-6-(4'-fluoro-4-biphenylyl)-2,3-dihydropyridazin-3-one obtained is filtered off and washed with water. m.p. 247°-248°.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12]Cl>C(Cl)(Cl)Cl>[Cl:12][C:7]1[CH:8]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: ClCl
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(N)c([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 25 %

Procedure:
To a stirred solution of 4-methyl-2-nitroaniline (19.69 g, 129.4 mM) in chloroform (200 mL) under a nitrogen atmosphere was added dropwise a solution of chlorine (10.15 g, 285.9 mM) in chloroform (100 mL) while maintaining the reaction mixture temperature below 30° C. The reaction mixture was stirred for 3 days and then washed with aqueous sodium bicarbonate. The organic phase was then concentrated and the residue chromatographed (eluant: hexane/diethyl ether; 9/1) over silica gel to provide (6.03 g, 25%) the title compound as an orange crystalline solid, mp 68.5°-69.5° C.; MS(CI): 187 (M+H).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[C:23]2[C:29]3[CH:30]=CC=C[C:28]=3[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)[CH2:19][CH2:18]1)=[O:16])[C:10](OC)=[O:11])=O)(C)(C)C>C(O)C.[H][H].[C].[Pd]>[CH:10]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:23](=[C:20]3[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][C@@H:9]([NH:8][C:6](=[O:5])[C:20]([CH3:23])([CH3:21])[CH3:19])[CH2:10][OH:11])[CH2:22][CH2:21]3)[C:29]=2[CH:30]=[CH:14][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H](CC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)N[C@@H](CO)CC(=O)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
745 mg (1.48 mmol) of methyl (R)-2-[(t-butoxycarbonyl)amino]-4-[4-(5H-dibenzo[a,d] [7]annulen-5-ylidene)-1-piperidinyl]-4-oxobutanoate was dissolved in 70 ml of ethanol. 1.49 g of palladium carbon (10% w/v) was added to the obtained solution, and they were stirred at room temperature in hydrogen gas atmosphere under 4.4 atm. for 3.5 hours. The catalyst was filtered out, and the filtrate was concentrated under reduced pressure. The intended product was obtained from the resultant residue in the same manner as that in steps 3 and 4 in Referential Example 50.
Reaction SMILES: [CH3:1]N(C=O)C.P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH3:26])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=1>ClCCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:18]=[C:19]([CH3:26])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:1]2
Reactant: CCOC(=O)C=C(C)Nc1ccc(Cl)cc1
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2cc(Cl)ccc2nc1C
Temperature: 25 °C

Procedure:
To a solution of 6.2 g (83 mmol) DMF in 50 ml of 1,2 dichloroethane was carefully added 19.1 g (126 mmol) of phosphoryl chloride. After stirring for 10 min at ambient temperature a solution of 20 g (83 mol) of ethyl 3-(4-chlorophenylamino)but-2-enoate in 50 ml of 1,2 dichloroethane was added slowly, while the mixture turned dark in an exothermic reaction. Stirring at ambient temperature was continued for another hour followed by heating with reflux for 6 h. The mixture was poured on to crushed ice, washed twice with water, dried over sodium sulfate, and concentrated under reduced pressure. The title ester was obtained from the residue via flash chromatography on silica gel with dichloromethane/hexane 4:1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C.[ClH:22]>CO.CCOC(C)=O>[ClH:22].[ClH:22].[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@@H]1CCN(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (5.0 g) in DMF (50 ml) was added 4-fluorobenzoylchloride (3.38 ml) and N,N-diisopropylethylamine (9.35 ml), the mixture was stirred at 70° C. for 2 hours. The mixed solution was poured into a mixture of water (300 ml) and AcOEt (300 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g). To a solution of [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g) in MeOH(34 ml) was treated with 4N HCl in AcOEt (29 ml) and was stirred at 25° C. for 12 hours. The solvent was removed under reduced pressure. Recrystallization (acetonitrile-MeOH) provided (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride as white solid (3.77 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([OH:38])=[O:37])(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([S:30]([C:33]3[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=3)[C:36]([OH:38])=[O:37])(=[O:32])=[O:31])[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(S(=O)(=O)c1cccc(C(=O)O)c1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a mixture of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile (Example 15a) (0.11 g, 0.26 mmol) and (3-(Chlorosulfonyl)benzoic acid (0.058 g, 0.26 mmol) in acetone and water (1:1 mL) was added sodium bicarbonate at room temperature. The reaction mixture was stirred at room temperature for forty minutes, quenched by the slow addition of 1N hydrochloric acid (1 mL) and partitioned between DCM (2×20 mL) and brine (25 mL). The DCM layer was dried over sodium sulfate, concentrated and column purified using silica gel chromatography using DCM and MeOH to yield the titled compound (0.12 g). Retention time: 3.39 min. YMC S5 Combiscreen ODS 4.6×50 mm (4 minute gradient). Solvent A=10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B=90% MeOH, 10% water and 0.2% phosphoric acid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7]>CCOC(C)=O.CCO.[Pd]>[CH2:6]([NH:5][CH2:4][C:3]1[C:2]([CH3:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH2:12])[CH3:7]
Reactant: CCNCc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNCc1cccc(N)c1C
Yield: 98.7 %

