Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:31]([O:33]C(C)(C)C)=[O:32])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:31]([OH:33])=[O:32])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1=C(CSc2nnnn2-c2ccccc2)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3ccccc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylate (1.0 g, purity 80%, 1.42 mmol) in dichloromethane (50 ml) was cooled to 0° C. Titanium tetrachloride (0.62 ml, 5.6 mmol) was added in 1 min. After stirring for 1 h at 0° C., the suspension was mixed with a chilled 2 M solution of hydrochloric acid in water (40 ml). The organic phase was separated and washed with a 1 M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was dried over magnesium sulphate and evaporated to give 0.55 g of (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylic acid-(purity 60%, yield 45.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([O-])=O.[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24].O>C1COCC1>[SH:24][C:23]1[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Cn1c(S)nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
In a test tube equipped with a septum, tert-butyl (2-nitro-4-trifluoromethyl-phenylamino)-acetate (Starting material 5-VIII, 80 mg, 0.25 mmol) is dissolved in dry THF (0.5 ml). Argon is allowed to bubble through this solution for 10 min. Then dry palladium on carbon (10% w/w, 26 mg, 10% mol) is added and the flask is set under H2 atmosphere. The resulting mixture is shaken vigorously at rt overnight. If necessary, another 8% mol of palladium on charcoal 10% w/w is added and the resulting suspension is stirred for another hour under H2 atmosphere. The crude mixture is then filtered over celite to remove any solid particle. The celite is rinsed once with dry THF. To the resulting light yellow solution is added, under argon, 1,1′-thiocarbonyldiimidazole (89 mg, 0.5 mmol, 2 eq.). The resulting orange solution is allowed to stir at rt for 5 h. Water is then added. The yellow solid formed is filtered over a fritted funnel, rinsed thoroughly with water and dried under high vacuum. This yields the title compound (60 mg) in 73% as a yellow solid: tR=1.10 min (LC-3), ESI-MS (pos.): m/z 332.99 [M+H]+, 331.13 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.41 (s, 9H, tBu), 5.06 (s, 2H, NHCH2CO2), 7.44 (s, 1H, Harom), 7.57 (s, 2H, Harom), 13.25 (br. s, 1H, SH).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[C:16](Cl)(Cl)(Cl)Cl>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[N:11][C:3]=1[O:2][CH3:1]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ncccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A mixture of 2-methoxy-nicotinic acid (5.00 g, 32.6 mmol), thionyl chloride (50 mL) and carbon tetrachloride (50 mL) was head at reflux for 2 h. The reaction mixture was allowed to cool and volatiles were removed on a rotary evaporator. The residue was co-evaporated three times with carbon tetrachloride to remove residual oxalyl chloride. Methanol (50 mL) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and chloroform (150 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate (2×150 mL) and brine (150 mL), dried (magnesium sulfate), filtered, and evaporated to give 2-methoxy-nicotinic acid methyl ester (4.42 g, 81%) as a clear yellow oil.
Reaction SMILES: COC(=O)C1C=CC(N[C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=CC=1Cl.[OH-:43].[Na+]>CO.O1CCCC1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:15]3([CH:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[CH:13]([C:11]([OH:43])=[O:12])[NH:17][CH:16]3[CH2:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 66 %

Procedure:
In a manner similar to the methods described in Example 16 and Example 22, rac-2-chloro-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 24 (78 mg, 0.12 mmol) was hydrolyzed with aqueous NaOH in methanol and tetrahydrofuran at 78° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (50 mg, 66%), then rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (30 mg, 0.049 mmol) was reacted with EDCI (19 mg, 0.097 mmol), HOBt (13 mg, 0.097 mmol), triethyamine (9.8 mg, 0.097 mmol), and NH4Cl (26 mg, 0.49 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-3-chloro-phenyl)-amide as a off white solid (Yield, 35 mg, 64%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.C(O)C.[NH2:21]N>>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:21]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)/C=C/C(=O)c1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CCO
Product: FC(F)(F)c1cccc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
The (2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one (0.32 g, 0.0013 mol) was dissolved in ethanol (10.0 mL, 0.171 mol) and hydrazine (0.24 mL, 0.0078 mol) under nitrogen and heated to reflux. The reaction was monitored by HPLC and was complete almost immediately. The mixture was allowed to cool to rt and concentrated to give the crude product as an oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to give 3-[3-(trifluoromethyl)phenyl]-1H-pyrazole as an oil (0.25 g, 89%), LC/MS (M+H)+: 213, 1H NMR (CDCl3) δ 8.06 (s, 1H), 7.99 (d, 1H, J=7.5), 7.66 (d, 1H, J=2.4), 7.57 (m, 1H), 7.55 (d, 1H, J=7.5), 6.69 (d, 1H, J=2.4).
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])C.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:20]([C:19](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)#[N:21]
Reactant: CCOC1(OCC)CCCN1C
Reactant: COc1ccc(CC#N)cc1
Solvent: c1ccccc1
Product: COc1ccc(C(C#N)=C2CCCN2C)cc1

