Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:14][C:15]1[CH:26]=[CH:25][C:18]([C:19](N(OC)C)=[O:20])=[CH:17][CH:16]=1>C1COCC1>[Cl:14][C:15]1[CH:26]=[CH:25][C:18]([C:19]([C:2]2[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: Cc1ncc(Br)n1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 50-mL round-bottom flask containing a solution of 5-bromo-1,2-dimethyl-1H-imidazole (440 mg, 2.51 mmol, Intermediate 24, step a) and THF (20 mL) under nitrogen was added isopropylmagnesium chloride in THF (2.0 M, 1.2 mL, 2.4 mmol) dropwise. The mixture was stirred for 0.5 hours at room temperature, and a solution of 4-chloro-N-methoxy-N-methylbenzamide (500 mg, 2.50 mmol, Intermediate 18, step a) in THF (5 mL) was introduced. After stirring for 7.5 hours at room temperature, the reaction was quenched by addition of 10 mL of EtOH, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 50% EtOAc in petroleum, 0-10% MeOH in CH2Cl2) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[C:6]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:3]1[CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]2.C([N-]C(C)C)(C)C.[Li+].[CH3:26][S:27]SC.[NH4+].[Cl-]>C1COCC1>[CH3:1][N:2]1[CH:7]([CH3:8])[C:6]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:3]1[C:4]([S:27][CH3:26])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]2
Reactant: CSSC
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(C)C2C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(SC)CC2(C)C(C)CC1N(C)C2C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.6 %

Procedure:
A solution of diisopropylamine (6.8 mL, 48 mmol) in THF (100 mL) was cooled to -70° C. and n-BuLi (17.6 mL, 44 mmol, 2.5M hexane) was added to afford lithium diisopropylamide (LDA). A solution of ethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6-carboxylate (9.6 g, 40 mmol) in THF (50 mL) was then added dropwise to the solution of LDA and the mixture was stirred for 2.5 hours. Methyl disulfide (4.3 mL, 48 mmol) was then added to the reaction mixture and the mixture was slowly warmed to room temperature and was stirred for 16 hours. The mixture was poured into saturated NH4Cl (200 mL), the organic layer was separated and the aqueous layer was extracted with ether (2×200 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by medium pressure liquid chromatography (10-15% ethyl acetate/hexane) to afford 9.2 g (81%) of ethyl 2,3,4,8-tetramethyl-6-(methylthio)-2-azabicyclo[2.2.2]octane-6-carboxylate. The product was dissolved in ether and treated with ethereal HCl to afford 6.5 g of the hydrochloride salt as a white powder, m.p. 143°-145° C. when recrystallized from ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2([OH:16])[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:17][OH:18]>>[CH3:17][O:18][C:2]1[C:3]([C:8]2([OH:16])[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CO
Reactant: OC1(c2nccnc2Cl)CN2CCC1CC2
Product: COc1nccnc1C1(O)CN2CCC1CC2

Procedure:
To a solution of 40 ml of methanol that had reacted with 0.5 g of Na (0.022 mol) was added 0.5 g of (7) (0.0021 mol). The reaction was heated to reflux for 1 h followed by evaporation of the solvent. The residue was treated with ice-water and extracted 3× with 25 ml of CH2Cl2. The extracts were dried and evaporated to give a yellow solid that was recrystallized from ethyl acetate to give (8), 0.12 g, mp 130°-131° C. NMR ppm (CDCl3) 1.15 (1H, m), 1.45 (2H, m), 2.25 (1H, m), 2.38 (1H, m), 2.7-3.15 (5H, m), 3.9 (1H, bs), 4.05 (3H, s), 4.3 (1H, d), 8.05 (1H, d), 8.15 (1H, d). Anal. C12H17N3O2 requires C: 61.26; H: 7.28; N: 17.86%. Found C: 61.02; H: 7.45; N: 17.95%.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([SH:10])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:14]1[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([C:5]1[S:9][C:8]([S:10][C:14]2[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to Example 1 by using 5-butyl-1,3,4-thiadiazole-2-thiol (260 mg, 1.49 mmol), NaH (60% dispersion in mineral oil, 66 mg, 1.65 mmol), and 3-chloropyrazine-2-carbonitrile (210 mg, 1.50 mmol) in DMF and benzene (4 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 3 hr.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25]C(=O)C)[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[CH:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25][S:34]([CH:31]5[CH2:33][CH2:32]5)(=[O:36])=[O:35])[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[CH:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-n3cccc3)c2)cn1