Procedure:
N-(2-methyl-3-nitrobenzyl)-1-ethanamine (0.46 g, 2.3 mmol) was hydrogenated over 5% palladium-charcoal 80 mg in EtOAc/EtOH 1:1 (14 ml) for four hours. The mixture was filtered through celite, and the filtrate was concentrated to give the title compound 0.373 g (97%) as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]([O:20]CC)=[O:19])([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([CH2:17][C:18]([OH:20])=[O:19])([OH:16])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A 2.0 M solution of sodium hydroxide in water (28 mL) was added to a solution of A1 (11.31 g) in methanol (40 mL). The reaction mixture was stirred for 1 h at RT. The organic solvent was removed under a vacuum and the remaining aqueous reaction mixture was repeatedly extracted with ether. The aqueous phase was acidified with 2.0 M hydrochloric acid solution in water and repeatedly extracted with DCM. The combined DCM organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. 7.9 g of the desired product 4-carboxymethyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (A2) were obtained and further reacted without purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH2:14][C:15]([NH2:17])=[O:16])[C:9]=2[CH:18]=1)[CH3:3].C[O:20][C:21](=O)[C:22]([C:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O.CC([O-])(C)C.[K+]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:16])[NH:17][C:21](=[O:20])[C:22]=3[C:24]3[C:32]4[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:9]=2[CH:18]=1)[CH3:3]
Reactant: Cc1oc2ccc(CN(C)C)cc2c1CC(N)=O
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1oc2ccc(CN(C)C)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of 2-(5-dimethylaminomethyl-2-methyl-benzofuran-3-yl)-acetamide (111 mg, 0.406 mmol) and (7-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (132 mg, 0.608 mmol) in anhydrous THF (4.0 mL) is added dropwise a 1 M solution of t-BuOK in THF (2.0 mL) at 0° C. under an argon atmosphere. The resulting deep red reaction mixture is stirred for 1 h at 0° C., diluted with EtOAc, washed with a saturated aqueous NH4Cl solution and washed with brine. The combined aqueous phases are extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford an orange solid. Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 7:1:1) affords the title compound as an orange solid (122 mg, 0.295 mmol, 73%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=11.88 (bs, 1H), 11.07 (bs, 1H), 7.91 (s, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 6.75 (d, J=6.8 Hz, 1H), 6.50 (t, J=7.5 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 3.40-3.16 (m, 2H), 2.40 (s, 2H), 2.12 (s, 2H), 1.84 (s, 6H). MS (ES+): 414 (M(C26H23N3O3)+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:24][NH2:25]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH3:24])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: FC(F)(F)Oc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 2,4-dichloro-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation AB) (80.7 mg, 0.221 mmol) in MeOH (2210 μL) was added methylamine (1000 μL, 2.0 mmol) (2M in THF). The reaction was allowed to stir overnight. Removed the solvent and applied to silica gel, eluting with an EtOAc/Hex gradient to afford 2-chloro-N-methyl-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (69.8 mg, 0.194 mmol, 88% yield). LC-MS (M+H)+=360.0.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:8])[CH3:7].O>CC(C)=O>[N:1]1([S:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 0 °C
Yield: 46.4 %