Procedure:
Boil 30.0 g of 2,2-diethoxy-1-methylpyrrolidine, 25 g of 4-methoxybenzylcyanide and 150 ml of benzene under reflux for 4 hours. Concentrate the refluxed reaction product and distil the residue twice under a vacuum to obtain 30.6 g (79% of theory) of the title compound (b.p. 158° at 0.005 mm of Hg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of 5.00 g (3.80 ml, 26.3 mmol) 4-trifluoromethoxy-benzaldehyde, 3.10 g (30.0 mmol) malonic acid, 0.26 g (3.0 mmol) piperidine and 15.0 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 50 g ice and 15 ml 6N HCl. The precipitate was isolated, washed with water and dried. Yield: 5.20 g (85%) 3-(4-Trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>C(Cl)Cl>[CH2:29]([NH:31][C:32]([NH:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][CH:8]=1)=[O:33])[CH3:30]
Reactant: CCN=C=O
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Solvent: ClCCl
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 at 0° C. were added TEA (0.064 mL, 0.44 mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J=4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]1[CH2:8][CH2:7][CH2:6][N:5]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>CC(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:3][C:4]2[CH2:8][CH2:7][CH2:6][N:5]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: NC1=NCCC1
Reactant: O=C=Nc1ccc(Br)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: O=C(NC1=NCCC1)Nc1ccc(Br)cc1

Procedure:
Following a procedure similar to that described in Example 2 but using 4.6 g. sodium in 300 ml. dry acetone, 23.2 g. 2-amino-1-pyrroline hydrochloride and 38.9 g. 4-bromophenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from ethyl alcohol 10.8 g. of the hydrochloride of 1-(4-bromophenyl)-3-(1-pyrrolin-2-yl)urea; m.p. 221°-224°C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:11]=1)[CH:7]([CH3:9])[CH3:8].[C:28]([O:32][CH3:33])(=[O:31])[CH2:29][SH:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:33][O:32][C:28](=[O:31])[CH2:29][S:30][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:11]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)CS
Reactant: CC(C)N(CCCCBr)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CSCCCCN(c1cnc(-c2ccccc2)c(-c2ccccc2)n1)C(C)C
Yield: 96.9 %

Procedure:
1.17 g of 1-bromo-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butane, 0.29 g of methyl thioglycolate, 0.46 g of potassium carbonate, a catalytic amount of potassium iodide and 27 ml of acetonitrile were mixed and the mixture was refluxed for 4 hours. The insoluble matter was removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.19 g of the desired compound as a pale yellow crystal having a melting point of 64 to 67° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C=O)c(Cl)nc1C
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: Cc1cc(C=CC(=O)O)c(Cl)nc1C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g) piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and evaporated to an oil. This oil was dissolved in sodium hydroxide solution and was extracted with chloroform (discarded). The aqueous phase was acidified with hydrochloric acid and was extracted with chloroform. The chloroform extracts were washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%) m.p. 150°-158°. This acid was esterified using ethanol and sulphuric acid to give the ethyl ester m.p. 85°-88°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(#N)C.C(=O)(O)[O-].[Na+].O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:17][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH:13]=2)[N:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccccc1CNc1ccc2cc(N)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1CNc1ccc2cc(NC(=O)C3CC3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (example 10, step B, 150 mg, 0.537 mmol) was dissolved in 6 mL acetonitrile and 6 mL saturated sodium bicarbonate solution. Cyclopropane carbonyl chloride (63 mg, 0.60 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 50 mL water and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (30 ml), dried with sodium sulfate and evaporated. The crude product was recrystallized from diisopropyl ether. The title compound was obtained as a white solid (123 mg, 66%), MS: m/e=348.3 (M+H+).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O.O>[C:13]([O:12][C:10]([N:1]1[CH:9]2[CH:4]([CH2:5][N:6]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:7][CH2:8]2)[CH2:3][CH2:2]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC2CNCCC21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CN(CCCCl)CCC21
Yield: 77 %

