Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1([NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:32]([CH:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN(C4CCCCC4)C4CCCCC4)n3)c2[C@@H]2CCN12
Yield: 51.2 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one were stirred at 65° overnight with 5 ml (25 mmol) of dicyclohexylamine and 7 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.8 g (51%) of (S)-8-chloro-1-(5-dicyclohexylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 155°-185°.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].CI.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1O>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[O:4][CH3:1]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Anhydrous K2CO3 (21.9 g, 0.159 mol) and methyl iodide (10.8 mL, 0.178 mol) were added to a solution of 2,5-dichlorophenol (23.5 g, 0.144 mol) in 215 mL acetone. The reaction was allowed to stir at room temperature for 20 hours, then filtered through a celite pad. The filtrate was concentrated to a residue which was taken up in diethylether. The ether solution was washed with 10% NaHSO3, water, several portions of 1M NaOH, and brine, then dried with anhydrous Na2SO4. Upon filtration and concentration, the residue was distilled (8 mm Hg, 110° C.) to yield 23.7 g (93.5%) of a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9]([Cl:15])=[O:10]
Reactant: CC1(C)CCC(C)(C)C1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)C1C(=O)Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
2.51 g of 2,2,5,5-tetramethylcyclopentanecarboxylic acid was dissolved in 10 ml of toluene, and 2.5 ml of thionyl chloride was added thereto. The mixture was stirred at 80° C. for 3 hours. The reaction solution was concentrated and then distilled under reduced pressure, whereby 2.0 g of 2,2,5,5-tetramethylcyclopentanecarbonyl chloride was obtained. Yield 69%. (b.p. 110-120° C./60 mmHg)
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:20])[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:20])[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][C:23](=[O:25])[CH3:24])[CH:8]=2)[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cccc(C2c3cc(N)ccc3OC(C)(C)C2O)c1=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(c1cccn(C)c1=O)C(O)C(C)(C)O2
Reaction time: 24 h

Procedure:
A mixture of 1 g of 2,2-dimethyl-4-(1-methyl-1,2-dihydro-2-oxo-3-pyridyl)-6-amino-3-chromanol, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20° for 24 hours. The mixture is evaporated, worked up in the customary manner and 2,2-dimethyl-4-(1-methyl-1,2-dihydro-2-oxo-3-pyridyl)-6-acetamido-3-chromanol is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:16])([F:15])[F:17])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:35])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1ccc(F)c2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC

Procedure:
In the same way as in Example 148, 300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 156 mg (0.88 mmol) of 5-amino-8-fluoroquinolin-2(1H)-one and 0.55 ml of titanium tert-butoxide is reacted to give 5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}-8-fluoroquinolin-2(1H)-one. 480 mg of crude imine are cyclized in the same way as in Example 148 at −30° C. with 7.6 ml (7.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-70%) yields 119 mg of desired product.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15]CC)=O)[C:8]([O:10]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2[NH2:28].C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[F:18][C:19]1[CH:27]=[CH:26][C:25]2[C:21](=[C:22]3[N:28]=[C:8]([OH:10])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:13]([OH:15])[N:23]3[N:24]=2)[CH:20]=1
Reactant: Nc1n[nH]c2ccc(F)cc12
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Oc1nc2c3cc(F)ccc3nn2c(O)c1-c1ccccc1
Yield: 78.8 %

Procedure:
14.3 g (60.2 mmol) Diethyl phenylmalonate, 9.1 g (60.2 mol) 5-fluoro-1H-indazol-3-ylamine and 25.3 mL tributyl amine were heated for 15 h at 180° C. The reaction mixture was treated with 2M sodium hydroxide and water and extracted with tert-butyl methyl ether. The organic phase was discarded and the aqueous phase was acidified with conc. hydrochloric acid. The precipitate was collected by filtration and washed with water to obtain 14 g of the desired product which is 90% pure. MS (Cl, M+1): 296
