Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:12][C:11]=2[C:31]([O:33]C)=[O:32])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:12][C:11]=2[C:31]([OH:33])=[O:32])=[CH:8][CH:9]=1
Reactant: COC(=O)c1nc(/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)[nH]c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(/C=C/c2nc(C(=O)O)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 100.5 %

Procedure:
A 2 N sodium hydroxide solution (1 mL) was added to a solution of methyl 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole-4-carboxylate (143 mg) in methanol (1 mL), and the reaction solution was stirred at room temperature for 1.5 hours and at 80° C. for 17 hours. The reaction solution was left to cool to room temperature. Then, 2 N hydrochloric acid (1 mL) was added to the reaction solution, which was then stirred at room temperature for 30 minutes. The solid precipitated from the reaction solution was collected by filtration to obtain 139 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=O.O>C1(C)C=CC=CC=1>[CH3:15][C:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC1C(=O)CCC1=O
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(Nc2ccc(C3=NNC(=O)CC3)cc2)CCC1=O

Procedure:
3.4 g of 4,5-dihydro-6-(4-aminophenyl)-3(2H)-pyridazinone and 2.0 of 2-methylcyclopentane-1,3-dione were suspended in 30 ml of toluene, to which a catalytic amount of p-toluene sulfonate-hydrate was add while the resulting suspension was heated to reflux with stirring for 8 hours, with removal of water as an azcotropic mexture. After cooled, deposited crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform:methanol=10:1), 4.7 g of the title compound was obtained. m.p. 284°-285° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:26][C:24]1([CH3:27])[CH2:23][C:22]([CH3:28])([CH3:29])[CH2:21][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[CH2:25]1
Reactant: CC1(C)CC(c2ccccc2C2=CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2C2=CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a solution of 4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (570 mg, 1.43 mmol) produced in Example (102d) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL), followed by stirring for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 430 mg of the title compound as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[CH:4][CH:3]=1.[N+](C1C=CC(S(O[CH2:38][C@H:39]2[CH2:41][C:40]2([F:43])[F:42])(=O)=O)=CC=1)([O-])=O>>[F:42][C:40]1([F:43])[CH2:41][C@@H:39]1[CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H](C)COc1cc2sc(-c3ccc(O)cc3)nc2cn1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Product: CC(=O)N[C@@H](C)COc1cc2sc(-c3ccc(OC[C@H]4CC4(F)F)cc3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-hydroxyphenyl)[1,3]thiazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@@H:29]([NH2:32])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@@H:29]([NH:32][C:14]([C@@H:9]3[CH2:10][C@@H:11]([F:13])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (2.87 g, 12.31 mmol) and (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Example 33 Step A (2.93 g, 13.54 mmol) in dichloromethane (16.97 mL) was added 1-hydroxybenzotriazole hydrate (2.073 g, 13.54 mmol). After 2 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (2.388 mL, 13.54 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The solvent was removed in vacuo. The crude material was purified using an 80 g silica gel cartridge eluted with a gradient of 0-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give (2S,4R)-tert-butyl 2-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.70 (s, 1H), 7.38-7.36 (m, 2H), 7.33-7.26 (m, 2H), 7.24-7.17 (m, 1H), 5.19 (dd, J=53.5, 3.3, 1H), 4.59 (t, J=7.8, 1H), 4.31-4.22 (m, 1H), 4.04-3.92 (m, 1H), 3.68 (dd, J=12.9, 3.7, 1H), 3.62-3.57 (m, 1H), 3.60-3.45 (m, 2H), 2.83-2.76 (m, 1H), 2.56-2.58 (m, 1H), 2.52-2.43 (m, 3H), 2.35 (m, 3H), 2.10 (dq, J=12.5, 6.3, 1H), 1.92-1.82 (m, 1H), 1.67-1.57 (m, 1H), 1.49 (s, 9H), 1.46-1.36 (m, 1H); MS (ESI+) m/z 432 (M+H)+.
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:38][CH:39]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 85%).
Reaction SMILES: NC1C=CC(Br)=CC=1C1C([C:15]([C:17]2[C:22]([C:23]3[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=3[NH2:30])=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=NC=CC=1.[BH4-].[Na+].C[OH:34]>>[NH2:30][C:24]1[CH:25]=[CH:26][C:27]([Br:29])=[CH:28][C:23]=1[CH:22]([OH:34])[C:17]1[CH:15]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CO
Reactant: Nc1ccc(Br)cc1-c1cccnc1C(=O)c1ncccc1-c1cc(Br)ccc1N
Agent: [BH4-]
Agent: [Na+]
Product: Nc1ccc(Br)cc1C(O)c1ccccn1
Reaction time: 0.5 h

