Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CN(C)C=O.[Cu]>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8]
Reactant: Ic1ccccn1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(Oc3ccccn3)cc2n1Cc1ccccn1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 220, 26 mg, 0.060 mmol) in dimethylformamide (1 ml) stirring at room temperature, was added cesium carbonate (83 mg, 0.25 mmol) and the reaction stirred for 5 minutes. 2-iodopyridine (0.05 mL, 0.09 g, 0.47 mmol) and then copper powder (7.0 mg, 0.11 mmol) was then directly added and the resulting mixture heated at 100° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (50% EtOAc-hexanes, 100 % EtOAc) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[Cl:17].Cl.N1C=CC=CC=1>Cl>[Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A mixture of 6.0 g of 6,7-dichloro-5-methoxy-2-phenylbenzo[b]thiophene and 42 g of pyridine hydrochloride is stirred at 190°-195° for 4 hours. The slightly cooled reaction mixture is poured into a mixture of 800 g of ice and 10 ml of conc. hydrochloric acid. Extraction with ether, followed by washing and drying, yields 5.23 g of 6,7-dichloro-5-hydroxy-2-phenylbenzo[b]thiophene as an off-white solid, mp 122°-124°. Recrystallization from ether-hexane yields prisms, mp 124°-126°.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C:5](=[O:7])[N:4]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:27])[O:6][C:5](=[O:7])[N:4]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)N(C2CCNCC2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 250-mL round-bottomed flask were added (S)-tert-butyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)piperidine-1-carboxylate (4530 mg, 12.10 mmol) and 2,2,2-trifluoroacetic acid (23.16 mL, 302 mmol) in DCM (24.200 mL). The mixture was then stirred at rt overnight. The reaction mixture was concentrated in vacuo. The material thus obtained was dissolved in DCM, and extracted with water (3×). The aqueous layers were combined and the pH of the solution was adjusted to above 8 by adding 35% NH4OH water solution. The solution was then extracted with EtOAc (3×). The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to give the residual material as a yellow solid. The material was used without further purification.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15]>O>[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]
Reactant: O=S(=O)([O-])[O-]
Agent: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=S(=O)(O)O

Procedure:
contacting glucosamine hydrochloride with a sulfate of said metal in the presence of water to form an aqueous solution of glucosamine sulfate metal chloride; and
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCCC2)c(C(=O)O)c1

Procedure:
30 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 150 ml piperidine. The temperature of the reaction was allowed to rise during the addition. After the addition was complete, the reaction was heated at reflux temperature for two hours. The hot reaction mixture was poured into ice water, made acid by the addition of concentrated HCl until precipitation of the product was complete and filtered. The filter cake was recrystallized from ethanol to give 30.4 grams 5-nitro-2-piperidinobenzoic acid. m.p. = 201°-203° C. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-piperidinobenzoic acid. m.p. = 232°-235° C.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:41][O:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[CH2:45][CH2:46][N:47]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C@@H:60]([NH2:62])[CH3:61])=[CH:56][CH:55]=1)[CH2:48]2>CN(C=O)C>[CH3:41][O:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[CH2:45][CH2:46][N:47]([CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C@@H:60]([NH:62][C:6]([C:5]3[S:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH3:61])=[CH:58][CH:59]=1)[CH2:48]2
Reactant: COc1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Reactant: O=C(O)c1cncs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c1CCN(Cc1ccc([C@H](C)NC(=O)c3cncs3)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
37 mg (0.29 mmol) Thiazole-5-carboxylic acid, 83 μl (0.48 mmol) DIPEA and 154 mg (0.481 mmol) TBTU in 0.5 mL DMF are stirred for 10 min at r.t. Then 80 mg (0.24 mmol) (S)-1-[4-(5-methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethylamine hydrochloride (example XXXIII.2) in 1.0 mL DMF and 102 μl (0.601 mmol) DIPEA are added and the resulting mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by the addition of 200 μL water and purified by HPLC.
Reaction SMILES: [NH:1]1[CH2:3][CH:2]1[C:4]([NH2:6])=[O:5].Cl[C:8]([O:10][CH3:11])=[O:9]>>[C:4]([CH:2]1[CH2:3][N:1]1[C:8]([O:10][CH3:11])=[O:9])(=[O:5])[NH2:6]
Reactant: NC(=O)C1CN1
Reactant: COC(=O)Cl
Product: COC(=O)N1CC1C(N)=O

