Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.N.[H][H]>[Ni].CO>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCc1ccc(OC(F)(F)F)cc1

Procedure:
650 ml of methanol, 260 g of (4-trifluoromethoxyphenyl)acetonitrile, and moist Raney nickel in an amount corresponding to 0.39 mol were initially charged in an autoclave, and 260 ml of ammonia were condensed in. The mixture was hydrogenated at 130° C. and a hydrogen pressure of 140 bar for 2 hours. The reaction mixture was then vented at room temperature, and the catalyst was filtered off. The filtrate was distilled at 10 hPa. This gave 224.5 g of 2-(4-trifluoromethoxyphenyl)ethylamine as a colorless liquid (86.7% of theory) of b.p. 84-86° C.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:17]=[CH:18][C:8]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[CH:9][CH:10]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCCOc1ccc(-n2ccnc2)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCOc1ccc(-n2ccnc2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A mixture of 2.04 g of 3-[4-(1H-imidazol-1-yl)phenoxy]propanamine dihydrochloride (Example 92) in 70 ml of methylene chloride is treated with 21 ml of 1N NaOH followed by 1.54 g of 4-bromobenzoyl chloride with stirring at room temperature for 18 hours. Additional methylene chloride and 5 ml of 1N NaOH is added and the organic layer separated, washed with water and filtered. The organic layer is evaporated in vacuo to a residue which is washed with ether and dried to give 1.3 g of off-white solid, m.p. 183°-185° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH3:10])[CH:5]=1.O.[NH2:13][NH2:14]>CO>[CH3:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=1)[C:3]([NH:13][NH2:14])=[O:2]
Reactant: COC(=O)c1ccnc(C)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)NN)ccn1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
2-Methyl-isonicotinic acid methyl ester (316.5 mg, 2.093 mmol) was dissolved in MeOH (7 mL) under Argon and hydrazine monohydrate 98% (1 mL, 20.93 mmol) was added. The reaction was allowed to stir under Argon at room temperature for eighteen hours. The reaction was concentrated to give the title compound (271.9 mg, 86%) as a white solid. 1HNMR CDCl3 □(ppm): 8.59 (d, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 3.09 (br. s, 3H), 2.60 (s, 3H).
Reaction SMILES: CC1C=CC=C(C)C=1NCCCCC1C=NC=CC=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][C:29](=O)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1cccc(C)c1NC(=O)CCCCCc1cccnc1
Agent: Cc1cccc(C)c1NCCCCc1cccnc1
Product: Cc1cccc(C)c1NCCCCCCc1cccnc1

Procedure:
N-(2,6-Dimethylphenyl)-3-pyridinehexanamine was prepared in a manner similar to that employed above for preparing N-(2,6-dimethylphenyl)-3-pyridinebutanamine. Starting with 6.4 g of N-(2,6-dimethylphenyl)-3-pyridinehexanamide, there was obtained 3.6 g of a yellow oil which was purified by silica gel chromatography eluting with 1:1 ethyl acetate-hexane to give 2.8 g of N-(2,6-dimethylphenyl)-3-pyridinehexanamine as an oil, bp 215°-230° C./0.1 mm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][CH:19]=1>>[N:8]1([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:14][C:15]3[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][CH:19]=3)=[CH:7][CH:6]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Product: C(=C/c1nc(COc2ccc(-n3ccnc3)cc2)co1)\c1ccccc1
Yield: 68 %

Procedure:
In substantially the same manner as in Working Example 37, 1-(4-hydroxyphenyl)imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole to give 4-[4-(1-imidazolyl)phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 160-162° C.
Reaction SMILES: [OH:1][CH:2]([CH:17]([OH:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH:13]([CH2:15][OH:16])[OH:14])[OH:12].C(O[C:31](=[O:33])[CH3:32])(=O)C>C(Cl)(Cl)Cl>[C:2]([C:15]([C:31](=[O:33])[CH3:32])([OH:16])[C:13]([C:13](=[O:14])[CH3:15])([OH:14])[C:11]([C:11](=[O:12])[CH3:10])([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH:17]([OH:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[OH:12])(=[O:1])[CH3:3]
Reactant: CCCCCCCCC(O)C(O)CCCCCCCCC(O)C(O)CO
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(O)C(O)CCCCCCCCC(O)(C(C)=O)C(O)(C(C)=O)C(O)(C(C)=O)C(C)=O
Reaction time: 2 h

