Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CO>CN1CCCC1=O>[CH2:25]([NH:32][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)[C:20](=[O:21])[N:19]([CH3:22])[C:10]=2[N:11]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(NCc3ccccc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl) pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8 made by replacing methyl 2-fluorophenoxyacetate with methyl 4-fluorophenoxyacetate—Steps A and B, 0.35 g, 1.0 mmol) and benzylamine (0.33 mL, 3 mmol) in 0.5 mL of 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the free amine. This was dissolved in ethyl acetate (1-2 mL) and hydrochloric acid in ether (1M, 1.5 eq) was added. Isolation of the solid via filtration and drying provided 0.317 g of the hydrochloride salt (Mass spec. M+1=377, MP=203.2-204° C.).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2=[O:16])=[CH:8][CH:7]=1.[ClH:17]>O.Cl[Cu]>[Cl:17][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
NaNO2 (0.7 g; 10 mmol) dissolved in water (10 mL) was added with stirring to an ice-cold solution of 7-amino-1-tetralone (1.4 g; 8.8 mmol; from step (i) above) in conc HCl (aq.) over a period of 5 minutes. The resultant cold solution was then added slowly to an ice-cold solution of CuCl (1.5 g, 15 mmol) in conc. HCl (aq.), whereafter the resultant solution was stirred at RT for 2 hours and at 60° C. for 30 minutes. The slurry was cooled with ice, and the resultant precipitate was suction filtered, washed with water, and air dried. Yield 1.50 g (94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccncc3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccncc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-hydroxyethyl)pyrrolidine (0.32 g, 0.83 mmol) and N,N-diisopropylethylamine (0.46 mL, 2.64 mmol) in dichloromethane (50 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (0.096 mL, 1.24 mmol). After 1 hour, warm to ambient temperature. Again cool in an ice bath and add N,N-diisopropylethylamine (0.23 mL, 1.32 mmol) followed by methanesulfonyl chloride (0.096 ml, 1.24 mmol). After 1 hour, dilute the reaction mixture with dichloromethane and extract with a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.24 (silica gel, 5% methanol/dichloromethane/0.1% concentrated aqueous ammonia).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: ICC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.05 g, 3.27 mmol) in N,N-dimethylformamide (15 mL) were serially added 2,2-diphenylethyl iodide (1.11 g, 3.60 mmol) and potassium carbonate (500 mg, 3.60 mmol) and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl [[2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate (1.11 g). To a solution of this compound (1.00 g, 1.99 mmol) in ethanol (45 mL)-water (5 mL) was added sodium periodate (0.51 g, 2.39 mmol) and the mixture was refluxed for 3 hours. To this reaction mixture were added ethyl acetate and water, and the resulting two layers were separated. The aqueous layer was extracted with ethyl acetate and the pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:8) and recrystallized from ethyl acetate to provide 0.64 g of the title compound. Yield 42%.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8].[Cl:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[O:24][CH3:25])=[O:13]>C(O)(C)C>[Cl-:10].[CH3:1][N+:2]([CH3:9])([CH2:11][C:12](=[O:13])[NH:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[O:24][CH3:25])[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8]
Reactant: CN(C)CCCNC=O
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)CCl
Solvent: CC(C)O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)C[N+](C)(C)CCCNC=O
Product: [Cl-]

Procedure:
In a manner similar to that described above in b-1a, and using 27.3 parts of N-(3-dimethylaminopropyl)formamide, 48 parts of 2-chloro-2'-methoxy-5'-nitroacetanilide, and 157 parts of isopropyl alcohol there was obtained 52.6 parts of N,N-dimethyl-N-(5-nitro-2-methoxyphenyl)carbamylmethyl-N-3-formamidopropylammonium chloride as a white solid, m.p. 86°-88°.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([C@@H:14]([NH2:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=[O:23].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22]([NH:16][C@H:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH:9]=1)[CH3:15])=[O:23]
Reactant: C[C@H](N)c1cccc(N2CCOCC2)c1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Mixture of (S)-1-(3-morpholin-4-yl-phenyl)-ethylamine hydrochloride, Preparation 21 (50 mg, 0.21 mmol), 2-fluorocinnamic acid (37 mg, 0.23 mmol), EDC (79 mg, 0.41 mmol), DMAP (25 mg, 0.21 mmol), triethylamine (0.11 ml, 0.82 mmol) in dichloromethane (1 mL) was stirred at room temperature for 10 hours. The reaction mixture was concentrated under vacuum and purified by filtering through 2 g silica-gel syringe with 80% ethyl acetate/hexanes. The filtrate was concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>CN(C)C(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(C#N)cc2)CC1