Procedure:
In an analogous manner, by reacting 2-aziridine-carboxamide with methyl chloroformate, there is obtained methyl 2-carbamoyl-1-aziridine-carboxylate which, after recrystallization from toluene, melts at 117°-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:18]([N:21](CC2C=CC(OC)=CC=2OC)[C:22]2[S:26][N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])[CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)#[N:2].Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([S:18]([NH:21][C:22]2[S:26][N:25]=[CH:24][N:23]=2)(=[O:19])=[O:20])[CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)#[N:2]
Reactant: COc1cccc(Sc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ncns3)cc2C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(Sc2ccc(S(=O)(=O)Nc3ncns3)cc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To 3-cyano-N-(2,4-dimethoxybenzyl)-4-[(3-methoxyphenyl)thio]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 17, 0.204 g, 0.368 mmol) was added a 4M solution of hydrogen chloride in 1,4-dioxane. The reaction was stirred at ambient temperature overnight. The reaction was quenched with methanol and passed through a plug of Arbocel™ to give a pale yellow solution. The solution was concentrated in vacuo to give a yellow solid. The solid was purified by silica gel flash column chromatography to give a white solid (0.141 g, 95%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:31][NH:32][O:33][CH3:34].Cl>C(Cl)Cl>[CH3:34][O:33][N:32]([CH3:31])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH:15]=1)=[O:18]
Reactant: CNOC
Reactant: O=C(O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a suspension of 2-phenylbenzo[d]oxazole-6-carboxylic acid (2.0 g, ca. 8.4 mmol) in CH2Cl2 was added CDI (1.6 g, 9.9 mmol, 1.2 eq) at 0° C. The reaction was warmed to room temperature then stirred for 1 h to give a homogeneous solution. The mixture was cooled to 0° C. before MeNHOMe-HCl (0.98 g, 10.0 mmol, 1.2 eq) was added. After 12 h, the reaction was quenched with H2O and extracted with CH2Cl2 (3×50 mL). Solvent was removed then crude product was purified by flash column chromatography (0-25% EtOAc in hexanes) to afford N-methoxy-N-methyl-2-phenylbenzo[d]oxazole-6-carboxamide (1.57 g, 5.6 mmol, 67% over two steps).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[Li+]>C1COCC1.O>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reaction time: 70 h
Yield: 92.4 %