Procedure:
In 100 ml of methanol was dissolved 10 g of 2-amino-5-bromophenyl-2-pyridylketone. To the solution was added 1.7 g of sodium borohydride and stirred for 30 minutes. The solvent methanol was evaporated off under reduced pressure. The residue was treated with an aqueous solution of hyrochloric acid. The decomposed residue was then neutralized with 200 ml of a sodium bicarbonate aqeous solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 2-amino-5-bromo-α-(2-pyridyl)benzyl alcohol (9.0 g) as prisms, m.p. 104°-105° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:11].[CH2:14]([N:16]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCCCN1CCc2cccc3c2C1CC3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CCCN1CCc2cccc3c2C1CC3)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
4-Methylbenzenesulfonyl chloride (20.9 mg, 0.11 mmol) was added to a solution of Ethyl-[3-(2,2a,4,5-tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-amine dihydrochloride (31.7 mg, 0.1 mmol) and N,N′-diisopropylethylamine (64.6 mg, 0.5 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (18.0 mg, 41%).
Reaction SMILES: C[O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18](OCOC)=[CH:17][CH:16]=3)C3CC(O)CC3[C:7]=2[CH:6]=1.[CH2:29]([Mg]Cl)C=C.CCOCC.C([O-])(O)=O.[Na+].C(C1CC2C(C3C=CC(OCOC)=CC=3)O[C:52]3[CH:53]=[CH:54][C:55]([C:58]([O:60][CH3:61])=[O:59])=C[C:57]=3C2C1)C>C1COCC1>[CH2:61]([O:60][C:58]([CH:55]1[CH:54]([CH2:53][CH:52]=[CH2:57])[C:6]2[C:5](=[CH:14][CH:13]=[C:12]([O:11][CH2:10][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=2)[O:4][C:3]1=[O:2])=[O:59])[CH3:29]
Reactant: CCC1CC2c3cc(C(=O)OC)ccc3OC(c3ccc(OCOC)cc3)C2C1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Reactant: C=CC[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1c2cc(OCc3ccccc3)ccc2OC(=O)C1C(=O)OCC