Yield: 88.3 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (9.19 g, 30.8 mmol) and 4-cyanobenzeneboronic acid (5.18 g, 35.2 mmol) in N,N-dimethylacetamide (90 mL) and water (35 mL), purge with nitrogen for 0.5 hr. and then add tetrakis(triphenylphosphine)palladium(0) (0.170 g, 0.15 mmol). Heat for 3 hr. at 110° C., allow to cool about 1.5 hr. to room temperature, filter and then dry the solid in an oven overnight to give 3′-(4-cyanophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester as a white solid (9.94 g, 88%). MS (ES): m/z=366 [M+H]+. Add 4 M HCl in 1,4-dioxane (10 mL) to 3′-(4-cyanophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (3.29 g, 9.0 mmol). Add more 4 M HCl in 1,4-dioxane (10 mL) to the reaction mixture and heat at 40° C. for 3 hr. Filter off the solid and wash with a mixture of 1,4-dioxane/isohexane to give the dihydrochloride salt as a yellow solid (4.2 g). MS (ES): m/z=266 [M+H]+. Dissolve the dihydrochloride in water (20 mL), add 2 N sodium hydroxide (10 mL), extract with DCM and concentrate the DCM extract to give the title preparation as a yellow solid (1.8 g). MS (ES): m/z=266 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:15]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=3[O:13][CH3:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.710 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.636 g, 90%). MS=328 (MH)+.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.Br.Br[CH2:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]>>[O:26]1[CH2:24][C@H:25]1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Product: c1cncc([C@@H]2CO2)c1

Procedure:
The title compound was prepared from (R)-2-methyl-CBS-oxazaborolidine monohydrate and 3-(2-bromoacetyl)pyridine hydrobromide in substantially the same manner, as described in Example 123. The product was obtained as an oil; 1H NMR (300 MHz, DMSO-d6) δ 2.94–2.97 (m, 1 H), 3.14–3.17 (m, 1 H), 3.99–4.01 (m, 1 H), 7.36–7.40 (m, 1 H), 7.63–7.66 (m, 1 H), 8.51–8.55 (m, 2 H); MS (ES) m/z: 121 (M+).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([Cl:9])=[O:8])[N:6]=1.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:12]=1>O1CCOCC1>[ClH:9].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:7]([C:5]3[N:6]=[C:2]([CH3:1])[O:3][CH:4]=3)=[O:8])[CH2:27][CH2:26]2)[N:12]=1
Reactant: Cc1nc(C(=O)Cl)co1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)c4coc(C)n4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
A solution of 2-methyloxazole-4-carbonyl chloride (1.01 g., 6.9 mmole) in dioxane was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.00 g., 6.9 mmole) in dioxane. The mixture was heated at reflux for 2 hours. Filtration gave the title compound having a m.p. of 278°-280° C. with decomposition after recrystallization from methanol.
Reaction SMILES: C[O:2]C1C=C2C(C=CC(=O)N2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O.[C:45]([O:49][C:50](=[O:73])[NH:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][N:60]2[C:69]3[C:64](=[CH:65][CH:66]=[C:67]([O:70][CH3:71])[CH:68]=3)[CH:63]=C[C:61]2=[O:72])[CH2:54][CH2:53]1)([CH3:48])([CH3:47])[CH3:46]>CN(C)C=O.ClCCl.CO>[C:45]([O:49][C:50](=[O:73])[NH:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][N:60]2[C:69]3[CH:68]=[C:67]([O:70][CH3:71])[CH:66]=[CH:65][C:64]=3[CH2:63][O:72][C:61]2=[O:2])[CH2:54][CH2:53]1)([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 7-methoxyquinolin-2(1H)-one (Intermediate 108, 310 mg, 1.8 mmol) in dry N,N-dimethylformamide (5 mL) was treated at 0° C. under stirring with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 1.9 mL, 1.9 mmol). The mixture was then stirred for 30 minutes at room temperature and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6, 2.03 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 333 mg (47%) of the product as a colorless solid.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=N[CH2:24][CH2:25][CH2:26][N:27]([CH3:29])C.C1C=CC2N(O)N=NC=2C=1.N1CCCC1>CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[CH2:4]([O:3][C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([N:27]1[CH2:26][CH2:25][CH2:24][CH2:29]1)=[O:15])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C([C@H]1CCCN1C(=O)OCc1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (+)-carbobenzyloxy-D-proline (1.5 g, 6 mmol), EDAC (2.3 g, 12 mmol), HOBt (800 mg, 6 mmol), TEA (1.5 mL) and pyrrolidine (853 mg, 12 mmol) in DMF (20 mL) was stirred at rt for 18 hours. The reaction was diluted with water and sodium bicarbonate, extracted with DCM (3×). The combined DCM was concentrated and purified on a silica gel column to give (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: Cl.[N:2]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH:17]([C@@H:19]1[C@@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][N:21]([C@H:30]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:31]([O:33]CC2C=CC(OC)=CC=2)=[O:32])[CH2:20]1)=O.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>C(O)=O>[N:2]1([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:19]3[C@@H:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][N:21]([C@H:30]([CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:31]([OH:33])=[O:32])[CH2:20]3)[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: c1ccc2c(c1)nnn2C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(n3nnc4ccccc43)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 4-benzotriazol-1-yl-piperidine HCl salt and of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) using procedures analogous to those described in Example 89 Steps C and D except TFA and anisole were used in place of formic acid in Example 89, Step D. ESI-MS 502 (M+1); HPLC A: 2.02 min.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13](C([O:18][C:19]([CH3:22])(C)C)=O)[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].CN1C=CN=C1.CC[O:44][C:45]([CH3:47])=[O:46]>ClCCl.[Cl-].[Na+].O>[C:45]([OH:44])(=[O:46])/[CH:47]=[CH:22]/[C:19]([OH:18])=[O:33].[CH2:30]([S:32]([N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:34])=[O:33])[CH3:31]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NCCC3
