Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[CH:43][C:44]([CH2:55][O:56][Si:57]([CH:64]([CH3:66])[CH3:65])([CH:61]([CH3:63])[CH3:62])[CH:58]([CH3:60])[CH3:59])=[C:45]([CH:54]=2)[O:46][CH2:47][CH2:48]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:67][NH:68][CH3:69]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[CH:43][C:44]([CH2:55][O:56][Si:57]([CH:58]([CH3:59])[CH3:60])([CH:64]([CH3:65])[CH3:66])[CH:61]([CH3:63])[CH3:62])=[C:45]([O:46][CH2:47][CH2:48][N:68]([CH3:69])[CH3:67])[CH:54]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCOS(C)(=O)=O)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCN(C)C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 55fB (100 mg, 0.11 mmol) and dimethylamine (2.0M in THF, 0.80 mL, 1.60 mmol) in THF (3 mL) was stirred at 60° C. for 18 h in a sealed vial. The volatiles were concentrated in vacuo and the residue was used in the next step without further purification (94 mg, 100%). LCMS (Method 3): Rt 3.75 min, m/z 893 [MH+].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[C:14]([CH3:27])[C:12]=1[NH2:13]>>[NH2:13][C:12]1[C:14]([CH3:27])=[CH:15][C:16]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:17][C:11]=1[CH3:10]
Reactant: Cn1nc(Cl)ccc1=O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Product: Cc1cc(-c2ccc(=O)n(C)n2)cc(C)c1N
Temperature: 60 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 6-chloro-2-methylpyridazin-3(2H)-one and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 60° C. LC (method 9): tR=0.78 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].[N:37]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([NH2:37])=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)nc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)nc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A mixture of {2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (210 mg), 1H-1,2,3-benzotriazol-1-ol (80 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (5 mL) was stirred at 50° C. for 30 min and cooled to 0° C. 10% Aqueous ammonia (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 2.5 days. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and subjected to silica gel short column chromatography (eluted with ethyl acetate-methanol (95/5, volume ratio)) to give pale-yellow crystals. The crystals were recrystallized from acetone-hexane to give the title compound (130 mg, yield 62%) as pale-yellow prism crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OCCCO2)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2ccccc2Br)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2ccccc2-c2cccnc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
After dissolving 575 mg of 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-bromophenyl)ethanone in 10 ml of N,N-dimethylformamide, there were added 489 mg of 2-(3-pyridyl)-1,3,2-dioxaborinane, 173 mg of tetrakis(triphenylphosphine) palladium(0) and 1.47 g of anhydrous cesium carbonate, and the mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (379 mg, 66% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:14]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc2ncccc2c1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of quinoline-6-carbonyl chloride (0-2) (2.2 g, 10.5 mmol) in THF (100 mL) was added ammonia (5 mL) at 0° C. The mixture was stirred at room temperature for 1 h, then concentrated and washed with water (15 mL) to afford the title compound (1.5 g). MS (m/z): 173 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([S:13](=[O:17])(=[O:16])[C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl([O-])=[O:19].[Na+]>S(=O)(=O)(O)O.O>[OH:19][C:15]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]2[C:14]=1[S:13](=[O:17])(=[O:16])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[N:6]=2
Reactant: O=S1(=O)c2ccccc2Nc2ccc(O)cc21
Reactant: [O-][Cl+][O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1C=CC2=Nc3ccccc3S(=O)(=O)C2=C1O
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
To a suspension of 3-hydroxy-10H-phenothiazine-5,5-dioxide (1.75 g, 7 mmoles) in 2% aqueous sulfuric acid (25 ml) there was added, at room temperature, a solution of 80% sodium chlorite (3.17 g, 28 mmoles) in water (25 ml). The mixture was stirred for 15 minutes, then the red-orange precipitate was filtered to afford crude product (1.73 g). Purification was achieved by crystallization from DMF-methanol, m.p. 266° (dec.).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[C:25]([Cl:31])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:10]2[CH2:11][CH2:12][N:8]([C@H:5]3[CH2:6][CH2:7][C@@H:2]([F:1])[CH2:3][CH2:4]3)[C:9]2=[O:13])=[C:25]([Cl:31])[CH:24]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: O=C1CCCN1[C@H]1CC[C@@H](F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Reaction time: 8 h