Procedure:
To a 0 C solution of Preparation 27 (10.0 g, 30.8 mmol) in THF (125 mL) add a solution of allyl magnesium chloride in Et2O (46 mL, 1.0 M, 46 mmol). Maintain the reaction at 0 C for 30 min, then pour the reaction contents into a solution of ½ satd, NaHCO3 (250 mL). Extract the solution with Et2O (2×150 mL) and EtOAc (150 mL). Wash the combined organic extracts with H2O(150 mL) and brine (150 mL), dry the organics over Na2SO4, and concentrate to afford a brown oil. Purify the product by MPLC (0% to 15% to 25% EtOAc/hexanes) to afford Preparation 38 (7.72 g, 68%) as a light yellow solid. 1H NMR (CDCl3) δ 7.31-7.43 (m, 5 H), 7.01 (d, J=8.8 Hz, 1 H), 6.87 (dd, J=8.8, 3.0 Hz, 1 H), 6.79 (d, J=3.0 Hz, 1 H), 5.71 (m, 1 H), 5.15 (dd, J=0.8, 9.8 Hz, 1 H), 5.10 (dd, J=0.8, 17.6 Hz, 1 H), 5.04 (A of AB, JAB=14.2Hz, 1 H), 5.03 (B of AB, JAB=14.2 Hz, 1 H), 4.08 (m, 2 H), 3.80 (d, J=2.4 Hz, 1 H), 3.41 (m, 1 H), 2.35 (m, 2 H), 1.08 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 50 parts of 4-nitroaniline, 40 parts of triethylamine and 525 parts of chloroform were fed, and then cooled to 5° C. or below. While the reaction solution obtained was kept at 5° C. or below, a solution prepared by dissolving 41 parts of methacrylic acid chloride in 30 parts of chloroform was dropwise added thereto. After its addition made dropwise was completed, the reaction solution was heated to room temperature, and, as it was, the reaction was carried out for 4 hours. After the reaction was completed, the organic phase formed was washed with 200 parts of ion-exchanged water. This organic phase was then dried with sodium sulfate, and thereafter the solvent was evaporated off under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 22 parts of an intermediate N-(4-nitrophenyl)methacrylamide (yield: 31%).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:32])([CH3:31])NC(=O)C.NS(O)(=O)=O.[Br:38]N1C(=O)CCC1=O>ClCCl>[Br:38][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:32])([CH3:31])[CH3:25])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N[Si](C)(C)C
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a refluxing suspension of 329 mg (0.95 mmole) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, 298 mg (2.27 mmoles) of N-trimethylsilylacetamide were added and a clear, colorless solution was obtained after 15 minutes. Refluxing was continued for another 30 minutes after which 300 mg (3.06 mmoles) of amidosulfonic acid were added. The mixture was diluted with dichloromethane to 40 ml and cooled in an ice-bath. Bromination was carried out in one hour using 280 mg (1.57 mmoles) of N-bromosuccinimide as the brominating agent to obtain a yield of 50% of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](C(O)=O)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:21]=1.CN([CH:34]=[O:35])C>ClCCl>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:34]([C:15]2[C:10]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:35])[CH:21]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: NCCCCc1cccnc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(NCCCCc1cccnc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A suspension of 5.0 g of biphenyl-4-carboxylic acid in 20 mL of dichloromethane and 0.5 mL of DMF was treated with 2.1 mL of thionyl chloride and the resulting mixture was heated to reflux until a clear solution was obtained. The mixture was cooled to room temperature and 7.8 g of 3-pyridinebutanamine was slowly added. The reaction mixture was stirred for 10 minutes. was diluted with 150 mL of dichloromethane and was washed with 50 mL of 1N sodium hydroxide. The organic layer was dried over potassium carbonate and evaporated and the residue was crystallized from ethyl acetate-hexane with a charcoal treatment to yield 5.0 g (61%) of N-[4-(3-pyridinyl)butyl][1,1'-biphenyl]-carboxamide, mp 122.5°-126° C. The hydrochloride salt was recrystallized from isopropanol-ether, mp 158°-160° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[CH:8]=1.C(N([CH2:22][CH3:23])CC)C.Cl>ClCCl>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][C:9]=1[O:16][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:15])[CH3:14].[CH:22]([O:15][CH:13]([CH3:10])[CH3:14])([CH3:23])[CH3:1]
Reactant: CCN(CC)CC
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Product: CC(C)OC(C)C
Reaction time: 1 h

Procedure:
4.42 ml of methanesulphonyl chloride are added dropwise to a solution of 10.0 g 1-(4-bromo-2-hydroxy-phenyl)-ethanone [30186-18-6] and 13.0 ml of triethylamine in 200 ml dichloromethane at 0° C. The reaction mixture is worked up after 1 hour by pouring into 250 ml cold 1N HCl and extracting with tert-butyl methyl ether (2×)—the combined organic layers are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as light yellow crystals from the residue by re-crystallization from diisopropyl ether. Rf=0.51 (1:1 EtOAc-heptane). Rt=3.94 (gradient I). m.p. 62.0-62.1° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:5][CH:4]=1)[CH3:2].O=C(Cl)[O:22][C:23](Cl)(Cl)Cl.[CH2:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:28]([NH:36][C:23]([N:16]1[CH2:17][CH2:18][C:11]2([C:10](=[O:19])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:13][CH2:12]2)[CH2:14][CH2:15]1)=[O:22])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCc1ccc(N2CCC3(CCN(C(=O)NCCc4ccccc4)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-Ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and phenethylamine. MS (ESI): 406.4 (MH+).
Reaction SMILES: [C:1]1([CH:11]2[CH2:16][CH2:15][N:14](NC(=O)OCC)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BrH:23]>>[BrH:23].[C:1]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NN1CCC(c2cccc3ccccc23)CC1
Agent: Br
Product: c1ccc2c(C3CCNCC3)cccc2c1
Yield: 86.64 %