Procedure:
The compound was prepared from the compound of Example 87 using the procedures of Example 88 and cyclopropane sulfonyl chloride. 1H-NMR (300 MHz, DMSO-d6): δ 10.2 (s, 1H), 8.71 (s, 1H), 8.2 (s, 1H), 7.99 (m, 1H), 7.95 (s, 1H), 7.68-7.59 (m, 3H), 7.44-7.41 (m, 4H), 6.31 (m, 2H), 3.95 (s, 3H), 2.95 (m, 1H), 1.0 (m, 4H); LC-MS (ESI): Calculated mass: 458.54; Observed mass: 459.2 [M+H]+ (rt: 1.29 min).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([NH2:12])=[N:11][C:6]2=[CH:5][CH:4]=1.[BrH:13]>O.C(O)(=O)C>[BrH:13].[BrH:13].[NH2:12][C:10]1[S:9][C:7]2[C:6]([N:11]=1)=[CH:5][CH:4]=[C:3]([OH:2])[N:8]=2
Reactant: COc1ccc2nc(N)sc2n1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(O)nc2s1

Procedure:
5-Methoxythiazolo[5,4-b]pyridin-2-amine (9, 1.0 g, 5.5 mmol) was hydrolyzed with mixture of 48% HBr in water and 45% HBr in acetic acid (4 ml, 1:1) at 135° C. in a pressure bottle for 2 h. The white dihydrobromide salt 10 was filtered and washed with diethyl ether, dried in vacuo 1.7 g (92%). 1H NMR (DMSO-d6): δ 7.64 (1H, m), 6.64 (1H, m); MS: 168 (M+H+).
Reaction SMILES: ClCCl.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([Cl:17])=[C:11]([S:13](Cl)(=[O:15])=[O:14])[CH:12]=1)([O-:6])=[O:5].[CH3:18][NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(N(CC)CC)C>[CH3:18][N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[S:13]([C:11]1[CH:12]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=[CH:9][C:10]=1[Cl:17])(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CCCCCCCCCCCCCCCCCCNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
Dichloromethane (100 ml) was mixed with 44 grams of 5-nitro-2-chlorobenzenesulfonyl chloride and a dichloromethane solution which contained 48.4 grams of methyloctadecylamine and 36.1 ml of triethylamine was added dropwise to the mixture. After the reaction had been completed the reaction solvent was removed by distillation under reduced pressure, 300 ml of methanol was added and a solution was formed by heating. Crystals precipitated out on cooling the solution slowly and these were recovered by filtration and dried.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=[O:26].[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25]([C:24]([F:29])([F:28])[F:23])=[O:26]
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2Cl)C(F)(F)OC3(F)F)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1nn(-c2cc3c(cc2Cl)C(F)(F)OC3(F)F)c(N)c1S(=O)C(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 18.6 %

Procedure:
To a suspension wherein 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyanopyrazole (600 mg, 1.80 mmol), sodium trifluoro-methanesulfinate (366 mg, 2.35 mmol) and dimethylamine tosylate (587 mg, 2.70 mmol) are in toluene (5 ml), thionyl chloride (278 mg, 2.34 mmol) was added dropwise over a period of about 10 minutes and then stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 150 mg of 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyano-4-trifluoromethylsulfinylpyrazole.
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH:15]([OH:17])[CH3:16])=[CH:9][C:8]=1[O:18][CH3:19].[H-].[Na+].IC>O>[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH:15]([O:17][CH3:2])[CH3:16])=[CH:9][C:8]=1[O:18][CH3:19]
Reactant: C1CCOC1
Reactant: COc1cc(C(C)O)cc(OC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc(C(C)OC)cc(OC)c1Br
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (100 mL) solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanol (7.24 g, 27.7 mmol) was added sodium hydride (1.33 g, 33.2 mmol) at 0° C., and the mixture was stirred for 10 minutes. To the mixture was added dropwise iodomethane (1.90 mL, 30.5 mmol), and the mixture was stirred at room temperature for one hour. After the reaction was completed, water was added to the reaction mixture while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 10/1 then 1/4) to obtain the title compound (7.39 g, 26.9 mmol).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7]C=[N:5][CH:4]1[C:8]([NH2:10])=[O:9]>Cl>[ClH:1].[Cl:1][CH2:2][CH:3]([OH:7])[CH:4]([C:8]([NH2:10])=[O:9])[NH2:5]
Reactant: NC(=O)C1N=COC1CCl
Agent: Cl
Product: NC(=O)C(N)C(O)CCl
Temperature: 50 °C