Procedure:
(prepared according to an analogous procedure described in U.S. Pat. No. 5,755,873) Step A: Pyrrolidine (16 ml, 0.1925 mol) was dissolved in acetone (40 ml) and cooled to 0° C.; 4-acetylaminobenzenesulfonyl chloride (15 g, 0.065 mol) was added over 10 min. Additional acetone (13 ml) was added and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was added to water (350 ml) and the resulting precipitate collected by filtration, the precipitate was washed with water until the washings were at pH 7. The solid was dried under vacuum to give 8.1 g of N-[4-(pyrrolidine-1-sulfonyl)phenyl]acetamide. Step B: The compound from step A (8.1 g) was suspended in water (37.5 ml) and treated with concentrated HCl (19 ml). The mixture was heated at reflux for 1 h. After cooling to rt, NH4OH (23 ml) was added with stirring. The resulting precipitate was collected by filtration and washed with water until the washings were pH 7. The solid was dried to give 6.0 g of 4-(pyrrolidine-1-sulfonyl)phenylamine. 1H NMR (DMSO) δ 7.40 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.02 (s, 2H), 3.03 (m, 4H), 1.61 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH2:36]O)[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.S(Cl)([Cl:41])=O>ClCCl.CN(C=O)C>[F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH2:36][Cl:41])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CO)C3)cs2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CCl)C3)cs2)CC1

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(hydroxymethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (0.55 g) in dichloromethane (10 ml) were added, at room temperature, thionyl chloride (0.24 g) and one drop of DMF, and the mixture was then refluxed for 2 hours. Subsequently, the reaction mixture was concentrated under reduced pressure. This gave, without further purification, 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (0.59 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:25]1[NH:29][N:28]=[N:27][N:26]=1)[C:20]1[NH:24][N:23]=[N:22][N:21]=1.[OH-].[Na+]>CO.O.Cl>[NH:26]1[C:25]([CH:19]([C:20]2[NH:21][N:22]=[N:23][N:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[N:29][N:28]=[N:27]1
Reactant: COC(=O)CCCCCCCCCCCCCCCC(c1nnn[nH]1)c1nnn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCCCCCCCCCC(c1nnn[nH]1)c1nnn[nH]1
Yield: 32.3 %

Procedure:
17,17-Bis(5-tetrazolyl)heptadecanoic acid methyl ester (1.70 g, 4.04 mmol) was dissolved in MeOH (40 ml), and a solution of NaOH (1.17 g, 29 mmol) in water (3 ml) was added. After stirring at room temperature for 19 h no more starting ester could be detected by 1H NMR, and the mixture was diluted with a mixture of water (130 ml) and 1N HCl (50 ml). The product was isolated by filtration, washed with water, and recrystallized from boiling MeCN (40 ml), to yield 0.53 g (32%) of the title compound as a solid. From the mother liquor more product (0.39 g) could be obtained. Total yield: 0.92 g, 56%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12](/[CH:22]=[C:23]2\[CH2:24][CH2:25][C@H:26]3[CH2:31][NH:30][CH2:29][C@@H:28]([C:32]4[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=4)[N:27]3[C:41]\2=[O:42])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1>N1C=CC=CC=1>[C:1]([N:30]1[CH2:29][C@@H:28]([C:32]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=2)[N:27]2[C:41](=[O:42])/[C:23](=[CH:22]/[C:12]3[CH:13]=[CH:14][C:15]([N:16]4[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]4)=[C:10]([O:9][CH3:8])[CH:11]=3)/[CH2:24][CH2:25][C@H:26]2[CH2:31]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(/C=C2\CC[C@H]3CNC[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Solvent: c1ccncc1
Product: COc1cc(/C=C2\CC[C@H]3CN(C(C)=O)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Acetic anhydride (0.5 mL) was added to a solution of (4R*,9aS*)-7-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-4-(3,4,5-trifluorophenyl)octahydropyrido[1,2-a]pyrazin-6-one (20 mg) in pyridine (1 mL), and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate->ethyl acetate:methanol 4:1) to obtain 10.2 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.O>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: ClCCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 105.4 %