Procedure:
To a solution of tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.63 g) in acetone (15 mL) was added K2CO3 (1.54 g) and 1-bromo-3-chloropropane (1.45 mL). The reaction mixture was heated to reflux overnight, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/MeOH) to give the title compound as pale yellow liquid (0.65 g, 77.00%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: Nc1ccc(CC2CCCC2)cc1Br
Product: Nc1ccc(CC2CCCC2)cc1-c1cccc(Cl)c1Cl

Procedure:
2-bromo-4-(cyclopentylmethyl)aniline and 2,3-dichlorobenzene boronic acid can be combined to form 2-(2,3-dichlorophenyl)-4-(cyclopentylmethyl)aniline, and
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]O)=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:34]=2[F:33])=[CH:46][CH:45]=1)=[O:17])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
First, 3.0 g of 2,2-bis(6-benzyloxyhexyl)acetic acid, 2.8 g of 2,3-difluoro-4'-[11-hydroxyundecyl]oxybiphenyl, 2.2 g of triphenylphosphine, and 50 ml of tetrahydrofuran were placed in a 100 ml flask. Then, 1.4 g of diethyl azodicarboxylate was added dropwise to the mixture at 5° C. The resultant mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to obtain 5 g of 11-[2,3-difluorobiphenyl-4'-yl]oxyundecyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 92.6%). The compound thus obtained had a purity of 98% by HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[C:28]#[N:29]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:32]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=4[F:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C#N)cc4F)ncnc32)CC1

Procedure:
4-[4-(4-Cyano-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluoro-4-hydroxybenzonitrile (available from Alfa Aesar, Ward Hill, Mass., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.98-2.07 (m, 4H), 2.99-3.07 (m, 2H), 4.07-4.12 (m, 2H), 5.00-5.05 (m, 1H), 7.76-7.80 (m, 1H), 7.88-7.90 (m, 1H), 8.16-8.19 (m, 1H), 8.50 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=439.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](/[CH:15]=[CH:16]/[C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.[H][H]>C(O)C.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][NH2:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(/C=C/C#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Rh]
Agent: N
Solvent: CCO
Product: CC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Yield: 63.4 %

Procedure:
Cis/trans-4-(2-cyanovinyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.0 mmol), 5% Rh/Al2O3 (0.500 g) and 28% aqueous NH3 (1.25 mL) are heated at 35° C. in ethanol (20 mL) and 50 psi hydrogen gas for 18 hours. The reaction mixture is filtered through Celite®, concentrated, and chromatographed with 0-20% (2M NH3 in MeOH) in dichloromethane to give the title compound as a clear oil (0.65 g, 63% yield).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:11][NH2:12])[CH2:8][CH2:9][CH3:10].O=[C:14]([CH2:20][C:21](=O)[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(O)C>[CH2:7]([N:11]1[C:21]([CH3:22])=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNN
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCn1nc(C(=O)OCC)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Butylhydrazine oxalate (25 g, 140 mmol) was added over a period of 15 minutes to a solution of ethyl 2,4-dioxovalerate (22.2 g, 140 mmol) and triethylamine (210 mmol) in ethanol (140 mL). The resulting solution was stirred overnight at ambient temperature and concentrated under reduced pressure. Hexane was added, and an insoluble solid was removed by filtration. The hexane was removed under reduced pressure; the residue was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with hexanes/ethyl acetate in a gradient from 80:20 to 45:55) to provide 18.1 g of ethyl 1-butyl-5-methyl-1H-pyrazole-3-carboxylate as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NC(C)=O)cc1
Yield: 84.5 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (2.65 g, 5.58 mmol) and acetic anhydride (0.79 ml, 8.37 mmol), the procedure of Inventive Example 94 was repeated to obtain 2.44 g (84.3%) of the title compound in a colorless amorphous form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][CH:9]([CH2:15][Br:16])[C:10]([N:12]=[C:13]=[O:14])=[O:11]>C1C=CC=CC=1>[C:2]1([NH:1][C:13]([NH:12][C:10](=[O:11])[CH:9]([Br:8])[CH2:15][Br:16])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)C(Br)CBr
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Br)CBr)Nc1ccccc1
Temperature: 12.5 °C
Reaction time: 2 h

Procedure:
9.5 g of aniline are dissolved in 100 ml of anhydrous benzene and a solution of 26.0 g of 2,3-dibromopropionyl isocyanate in 100 ml of benzene is added dropwise with cooling at 10 to 15° C. After stirring for 2 hours, the crystal sludge is diluted with the same volume of petroleum ether, filtered, washed with petroleum ether and dried. Yield: 30.0 g, m.p: 160°-161° C.