Procedure:
5-(Chloromethyl)-4,5-dihydro-4-oxazolecarboxamide was dissolved in 1500 ml of 2N hydrochloric acid and warmed to 50° C. for 2 hours. The hydrochloric acid was removed in vacuo and the residue was triturated with isopropanol to yield the title compound as brownish crystals; yield 133.9 g.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].CN(C=O)C.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][OH:22]>C1COCC1>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][O:22][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CBr
Reactant: OCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)COCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a stirred suspension of NaH (60% dispersion in mineral oil, 4.80 g, 120 mmol) in THF, at 0° C., was added a THF solution (15 ml) of bromoacetic acid (6.11 g, 44 mmol). Mixture was stirred at room temperature 0.5 hr, then a DMF solution (15 ml) of alcohol 1 (5.84 g, 40 mmol) was added dropwise. Mixture was stirred at room temperature for 17 hrs then quenched with H2O and extracted twice with ether. Aqueous layer was acidified to pH 2-3 and extracted with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated to give pure compound 2 as a pale yellow oil (6.93 g, 85%) used for next step without further purification.
Reaction SMILES: C[O-].[Na+].NC(N)=O.[NH2:8][C:9]([NH:11][N:12]([CH2:26][C:27]([O:29]C)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:14]=1)=[O:10].P([O-])([O-])([O-])=O>COCCOC.CCCCCC.CCOCC>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([N:12]2[CH2:26][C:27](=[O:29])[NH:8][C:9](=[O:10])[NH:11]2)[CH:18]=[CH:17][CH:16]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCOc1cccc(N(CC(=O)OC)NC(N)=O)c1
Agent: C[O-]
Agent: NC(N)=O
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: COCCOC
Product: CCCCCCOc1cccc(N2CC(=O)NC(=O)N2)c1
Yield: 67 %

Procedure:
Sodium methoxide (0.33 g, 6.2 mmol) was added under nitrogen to a stirred solution of the urea (Intermediate 70, 1.00 g, 3.1 mmol) in 1,2-dimethoxyethane (25 ml) over 4 A° molecular sieves. After 15 minutes the mixture was poured into pH6.5 aqueous phosphate buffer (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried (MgSO4) and evaporated to afford the crude product as an off-white solid. Trituration with hexane/ether (ca. 1:2) (25 ml) gave the title compound as a white powder (600 mg, 67%) m.p. 161°-163° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH2:17]COC[CH2:13]1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH3:13][O:12][CH2:17][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: COCc1ccc(C(=O)OC)cc1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 33 %