Reactant: CCOC(C)=O
Agent: Cn1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCS(=O)(=O)N1CCCc2cc3c(cc21)CCNCC3
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 200 mg of t-butyl 1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 6 ml of dichloromethane were added 0.148 ml of triethylamine, 0.093 ml of ethanesulfonyl chloride, and 54 mg of 1-methylimidazole under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added EtOAc and saturated brine, and the organic layer was washed with saturated brine and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc). The resulting substance was dissolved in 4 ml of chloroform, followed by adding 2 ml of trifluoroacetic acid and stirring for 30 minutes. After concentration under reduced pressure, the resultant was dissolved in 4.5 ml of EtOH, neutralized by the addition of triethylamine, and then concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (elution solvent: chloroform-MeOH-aqueous ammonia). The resulting substance was dissolved in EtOH and 76 mg of fumaric acid was added thereto. The resulting white solid was collected by filtration and dried to obtain 61 mg of 1-(ethylsulfonyl)-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline monofumarate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]3)=[C:10]([CH3:29])[CH:9]=1.Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]4)=[C:10]([CH3:29])[CH:9]=2)=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3C)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc2n1
Yield: 67.7 %

Procedure:
Cesium carbonate (55.4 mg, 170.0 μmol) was added to ethyl 6-(4-hydroxy-2-methylphenyl)-2-quinolinecarboxylate (47.5 mg, 154.5 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (51.8 mg, 170.0 μmol) in N,N-dimethylformamide (3.1 mL) at room temperature. The resulting suspension was stirred for eighteen hours, then water added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 60.2 mg (68%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-methylphenyl]-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (d, J=9 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 7.97 (d, J=2 Hz, 1H), 7.80 (dd, J=9, 2 Hz, 1H), 7.66-7.60 (m, 2H), 7.56 (dd, J=9, 7 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 6.73 (dd, J=9, 2 Hz, 1H), 4.86 (s, 2H), 4.43 (q, J=7 Hz, 2H), 3.47 (septet, J=7 Hz, 1H), 2.21 (s, 3H), 1.38 (t, J=7 Hz, 3H), 1.35 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.C(N(CC)CC)C.[N:20]([C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)=[C:21]=[O:22]>C(Cl)Cl.CCOC(C)=O>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:28]=[C:23]([NH:20][C:21]([N:10]2[CH2:9][CH2:8][N:7]([C:3]3[C:2]([Cl:1])=[N:6][S:5][N:4]=3)[CH2:12][CH2:11]2)=[O:22])[CH:24]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=1
Reactant: Clc1nsnc1N1CCNCC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine (7.8 g, 32.6 mmol, 1.0 eq.), dry CH2Cl2 (130 mL), triethyl amine (11.66 g, 16 mL, 115.2 mmol, 3.5 eq). To this mixture cooled in an ice bath was added 1-isocyanato-3,5-bis-trifluoromethyl-benzene (11.6 g, 7.9 ml, 45 mmol, 1.4 eq.) dissolved in dry CH2Cl2 (20 mL) dropwise. The resulting mixture was allowed to warm up to room temperature with stirring. After stirring for 3 hour, the reaction mixture was diluted with EtOAc. This solution was then washed with aqNaHCO3, and brine. The organic layer was dried with Na2SO4, concentrated. The residue was purified by column chromatography using acetate/hexane (1:1 to 3:1), affording 4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (11.8 g, 79% yield) as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.CC1(C)C2[C:41](=[C:42](P(C3C=CC=CC=3)C3C=CC=CC=3)[CH:43]=[CH:44][CH:45]=2)[O:40]C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.C(=O)([O-])[O-:63].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:45][CH:44]1[C:43]([N:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[C:2]2=[O:1])=[CH:42][C:41](=[O:63])[O:40]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1OC(=O)C=C1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 2-methyl-5-oxo-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (232 mg, 0.944 mmol), Xantphos (45.5 mg, 0.079 mmol), palladium (II) acetate (8.83 mg, 0.039 mmol), water (0.043 mL, 2.359 mmol), and potassium carbonate (217 mg, 1.573 mmol) in toluene (20 mL) was degassed by nitrogen and heated at 65° C. for 16 h. After filtration through CELITE® the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate and hexane as eluting solvents to give the title compound. LCMS: (M+1)+: 351.15.