Procedure:
10.5 g of the compound obtained in Stage A in 300 ml of a 48% hydrobromic acid solution, are refluxed for 20 hours. After evaporation and washing twice with ethanol, the residue is taken up in acetone and the mixture then filtered to give 4-(naphth-1-yl)piperidine hydrobromide.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH:17]1([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:17]1([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH2:24][CH2:23]2)[CH2:18][CH2:19]1
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](CN1CCC(OCC2CC2)CC1)CN1C(=O)COc2ccccc21
Reaction time: 72 h
Yield: 64.2 %

Procedure:
A reaction flask was charged with (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.199 g, 0.6 mmol), 4-cyclopropylmethoxypiperidine (0.093 g, 0.6 mmol), and K2CO3 (0.124 g, 0.9 mmol) in MeCN (2 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiO2; EtOAc) to give the title compound (0.138 g, 64%). 1H NMR (CDCl3) δ 6.99-6.97 (m, 1H), 6.85-6.79 (m, 3H), 4.47-4.35 (m, 2H), 3.85-3.74 (m, 2H), 3.14-3.08 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.64-2.61 (m, 1H), 2.49-2.46 (m, 1H), 2.10-2.04 (m, 2H), 2.00-1.68 (m, 6H), 1.47-1.38 (m, 2H), 0.90-0.84 (m, 1H), 0.71 (d, J=6.6 Hz, 3H), 0.37-0.33 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CDCl3) δ 164.6, 145.4, 128.5, 123.4, 122.4, 116.9, 115.3, 75.0, 72.5, 67.5, 63.3, 52.6, 51.6, 45.0, 31.6, 31.5, 29.1, 16.7, 10.9, 2.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:13]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21](=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:30])[N:14]=1)[CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH:32](=O)[CH3:33].[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:36].[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:13]1[N:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:21](=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:30])[N:14]=1)[CH2:9][CH2:10][CH2:11][N:12]([CH2:32][CH3:33])[CH2:35][CH3:36])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC=O
Reactant: Cc1cccc2nc(C(CCCN)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)CCCC(NC(=O)OC(C)(C)C)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 10-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen, and then charged with the compound 104 (100 mg, 0.24 mmol) and 1,2-dichloroethane (2 mL). Acetaldehyde (42 mg, 0.85 mmol) and sodium triacetoxyborohydride (400 mg, 1.90 mmol) were subsequently added. The reaction mixture was stirred for 18 h at ambient temperature, evaporated to dryness, and the resulting residue was dissolved in methanol (20 mL). This methanolic solution was treated with 10% palladium on carbon (5 mg, 50% wet), stirred for 30 min, evaporated to dryness, and partitioned between 10% aqueous potassium carbonate (20 mL) and methylene chloride (20 mL). The organic layer was separated and dried over sodium sulfate. Filtration of the organic layer followed by concentration gave the compound 105 as a yellow oil, which was used without any further purification. 1H NMR (CDCl3) δ 7.51-7.63 (m, 5H), 7.41 (d, 1H, J=7.4 Hz), 7.29 (d, 1H, J=7.15 Hz), 7.22 (d, 1H, J=7.1 Hz), 6.10 (d, 1H, J=8.8 Hz), 4.38-4.52 (m, 1H), 2.81 (s, 3H), 2.32-2.50 (m, 4H), 2.08-2.27 (m, 2H), 1.47-1.73 (m, 4H), 1.42 (s, 9H, 1.25-1.38 (m, 1H), 0.96 (t, 6H, J=7.2 Hz); ESI-MS m/z=479 (MH+). The reaction described above and compound 105 are shown below.