Procedure:
To a solution of cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (Preparation 26) (190 mg, 1.03 mmol) in 5 mL dry THF, add 1.29 mL of 2M LDA (2.5 eq.) in THF dropwise at −78° C. Then, add 16 mg of 4-Bromo-1-bromomethyl-2-chloro-benzene (2 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, brine, dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 389 (M+1).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:3].FC(F)(F)C(O)=O.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[CH2:22][NH:23][NH2:24]>O1CCOCC1>[NH2:3][C:2]1[N:23]([CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[F:19])[N:24]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=1
Reactant: CCOC(=O)C(=O)CC#N
Reactant: NNCc1ccccc1F
Agent: [Na]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Reaction time: 8 h

Procedure:
100 g (0.613 mol) of sodium salt of ethyl cyanopyruvate (preparation analogously to Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) are treated with 111.75 g (75 ml, 0.98 mol) of trifluoroacetic acid at room temperature in 2.5 l of dioxane under argon with good stirring and the mixture is stirred for 10 min, a large part of the starting material going into solution. 85.93 g (0.613 mol) of 2-fluorobenzylhydrazine are then added and the mixture is boiled overnight. After cooling, the deposited crystals of sodium trifluoroacetate are filtered off with suction, washed with dioxane and the solution is reacted further in crude form.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]C)=[O:23])[C:17](=[O:26])[CH:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[C:17](=[O:26])[CH:16]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CCC([C@H](C)NC(=O)OCc2ccccc2)=CC(Cc2ccccc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OCc1ccccc1)C1=CC(Cc2ccccc2)C(=O)C(CC(=O)O)CC1

Procedure:
To a stirred solution of the above ester (35) (1.2 g) in dioxane (12 mL) was added a solution of NaOH (5.3 mL, 1N in H2O). After stirring for 4 h at room temperature 1N HCl (5.3 mL) was added and the reaction extracted with ethyl acetate, washed with saturated NaCl, dried over MgSO4 and evaporated. The product (37) was obtained by flash chromatography (silica gel, 98:2:0.1 CHCl3 :MeOH:HOAc) (1.0 g, 86%). TLC Rf 0.53 (95:4:1 CHCl3 :MeOH:HOAc); MS DC I/NH3 (M+H)+ =436.3; 1H NMR (CDCl3) δ1.13(3H, d, J=7 Hz ), 1.6-3.3 (9H, m), 3.65 (1H, m), 4.1 (1H, br m), 5.1 (2H, s), 5.45(1H, d), 7.2(5H, s), 7.35(5H, s), 10.65 (1H, br s).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([OH:19])=[C:4]([C:20]([OH:22])=[O:21])[N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].S([O-])(OC)(=O)=O>CC(C)=O>[CH3:23][O:21][C:20]([C:4]1[N:3]=[C:2]([Br:1])[C:11]2[C:6]([C:5]=1[OH:19])=[CH:7][CH:8]=[C:9]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=2)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Yield: 92.5 %