Procedure:
To a solution of 4-iodophenol (20.0 g) and 1-bromo-3-chloropropane (18.6 g) in 2-butanone (200 mL), potassium carbonate (25.1 g) was added and stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the titled compound (28.4 g) as an orange-colored oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]1)=O.[N-:15]=[N+:16]=[N-:17].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C.CCOC(C)=O>[CH3:1][N:2]1[C:3]([C@@H:5]2[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2)=[N:17][N:16]=[N:15]1
Reactant: CNC(=O)[C@@H]1CCC[C@H](C(=O)OC)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@H]1CCC[C@@H](c2nnnn2C)C1
Temperature: 0 °C
Yield: 67.6 %

Procedure:
(±)-cis-Methyl 3-(methylcarbamoyl)cyclohexanecarboxylate (460 mg, 2.309 mmol) was dissolved in Acetonitrile (5 mL) at 25° C. under nitrogen with stirring, then sodium azide (150 mg, 2.309 mmol) was added. Cooled to 0° C. then added trifluoromethanesulfonic anhydride (0.390 mL, 2.309 mmol) dropwise over 2 minutes. The reaction was a colorless solution. Stirred for 20 hours then added sat'd sodium bicarbonate and stirred for 15 minutes, then added a little EtOAc and concentrated in vacuo the acetonitrile. Added more EtOAc and separated the layers. The EtOAc layer was rinsed again with sat'd sodium bicarbonate then 1 time with brine. The EtOAc layer was dried over sodium sulfate and stripped to give of a colorless oil. Obtained (±)-cis-methyl 3-(1-methyl-1H-tetrazol-5-yl)cyclohexanecarboxylate (350 mg, 1.561 mmol, 68% yield) as a colorless oil for product. MS found: (M+H)+=225.00.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][CH3:10])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[C:11]1(OB(C2C=CC=CC=2)O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:7][C:5]1[N:6]=[C:2]([C:19]2[C:20]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[CH:17][CH:18]=2)[N:3]([CH2:9][CH3:10])[C:4]=1[Br:8]
Reactant: CCn1c(Br)nc(Br)c1Br
Reactant: OB(Oc1cccc2ccccc12)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCn1c(-c2cccc3ccccc23)nc(Br)c1Br
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4,5-tribromo-1-ethyl-1H-imidazole (13.19 g, 40 mmol) and 1-naphthylphenylboronic acid (6.88 g, 40 mmol, 1.0 eq.) in toluene (100 ml) is added aqueous potassium carbonate solution (2.0 N, 40 ml, 2.0 eq.), followed by the addition of Pd(PPh3)4 (1.154 g, 1 mmol, 0.025 eq.). The resulting mixture is degassed with nitrogen, and then stirred at 90° C. for 16 hr. After cooling to rt, the reaction mixture is diluted with EtOAc (100 ml), washed with water and brine, and dried over sodium sulfate. After the solvent is removed, the crude product is purified through flash chromatography to afford the title product LCMS 380 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[F:11][C:12]([F:18])([F:17])[C:13](OC)=[O:14].Cl>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13](=[O:14])[C:12]([F:18])([F:17])[F:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C(F)(F)F
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
At −60° C., a solution of 10.5 g of 4-methoxyphenylmagnesium bromide in 50 ml of THF was added dropwise over a period of 1 hour to a solution of 7.2 g of methyl trifluoroacetate in 50 ml of ether. Stirring was then continued at −20° C. for 2 hours and at 0° C. for a further hour. The reaction solution was mixed with 25 ml of 2N hydrochloric acid and extracted with ethyl acetate. The extract was dried and concentrated. The residue was distilled under reduced pressure (b.p. 41° C., 4.5×10−1 torr), to give the title product as a colourless oil.