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH:22](=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][O:7][C:6]1[CH:5]=[C:4]([CH:21]=[CH:20][CH:19]=1)[CH2:3][O:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[CH:22]=[O:30]
Reactant: O=Cc1ccccc1O
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
2-(3-Chloromethyl-phenoxymethyl)-quinoline (371 mg, 1.3 mmol, example 49) and salicylaldehyde (133 μL, 1.25 mmol) are dissolved in acetone (10 mL). K2CO3 (525 mg, 3.75 mmol) is added and the contents are heated to reflux for 16 hrs. The reaction is cooled to r.t., poured into water (100 mL) and extracted with ethyl ether (3×50 mL). The ether layers are combined and washed with Brine (3×75 mL) and dried over MgSO4. The crude material is preadsorbed onto silica gel and purified by flash chromatography (silica, 20 to 25% ethyl acetate in hexanes) to give the title compound. MS (ion spray) 370 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:32].C(OCC)C>CO>[IH:32].[F:27][C:24]([F:25])([F:26])[CH2:23][O:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOCC(F)(F)F)CC1
Agent: I
Solvent: CO
Solvent: CCOCC
Product: FC(F)(F)COCCn1c(N2CCCNCC2)nc2ccccc21
Reaction time: 4 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.47 g, 1.1 mmol) and aqueous hydriodic acid (0.70 mL, 9,42 mmol) in methanol (10 mL). After 4 hours, evaporate to remove most of the methanol to give a residue. Combine the residue and diethyl ether (50 mL) and stir to give a solid. Collect the solid by filtration to give, after drying, the title compound: Rf =0.39 (silica gel, 10% methanol/dichloromethane/5% acetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([N+:15]([O-])=O)[CH:4]=1.C(O)C>[Ni].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccccc2)c(N)c1
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A Parr bottle charged with 4-methoxy-2-nitrobiphenyl (27.6 g, 120 mmol), Raney nickel (1.5 g), ethanol (100 mL), and H2O (100 mL) was rocked under hydrogen (60 psi) for 3 h. The suspension was filtered through Celite, the cake washed with ethanol (500 mL) and tetrahydrofuran (500 mL), and the filtrate concentrated in vacuo. The residual suspension was digested with CH2Cl2 (300 mL), washed with H2O (300 mL), and the organic portion extracted with 1 N HCl (4×200 mL). The combined extracts were made basic with 50% NaOH, extracted with CH2Cl2 (3×200 mL), and the organic extracts washed with brine (300 mL), dried (K2CO3), filtered, and concentrated in vacuo to give 24 g (100%) of the title compound which was used without further purification: 1H NMR (300 MHz, CDCl3) δ 3.78 (s, 3H), 3.90 (br s, 2H), 6.34 (d, J=2 Hz, 1H), 6.41 (dd, J=8, 2 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 7.15-7.33 (m, 2H), 7.36-7.41 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:17][Si](C)(C)N[Si](C)(C)C>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)([OH:9])[CH3:17])=[CH:11][CH:12]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Product: CC(O)(c1ccc(O)cc1)c1ccc(Br)cc1

Procedure:
Ea) A mixture of 2.77 g of 4-hydroxyphenyl-(4-bromo-phenyl)-methanone and 50 ml of hexamethyidisilazane is heated under reflux for 4 h., then concentrated and dried. The resulting 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone is dissolved in 60 ml of toluene and treated at room temperature under argon with 11 ml of methylmagnesium chloride solution (22% in THF). The mixture is boiled under reflux. After cooling the mixture is treated with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and dried. After evaporation of the ethyl acetate extracts there are obtained 3.36 g of (RS)-4-[1-(4-bromo-phenyl)-1-hydroxy-ethyl]-phenol, MS: m/e 293 (M+H+, 1Br).