Procedure:
0.2 g of the 9,10-dihydroxy-octadecyl glycerol (III) was dissolved in a small volume of chloroform (0.5 ml) in a screw tube and 2 ml acetic anhydride added. The reaction mixture was placed in a water bath for 2 h at 60° C., then dried down under a nitrogen stream. The residue was redissolved in chloroform:methanol:water (1:2:0.8) (v/v/v) and separated into phases by the addition of the appropriate amounts of chloroform and water to a final ratio of 1:1:0.9 (v/v/v). The synthesized compound (IV) is partioned in the chloroform phase.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:13][C:14](=[O:16])[CH3:15].[Cl-].[NH+]1C=CC=CC=1>Cl.C(OCC)(=O)C>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:13][C:14](=[O:16])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(CC(C)=O)c1F
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 180 °C
Reaction time: 1.25 h
Yield: 96 %

Procedure:
A mixture of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (183 g) and potassium carbonate (100 g) in methanol (1 L) was heated at reflux for 3 h. The reaction mixture was then cooled and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (1 L), filtered and washed with water. The separated aqueous layer was neutralized with 2N HCl and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was triturated with diethyl ether and filtered to provide 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one (121 g, 71%) as a yellow solid. LC/MS; (M+H)+=228.2. N. A mixture of 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one from previous step (454 mg, 21 mmol) and pyridinium chloride (0.9 g, 7.8 mmol) was stirred at 180° C. for 75 min. The reaction was cooled to room temperature, diluted with 1N HCl (3 mL) and ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (2×), dried and concentrated in vacuo to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (410 mg, 96%) as a grey solid, which was used without further purification for the next step. LC/MS; (M+H)+=214. 1HNMR (CDCl3): δ 2.37 (s, 3H), 4.22 (s, 2H), 6.95 (dd, 1H), 7.95 (d, 1H, J=9.35 Hz). O. 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from previous step (50 g, 0.234 mol) was added to 2 liter round bottom flask. Water (1 L) was added, and the yellow suspension was stirred at RT. Sodium dithionite (225 g, 5.5 eq) was added in one portion and the reaction mixture was stirred and kept <30° C. until HPLC analysis indicated no starting material remained (typically less than 1 hour). Upon completion, the reaction mixture was cooled to 0° C. and the tan solid product was collected by vacuum filtration. The wet product was dried at <50° C. under house vacuum to afford 4-fluoro-2-methyl-1H-indol-5-ol (31.4 g, 81% yield) which was isolated as a tan crystalline powder. The material had an HPLC purity of >99.8. 1H NMR (CDCl3, 400 MHz) δ 7.8 (s, 1H), 6.9-6.7 (m, 2H), 6.2 (s, 1H), 4.7 (s, 1H), 2.4 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 145.7, 143.4, 137.5, 136.7, 134.4, 120.1, 112.7, 106.8, 95.4, 13.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([F:16])[CH:5]=1)(=O)[CH3:2].O.NN.[OH-].[K+].C(O)COCCO>C1(C)C(C)=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:6]([F:16])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccccc2)c(F)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Solvent: Cc1ccccc1C
Product: CCc1ccc(-c2ccccc2)c(F)c1
Yield: 67.8 %

Procedure:
4-Acetyl-2-fluorobiphenyl (150 gram), 99% hydrazine hydrate (150 ml), potassium hydroxide (105 gram), digol (900 ml) and xylene (150 ml) were heated at 125° C. for 16 hours with stirring, after which the xylene and excess hydrazine hydrate were distilled until the internal temperature reached 165° C. The mixture was heated under reflux for three hours, cooled to 40° and poured into 5 liters of water. The product was extracted with petroleum ether (bp 60°-80°, 2×2 liter), the extract washed with water, dried over anhydrous sodium sulphate and evaporated. 4-Ethyl-2-fluorobiphenyl (95 gram, 68% theory) formed a colourless oil bp 130°/0.8 mm. Other 4-Alkyl-2-fluorobiphenyls were prepared by reaction of 2-fluoro-4-biphenylyl magnesium bromides with n-alkyl bromides and were colourless oils with the following properties listed in Table 5.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[F:30][C:31]([F:38])([F:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([S:33]([CH2:32][C:31]([F:38])([F:37])[F:30])(=[O:35])=[O:34])[CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)CC(F)(F)F)CC4)cc3c2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and 2,2,2-trifluoro-ethanesulfonyl chloride. Off-white solid. MS (m/z): 517.3 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=O)=O.[NH3:14].CO>C(Cl)(Cl)Cl.CCCCCC.CCOC(C)=O>[Cl:1][CH2:2][C:3]1[N:14]=[CH:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1
Reactant: O=Cc1ccccc1NC(=O)CCl
Reactant: N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: ClCc1ncc2ccccc2n1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 53.2 %