Procedure:
To a mixture of Methyl 2-(3-(trifluoromethoxy)phenyl)quinoline-8-carboxylate (1.1 g, 3.16 mmol) dissolved in THF (20 mL) was added a mixture of lithium hydroxide (227 mg, 9.5 mmol) in water (15 mL). The reaction was stirred 70 hours. The reaction mixture was concentrated to remove the THF and the aqueous solution was adjusted to pH=1 with 4N HCl (aq). The solid was collected by filtration, rinsed with water, and dried under vacuum to obtain 2-(3-(trifluoromethoxy)phenyl)quinoline-8-carboxylic acid as a tan solid (973 mg, 92% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.[C:14]12([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[C:27](Cl)=[O:28])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:12][CH:13]=3)=[O:28])[CH2:15][CH:16]3[CH2:22][CH:20]([CH2:19][CH:18]([CH2:17]3)[CH2:23]1)[CH2:21]2
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C=CCOC(=O)c1ccc(N)cc1
Product: C=CCOC(=O)c1ccc(NC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a manner analogous to Example 1(a) starting with 12.6 g (71 mmoles) of allyl 4-aminobenzoate and 21.6 g (71 mmoles) of 3-(1-adamantyl)-4-methoxy benzoyl chloride, 32 g of the expected amide whose melting point is 191°-192° C. are isolated.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH3:26][C:27](O)(C#C)C.[OH-].[K+]>C1COCC1.C(N(CC)CC)C.C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:26]([C:2]1[N:3]=[CH:4][N:5]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1)#[CH:27]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
To a stirred solution of 4-iodo-1-trityl-1H-imidazole (830 mg, 1.96 mmol) and Pd(Ph3P)2Cl2 (40 mg, 3 mol %) in THF (8 mL) and triethylamine (2 mL) was added 2-methyl-but-3-yn-2-ol (0.30 mL, 3.10 mmol) and the reaction vessel was evacuated and backfilled with nitrogen three times to remove atmospheric oxygen. Copper (I) iodide (40 mg, 10 mol %) was added and the reaction was stirred at room temperature for 5 h. After this time the solvent was removed under vacuum and the residue was filtered through a plug of silica gel (eluent=2:1 hexane:ethyl acetate) to give the crude alkynol product. This material was dissolved in isopropanol (10 mL) and treated with potassium hydroxide (150 mg, 2.67 mmol). The reaction mixture was heated to 70° C. for 4 h and then concentrated under vacuum and purified by silica-gel chromatography (eluent=4:1 hexane:ethyl acetate) to afford the product as a white solid (258 mg, 41% yield over two steps). 1H-NMR (CDCl3) δ 7.41 (s, 1H), 7.38-7.31 (m, 9H), 7.13-7.07 (m, 6H), 7.05 (d, J=1 Hz), 3.05 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]=[CH:10][C:11](=[CH:12][CH:13]=[CH:14][C:15](OC)=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[CH:12][CH:13]=[CH:14][CH2:15][OH:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C=CC=C1C=CCCc2ccccc21
Solvent: CCOC(C)=O
Product: OCC=CC=C1CCCCc2ccccc21

Procedure:
By the method of Preparation 2, except to quench into saturated NH4Cl and extract into ethyl acetate, methyl 4-(8,9-dihydrobenzocyclohepten-5-ylidene)-2-butenoate (7.7 g., 0.032 mol) was reduced to yield present title product which was recrystallized from isopropyl ether (3.8 g, 56%, mp: 108-109° C). 1H-NMR (CDCl3) delta: 7.61 (d, 7Hz, 1H); 7.25-7.02 (m, 3H); 5.51-5.79 (m, 2H); 4.02 (d, 4Hz, 2H); 2.39-3.01 (m, 6H); 1.80-2.01 (m, 4H). Anal Calcd. for C15H20O2 : C, 77.55; H, 8.68. Found: C, 77.72; H, 8.69.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.[F-:25].[K+].O>CN(C=O)C>[F:25][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: [F-]
Reactant: CCCc1c2c(c(Cl)c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c2c(c(F)c3c(=O)cc(C(=O)OCC)oc13)CCCC2

Procedure:
A solution of ethyl 5-chloro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (9 g) and desiccated potassium fluoride (2.32 g) in DMF (50 ml) was heated at 160° for 3.5 hours. After cooling, the reaction mixture was poured into water (250 ml) and the precipitate filtered off, washed with water and dried. Recrystallisation from cyclohexane gave the title compound as a pale-yellow solid, mp 126°-9°.
Reaction SMILES: C1(=O)CCCCCCCCCCC1.NO.[C:16]1(=[O:29])[NH:28]CCCCC[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C1C=CC=CC=1>[C:16]([NH2:28])(=[O:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCCCCCCCCCCN1
Agent: NO
Agent: O=C1CCCCCCCCCCC1
Solvent: N#Cc1ccccc1
Product: NC(=O)c1ccccc1

Procedure:
The reaction was carried out in a similar manner to Example 1 except that the rearrangement solvent was replaced with benzonitrile. As the passage of operation time benzamidoxime was detected which was generated by reaction of benzonitrile contained in the recycled liquid to the oxime-forming step with hydroxylamine. As this progress, an amount of cyclododecanone increased due to a shortage of hydroxylamine to be used for the oxime-formation reaction. Although the yield of laurolactam until the rearrangement step was initially 96.0%, the yield declined to 82% as a result of the operation after 8 hours. In addition, benzonitrile was hydrolyzed to yield benzamide and the like during the treatment with sodium hydroxide, and the purity of laurolactam obtained by distillation was 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:15][C:16]([NH2:18])=[O:17]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:15][C:16]([NH2:18])=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccn(CC(N)=O)c2c1