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])=[C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH:14]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 464.4 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.80-6.65 (m, 8H), 4.95-2.70 (m, 5H), 1.95-0.65 (m, 8H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:25]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]=2[OH:32])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](F)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[F:33]C1C=C(NC(N)=O)C=C(C(F)(F)F)C=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:25]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]=2[OH:32])[NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:17]=[C:18]([F:33])[CH:19]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: NC(=O)Nc1cc(F)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Product: N#Cc1ccc(C(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 44), using 1-(3-fluoro-5-(trifluoromethyl)phenyl)urea (intermediate 43, 630 mg, 1.99 mmol) as starting material. Yield: 378 mg; ESI mass spectrum [M+H]+=448; Retention time HPLC: 1.07 min (Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:24]3[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: FC(F)(F)c1ccc(Cl)c(I)c1
Product: O=C1N(c2cc(C(F)(F)F)ccc2Cl)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-chloro-2-iodo-4-trifluoromethyl-benzene. White solid. MS (ESI): 507.0 MH+).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[C:5]([CH3:13])[CH:4]=1)#[CH:2].Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(NC(C)C)(C)C>C1COCC1.[Cu]I>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[C:5]([CH3:13])[CH:4]=2)=[N:16][CH:17]=1
Reactant: C#Cc1ccc(OCCO)c(C)c1
Reactant: Brc1ccc(Br)nc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(Br)cn2)ccc1OCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.26 g (1.36 mmol) of CuI was added to a degassed solution of 11.98 g (68.00 mmol) of 2-(4-ethynyl-2-methylphenoxy)ethanol, 16.11 g (68.00 mmol) of 2,5-dibromopyridine, 0.96 g (1.36 mmol) of bis(triphenylphosphane)palladium (II) chloride, and 19.22 mL (136.00 mmol) of diisopropylamine in 500 mL of THF and the mixture was stirred for 4 hours at RT. The reaction mixture was evaporated down in vacuo and the residue taken up in 800 mL of EtOAc. The organic phase was with water and saturated aqueous NaCl solution washed, dried over sodium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, gradient DCM/EtOAc 90:10→80:20). Yield: 13.20 g (58% of theoretical); C16H14BrNO2 (M=332.192); calc.: molpeak (M+H)+: 332/334 (Br); found: molpeak (M+H)+: 332/334 (Br); Rf value: 0.39 (silica gel, cyc/EtOAc 1:1).
Reaction SMILES: [O:1]1CCOCC1.[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][N:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[C:32]([CH3:41])=[CH:31][C:30]4=[O:42])([C:25]#[N:26])[CH2:21][CH2:20]3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1.[OH-].[K+].C(O)C>C(OCC)C>[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][N:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[C:32]([CH3:41])=[CH:31][C:30]4=[O:42])([C:25]([NH2:26])=[O:1])[CH2:21][CH2:20]3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: C1COCCO1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3(C#N)CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc2c(C)cc(=O)n(CCC3(C(N)=O)CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C

Procedure:
To 1 mL of a 1,4-dioxane solution containing 30 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)cyclohexanecarbonitrile, 1 mL of 20% aqueous potassium hydroxide solution and 1 mL of ethanol were added at room temperature and refluxed with heating for 4 hours. Further, 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 4 hours, thereafter 1.5 mL of 20% aqueous potassium hydroxide solution was further added and refluxed with heating for 9.5 hours. After 1 mL of 20% aqueous potassium hydroxide solution and 0.5 mL of ethanol were added and refluxed with heating for 1 hour, further 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 8 hours. After 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 6 hours, the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure. The residue was adjusted to pH 11 with 2.0 mol/L hydrochloric acid and chloroform was added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained, diethyl ether was added, and the resulting solid was filtered to give 21 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)cyclohexanecarboxamide as a white solid.