Procedure:
The product of the first step, 2-chloro-N-(2-formylphenyl)acetamide (0.869 g, 4.40 mmol) and ammonia, 7N solution in methanol (4.4 mL, 30.8 mmol) were stirred together at ambient in a sealed tube for 4.5 hours. A TLC (9:1 hexane EtOAc) check indicated that a new lower Rf spot had formed, however, plenty of starting material remained so stirring at ambient temperature was continued for another 19.5 hours, during which time a white precipitate had formed. Volatiles were removed under reduced pressure to give a beige solid that was treated with CHCl3. The portion that was soluble was checked by TLC (7:3 hexane/EtOAc). The major spot in the CHCl3-soluble portion was a new one with lower Rf than the starting material. The CHCl3 mixture was placed in the 0° C. freezer over the weekend. Insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on an Analogix IF-280 (Agilent SF10-4 g, 100% CHCl3). The product eluted in fractions #1-10. The product fractions were combined and concentrated under reduced pressure to give 2-(chloromethyl)quinazoline as a white solid (418 mg, 53.2%). 1H NMR (300 MHz, CDCL3) δ 9.45 (s, 1H), 8.09 8.04 (m, 1H), 7.99-7.92 (m, 2H), 7.70 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 4.92 (s, 2H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[NH2:8][C:9]1[S:16][C:15]2[CH2:14][N:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][C:11]=2[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(OC(OCC)OCC)C>[CH2:1]([O:4][CH:5]=[N:8][C:9]1[S:16][C:15]2[CH2:14][N:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][C:11]=2[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(N)sc2c1CN(C(=O)OCC)C2
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc2c(c1C(=O)OCC)CN(C(=O)OCC)C2
Yield: 99 %

Procedure:
0.3 ml of acetic anhydride was added to 1.4 g (4.8 mM) of 2-amino-3,5-dicarbethoxy-4,6-dihydrothieno[3,2-c]pyrrole in 14 ml of triethylorthoformate and refluxed under nitrogen for 1 h. The mixture was then completely evaporated in a rotary evaporator at 80° C. 1.6 g (99%) of crude product were isolated as a viscous oil which is sufficiently pure for further reactions.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([CH3:11])[CH2:8][CH2:9][OH:10].N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[Si:30]([O:10][CH2:9][CH2:8][C@@H:7]([CH3:11])[C@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([C:27]([CH3:29])([CH3:28])[CH3:26])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](CCO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 2.18.1d (1.87 g, 6.60 mmol) in DMF (9.7 mL) at 0° C. was added imidazole (988 mg, 14.52 mmol, 2.2 equiv) and TBDPSCl (2.18 g, 7.92 mmol, 1.2 equiv). After stirring at room temperature for 12 hours, the reaction mixture was diluted with EtOAc (20 mL) and washed sequentially with water (5 mL), aqueous 1.0 M HCl solution, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane) to give product 2.18.1e (3.55 g, yield 100%).
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=O)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:33]=[C:24]1[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[C:18]([F:34])[CH:19]=2)[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
A solution of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 20, Step 9, 10.44 g) in dry methylene chloride (100 mL) at 0° C. under N2 is treated with trifluoroacetic acid (24.0 mL) over one minute, and the resulting mixture is stirred at 0° C. for 1.75 hours, concentrated under reduced pressure, diluted with water (100 mL), cooled in an ice bath, adjusted to pH 11 with saturated aqueous potassium carbonate, and extracted with methanol/methylene chloride (5/95, 6×100 mL). The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 163-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[Br:10]N1C(=O)CCC1=O>C(#N)C.OS([O-])=O.[Na+]>[Br:10][C:8]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:5])=[CH:6][C:7]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1cc(Cl)c(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,5-Dichloroaniline (10 g, 61.7 mmol) in acetonitrile (100 mL) was taken in a 3-necked flask fitted with a thermometer, condenser and a dropping funnel containing N-bromosuccinimide (10.99 g, 61.7 mmol) in acetonitrile (30 mL). N-bromosuccinimide solution was added slowly to the 3,5-dichloroaniline solution in the flask at 0° C. by maintaining the internal temperature below 5° C. After the addition of NBS, the reaction mixture was warmed to RT and stirred for further 3 h. After the completion of the reaction as evidenced by LC-MS, the mixture was diluted with 10% aq. NaHSO3 (150 mL). The solution was stirred for 15 min and evaporated to ⅓ of the total volume of the solvents. The resultant mixture was then diluted with water and extracted with ethyl acetate. The organic solvent was dried, evaporated and purified by CombiFlash to give pure 4-bromo-3,5-dichloroaniline. Yield 13.6 g. 1H NMR (400 MHz; d6-DMSO): δ 5.82 (bs, 2H), 6.75 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([OH:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]1[O:24][C@H:23]1[CH2:25]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>CC(C)=O>[CH2:25]([O:15][C:5]1[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:13][C:14]=2[C:2]([F:1])=[CH:3][CH:4]=1)[CH:23]1[O:24][CH2:22]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Oc1ccc(F)c2[nH]c3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCC2CO2)c2c1[nH]c1ccccc12
Yield: 48 %