Procedure:
Intermediate C12 was prepared as described for Intermediate C2 using 6-methoxyindole (489 mg, 3.32 mmol), sodium hydride (160 mg, 3.98 mmol) and iodoacetamide (615 mg, 3.32 mmol) in DMF (50 mL). Two recrystallizations from ethyl acatete yielded intermediate C12 as a whte solid (252 mg, 37%). m.p. 210.1–211.0° C. 1H NMR (200 MHz, DMSO-D6) δ 7.48 (br s, 1H), 7.41 (d, 8.6 Hz, 1H), 7.25 (br s, 1H), 7.16 (d, 3.2 Hz, 1H), 6.91 (d, 2.0 Hz, 1H), 6.69 (dd, 6.4 Hz, 2.2 Hz, 1H), 6.35 (d, 0.8 Hz, 1H), 4.74 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: B.C1COCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][C:14](O)=[O:15]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][CH2:14][OH:15]
Reactant: COc1cccc(OCC(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: COc1cccc(OCCO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A 250 ml three-necked round-bottomed flask equipped with temperature probe and nitrogen bubbler was charged with 1M Borane/THF solution (60.4 ml, 60.4 m mol) and a solution of (3-Methoxy-phenoxy)-acetic acid (5.00 g, 27.4 mmol) in THF (2.0 ml) was added dropwise, maintaining reaction temperature below 30° C. The reaction was allowed to stir at room temperature overnight. The reaction was quenched by dropwise addition of methanol (20 ml) maintaining the reaction temperature below 35° C. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to yield 2-(3-Methoxy-phenoxy)-ethanol (4.51 g, 98%) as a clear oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH:14]=[CH2:15])[NH:9]2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C(Cl)(Cl)Cl.Cl.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH:14]=[CH2:15])[N:9]2[C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])=[CH:6][CH:7]=1
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1
Reactant: C=CCCC(=O)Cl
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=CCCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidine (460 mg) and diisopropylamine (0.59 mL) in methylene chloride (10 mL), 4-pentenoyl chloride (0.37 mL) was added, and the reaction solution was stirred at room temperature for 1.5 hours. Chloroform and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 307 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([CH3:28])[N:4]=1>[Pd].CO>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([CH3:28])[N:4]=1
Reactant: Cc1cc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2cccc(C(=O)Nc3ccc(N)cc3)c2)nc(N)n1
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
To a suspension of compound B2 (1.41 g, 3.51 mmol) in (MeOH) 30 (mL) was added 10% Pd/C (20 mg) and hydrogenated under 45 Hg mm for 5 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness. The residue was dissolved in a small volume of MeOH then 1 ml of 1.25M HCl in MeOH was added, stirred 10 min and evaporated to dryness. The residue was recrystallized from MeOH/EtOAc to give B3 (758 mg, 58%); m.p. (MeOH/EtOAc); 1H NMR [(CD3)2SO] δ 12.70 (br, 1H, NH), 10.83 (brs, 1H, NH), 10.43 (s, 1H, NH), 9.70 (v br, 2H, NH2), 8.05-7.84 (br m, 2H, ArH), 7.85-7.75 (m, 4H, ArH & NH2), 7.55 (t, J=7.9 Hz, 1H, ArH), 7.28 (d, J=8.7 Hz, 2H, ArH), 6.24 (s, 1H, ArH), 2.30 (s, 3H, CH3); mass APCl+335.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH2:13]1)[CH:6]=[CH:5]2.Cl>ClCCl.CO>[Cl:1][C:2]1[C:3]([NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][OH:20])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(CCC1CCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a stirred solution of N-[6-chloro-2-[(3S)-3-[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclopentanepropanamide (Example 63(a)) (200 mg) in dichloromethane:methanol 1:1 (3 mL) under nitrogen, was added HCl (1 mL, 4M solution in dioxane). The reaction mixture was stirred at room temperature for 30 minutes, then evaporated to dryness. Purification (HPLC, Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) gave the title compound as a solid (35 mg).