Reaction SMILES: C[N:2]([CH3:5])C=O.[N-]=[N+]=[N-].[Na+].N([C:13]1[CH:14]=[C:15]([CH:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:20]C)[CH:16]=[CH:17][CH:18]=1)=[N+]=[N-].C(O)(C)C>O>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH:19]([C:15]1[CH:14]=[CH:13][CH:18]=[CH:17][CH:16]=1)[CH2:20][CH2:5][NH2:2]
Reactant: CCC(Oc1ccccc1OC)c1cccc(N=[N+]=[N-])c1
Reactant: CN(C)C=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccccc1OC(CCN)c1ccccc1
Temperature: 95 °C

Procedure:
A solution of 2.6 g. of sodium azide in 10 ml. of water was placed in a 100 ml. three-neck, round-bottom flask equipped with stirrer, condenser and thermometer. A second solution containing 2.76 g. of 3-chloro-1-(o-methoxyphenoxy)propylbenzene (as provided by the procedure of Example 2) in 30 ml. of dimethylformamide was added to the sodium azide solution, and the resulting mixture heated at 95° C. overnight. The reaction mixture was cooled, diluted with water and extracted three times with ether. The ether extracts were combined, the combined extracts were washed five times with water followed by a saturated aqueous sodium chloride wash, and were then dried. Evaporation of the ether in vacuo yielded a colorless liquid comprising 3-azido-1-(o-methoxyphenoxy)propylbenzene. Forty-one grams of this latter compound were dissolved in 350 ml. of isopropanol. The resulting solution was placed in a 1 l. round-bottom flask equipped with magnetic stirrer condenser and drying tube. Fifteen and two-tenths grams of 96% sodium borohydride in the solid form were added to the azide solution. The resulting mixture was heating to refluxing temperature overnight and then cooled. The alcohol was evaporated therefrom in vacuo. About 1.5 l. of water were added, and the resulting aqueous mixture acidified cautiously with 2N aqueous hydrochloric acid. 3-(o-methoxyphenoxy)-3-phenylpropylamine produced in the above reaction was soluble in the aqueous acidic layer as the hydrochloride salt. The acidic aqueous layer was extracted three times with ether, and the ether extracts saved to recover unreacted starting material. The acidic layer was then made basic with 5N aqueous sodium hydroxide. The primary amine, being insoluble in base, separated and was extracted into ether. The ether layer was separated, and the aqueous alkaline layer extracted twice more with ether. The ether extracts were combined, and the combined layers washed with a saturated aqueous sodium chloride solution. Evaporation of the ether in vacuo yielded about 17 g. of 3-(o-methoxyphenoxy)-3-phenylpropylamine which was converted to the oxalate sale by the procedure of Example 1. 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate thus prepared melted at 118°-121° C. after recrystallization from an ethyl acetate-cyclohexane solvent mixture. The oxalate salt was converted to the hydrochloride salt by forming the free base in ether solution and then saturating the ether solution with gaseous hydrogen chloride. The hydrochloride salt melted at 77°-8° C. Analysis calc.: C, 65.91; H, 6.86; N, 4.77; Cl, 12.07; Found: C, 65.13; H, 7.12; N, 4.61; Cl, 12.21.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[N+:13]([O-])([OH:15])=[O:14].O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: COC(=O)Nc1ccc(C)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1ccc(C)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
100 ml of methylene chloride are introduced into a 2 l four-necked flask equipped with a stirrer, reflux condenser, thermometer and two dropping funnels, and 165.2 g (1 mol) of 4-tolylcarbamic acid methyl ester, dissolved in 400 ml of methylene chloride, and 109.3 g of 98% strength (1.7 mols) nitric acid dissolved in 150 ml of methylene chloride are added simultaneously in the course of 1 hour, at 20° C. and under normal pressure, the temperature being maintained by external cooling. After completion of the dropwise addition, the mixture is stirred for a further hour at 20° C., the resulting solution is extracted twice with 100 ml of water at a time, and the organic solvent is then distilled off. Yield: 209.3 g of crude product, of melting point 96° to 102° C. This crude product is introduced into dilute sodium hydroxide solution, consisting of 450 ml of water and 112 g (2.8 mols) of NaOH, and the mixture is heated to 95° C. and kept at this temperature for 3 hours, whilst distilling off the methanol formed during hydrolysis of the 2-nitro-4-tolylcarbamic acid methyl ester to the amino group. The mixture is cooled to 60° C. and stirred for a further 30 minutes at 60° C., and the product is filtered off and washed alkali-free with water. The moist product is dried to constant weight in vacuo at 60° C. Yield: 144.4 g of dry product (94.6% of theory); purity: 99.7%.