Procedure:
A mixture of 1-fluoro-4-hydroxycarbazole (470 mg, 2 mmol), potassium carbonate (345 mg, 2.5 mmol), (2R)-(−)-glycidyl 3-nitrobenzenesulfonate, (518 mg, 2 mmol), and 20 mL of acetone was heated to reflux for about 18 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 10% ethyl acetate/hexanes to give 247 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].C[OH:28].[OH-].[Na+]>O1CCCC1>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][C:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:28])[NH2:26])=[CH:21][CH:20]=2)([C:3]([OH:2])=[O:4])[CH2:10][CH2:9]1)=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: CO
Reactant: COC(=O)C1(Cc2ccc(C#N)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(N)=O)cc2)(C(=O)O)CC1

Procedure:
To a solution of 4-(4-cyanobenzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (23.04 mmol; 8.26 g) (prepared as in Example 1, but substituting 4-cyanobenzylbromide for 4-biphenylmethyl bromide), in tetrahydrofuran (50 mL) and methanol (50 mL) was added an aqueous 1M NaOH solution (46.1 mmol; 46.1 mL), and the resulting solution was heated to reflux for 48 hours. The mixture was then evaporated and an aqueous 1N HCl solution (50 mL) was added, resulting in the formation of a precipitate. The solid was separated via filtration and dried under vacuum to yield 4-(4-carbamoylbenzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. MS (ESI) m/z 384.89 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:21][C:10]3=[CH:11][C:12]4[C:13]([CH3:20])([CH3:19])[C:14](=[O:18])[NH:15][C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[CH3:20][C:13]1([CH3:19])[C:12]2[CH:11]=[C:10]3[NH:21][C:7]([C:3]4[C:2]([NH:1][C:22](=[O:24])[CH3:23])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[NH:15][C:14]1=[O:18]
Reactant: CC1(C)C(=O)Nc2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3

Procedure:
N-[3-(7,7-Dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.53 mmol) and acetic anhydride. The title compound was obtained as white powder (73 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].CCO[C:15]([S-])=[S:16].[K+].Cl>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:15](=[S:16])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
Combine 2-amino-4-nitrophenol (15.8 g, 102 mmol) and potassium xanthate (18.2 g, 114 mmol) in pyridine (200 mL). Reflux for 1 hour and then cool to room temperature. Pour the reaction into concentrated HCl (100 mL) and ice. Filter and wash the product with 1 N HCl to remove excess pyridine. Dry in a vacuum oven at 50° C. for 48 h to afford the title compound (15.9 g, 79%). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (dd, 1H, J=8.8, 2.2 Hz), 7.93 (d, 1H, J=2.2 Hz), 7.73 (d, 1H, J=8.8 Hz).
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][CH3:14])[CH2:7][CH2:6][CH2:5][N:4](C(OC)=O)[CH2:3]1>O>[OH:1][C:2]1([CH2:12][NH:13][CH3:14])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CNCC1(O)CCCN(C(=O)OC)C1
Solvent: O
Product: CNCC1(O)CCCNC1

Procedure:
8.7 g (43 mmol) of methyl 3-hydroxy-3-methylaminomethylpiperidine-1-carboxylate are heated overnight under reflux with 24 g of Ba(OH)2 . 8H2O in 240 ml of water. The product is filtered off from BaCO3 with suction and concentrated. The residue is boiled five times using 100 ml of dioxane each time, and the dioxane solution is concentrated and distilled.
Reaction SMILES: Cl[Sn]Cl.[CH3:4][O:5][C:6]1[C:11]2[O:12][CH2:13][C:14]3[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=3[C:16](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1>>[CH3:4][O:5][C:6]1[C:11]2[O:12][CH2:13][C:14]3[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=3[C:16](=[CH:17][C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc2c1OCc1ccccc1C2=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: COc1cccc2c1OCc1ccccc1C2=Cc1cccc(N)c1

Procedure:
Prepare the title compound by SnCl2 reduction of 4-methoxy-11-(3-nitro-benzylidene)-6,11-dihydro-dibenzo[b,e]oxepine (from Example 270) to provide 267 mg of product (93.7% yield). This material is used without further characterization.