Procedure:
To a mixture of methyl 4-bromobenzoate (50 mg, 0.233 mmol) and 1,4-dioxane (1 ml) were added water (0.1 ml), cesium carbonate (228 mg, 0.7 mmol), potassium methoxymethyl trifluoroborate (71 mg, 0.467 mmol) and 1′,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (17 mg, 0.023 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 4.5 hours. After the reaction mixture was cooled at room temperature, water and methylene chloride were added to the mixture, followed by filtration using celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethylacetate=10:1) to obtain the title compound (13.9 mg, 33%).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:21]4=[O:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>C(O)C.[C].[Pd]>[CH:1]1([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:21]4=[O:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OC2C=CCCC2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(c1ccc(OC2CCCCC2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
1-{1-[4-(2-Cyclohexenyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (200 mg) is dissolved in ethanol (5 ml) and thereto is added 10 % palladium-carbon (50 mg). The mixture is stirred at room temperature under atmospheric pressure under hydrogen atmosphere. After the completion of the reaction, the catalyst is removed by filtration. The resulting filtrate is concentrated and purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate =1) to give 1-[1-(4-cyclohexyloxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (174 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:34](=[O:36])[CH3:35])[C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:15]([CH3:33])[CH2:14]2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO>[C:34]([N:12]([C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:15]([CH3:33])[CH2:14]1)[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:11][CH:10]=1)(=[O:36])[CH3:35]
Reactant: COC(=O)COc1ccc(N(C(C)=O)[C@@H]2C[C@H](C)N(C(=O)c3ccc(OC)cc3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(OCC(=O)O)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
(2S,4R)-(4-{Acetyl-[1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenoxy)-acetic acid was prepared from (2S,4R)-(4-{acetyl-[1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenoxy)-acetic acid methyl ester (15 mg, 0.03 mmol). The methyl ester was dissolved in methanol (1 mL), sodium hydroxide (1 mL, 0.1 M in water) was added and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was acidified with hydrochloric acid (1 M) and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed thrice with water, brine, dried over sodium sulphate, filtered and concentrated to yield the title compound (13 mg, 89%).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:32]([F:35])([F:34])[F:33])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:41][NH:42][CH3:43]>ClCCl.CN(C=O)C>[CH3:41][N:42]([CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:32]([F:33])([F:35])[F:34])[C:24]([N:26]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1)[CH3:43]
Reactant: CNC
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 117) (300 mg, 0.62 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as a light brown solid (110 mg, 35%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:30])([F:29])[CH2:27]I>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: FC(F)(F)CI
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC(F)(F)F
Temperature: 70 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.4 g, 1.311 mmol), potassium carbonate (0.544 g, 3.93 mmol) and 1,1,1-trifluoro-2-iodoethane (0.826 g, 3.93 mmol) in DMF (2 ml) was heated at 70° C. under stirring for 18 h The reaction mixture was cooled down and diluted with water (15 ml) and extracted with DCM (15 mlX3). The combined organic phase was washed with water (25 ml) and dried with Na2SO4 and concentrated. The residue was purified by column chromatography (biotage 25 g) eluted with ethyl acetate/cyclohexane 0-60% to afford product 6-bromo-7-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.17 g) 1H NMR (500 MHz, CDCl3) 7.45-7.50 (m, 3H), 7.38-7.40 (m, 2H), 7.28 (s, 1H), 4.94 (s, 2H), 4.55 (q, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (5.0 g, 10 mmol) and (4-formylphenyl) boronic acid (2.35 g, 15.8 mmol) in dioxane/water (30 mL/10 mL) was added Na2CO3 (4.01 g, 37.9 mmol). The solution was purged with argon for 15 min., Pd(PPh3)4 (1.21 g, 1.05 mmol) and the mixture was heated at 100° C. for 2 h. The mixture was allowed to cool to room temperature, diluted with water and extracted with 10% MeOH/CH2Cl2. The combined organic layers were dried over sodium sulphate and the solvent removed under reduced pressure. The resulting crude material was purified by column chromatography over silica gel to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (3.5 g, 66%).
Reaction SMILES: I/[CH:2]=[CH:3]/[CH:4]([O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1.C([Li:41])CCC>CCCCCC>[C:12]1([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])/[CH:3]=[CH:2]/[Li:41])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: [Li]/C=C/C(CCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -40 °C

Procedure:
To a solution of 4.96 g. of 1-iodo-3-triphenylmethoxy-trans-1-octene (Example 24) in 10 ml. of toluene cooled to -78° C. is added under an inert atmosphere 1 molar equivalent of n-butyllithium dissolved in hexane. The reaction muxture is allowed to warm to -40° C. and is then maintained at that temperature for 1 hour to yield a hydrocarbon solution of 3-triphenylmethoxy-trans-1-octenyllithium.