Procedure:
1-Bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid (10.0 g), potassium carbonate (3.7 g) and methyl sulfate (3.4 g) were suspended in 500 ml acetone and stirred at reflux overnight. Reaction mixture was concentrated and residue partitioned between 1 N hydrochloric acid and ethyl acetate. Organic layer was dried over magnesium sulfate and filtered. Filtrate concentrated to give title compound (9.6 g). MS-(+)-ion M+1=389.9, 391.9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[O:34][C:33]([C:35]([F:38])([F:37])[F:36])=[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:31]=1>CC(=O)CC>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:29][C:30]1[O:34][C:33]([C:35]([F:38])([F:36])[F:37])=[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:31]=1
Reactant: CCOC(=O)c1cc(CBr)oc1C(F)(F)F
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (4.26 g, 15.10 mmol) in 2-butanone (120 mL) was added cesium carbonate (14.76 g, 45.30 mmol) and ethyl 5-(bromomethyl)-2-(trifluoromethyl)furan-3-carboxylate (Lyalin, V. V.; et al., Zhurnal Organicheskoi Khimii (1984), 20(4):846) (4.80 g, 15.90 mmol). The reaction mixture was heated at 60° C. to 70° C. for 18 h, cooled to ambient temperature and filtered. The solid was washed with ethyl acetate. The filtrate was concentrated in vacuo, the residue was purified by column chromatography with ethyl acetate and hexanes to afford ethyl 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylate (4.65 g, 61%): mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ 7.23-7.17 (m, 2H), 7.12-7.06 (m, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 5.86-5.85 (m, 2H), 5.05-4.87 (m, 3H), 4.68-4.64 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.2, 160.4, 155.9, 150.6, 149.1, 143.5, 142.5, 141.1, 132.0, 129.1, 124.2, 124.0, 120.7, 120.0, 119.0, 116.4, 111.1, 108.7, 103.0, 101.6, 93.7, 80.4, 61.7, 58.2, 36.7, 13.9; MS (ES+) m/z 502.1 (M+1).
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.C[C:7]([CH3:10])([O-])[CH3:8].C[C:12](C)([O-:14])C.O.[Al+3].[Li+].[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]=[CH:23][CH2:19][CH2:20][CH2:21][CH2:8][CH2:7][CH2:10][CH2:5][C:2]([O:14][CH3:12])=[O:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [Al+3]
Agent: [Li+]
Solvent: O
Product: COC(=O)CCCCCCCC=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
To a solution of the crude product (4.71 g) in THF (50 ml) was dropwise added a solution of lithium aluminum hydrate tri-tert-butoxide (6.1 g) in THF (50 ml) and then stirred for 1.5 hours at room temperature. The reaction mixture which volume was reduced to about 50 ml by partial evaporation of the solvent under reduced pressure, was poured into 1N hydrochloric acid (200 ml) and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, and then dried over magnesium sulfate anhydride. The solvent was evaporated under reduced pressure to give methyl 9-oxononanate (3.33 g 89.3%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[C:4]([CH3:15])[CH:3]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)(Cl)Cl>[CH3:15][C:4]1[CH:3]=[C:2]([O:25][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1cc(Cl)c2cc3c(cc2n1)OCO3
Solvent: ClC(Cl)Cl
Product: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)c2cc3c(cc2n1)OCO3
Temperature: 145 °C

Procedure:
A mixture of known 8-chloro-6-methyl[1,3]dioxolo[4,5-g]quinoline (2.216 g, 10 mmol)56 and 4-nitrophenol (2.08 g, 15 mmole) was heated at 140-150° C. for 2 h. The resulting solution was dissolved in chloroform and washed with 10% aq. solution of NaOH and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduce pressure. The resulting solid was collected by filtration, washed with ether and dried to 6-methyl-8-(4-nitrophenoxy)[1,3]dioxolo[4,5-g]quinoline, 2.94 g of (90.60%); mp 210-212° C.; 1H NMR (DMSO-d6) δ 2.52 (3H, s, Me), 6.21 (2H, s, CH2), 6.86 (1H, s, ArH), 7.30 (1H, s, ArH), 7.34-7.38 (3H, m, ArH), 8.29-8.33 (2H, m, ArH). Anal. Calcld. for (C17H12N2O5): C, 62.96; H, 3.73; N, 8.64. Found: C, 62.27; H, 3.84; N, 8.58.
Reaction SMILES: N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:25]I.[C:27]1([S:33]([CH2:36][CH2:37][CH2:38][CH2:39]O)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.O>[I:25][CH2:39][CH2:38][CH2:37][CH2:36][S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(CCCCO)c1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(CCCCI)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of imidazole (1.4 g, 20.5 mmol) in CH2Cl2 (20 mL) is added PPh3 (5.4 g, 20.5 mmol). The solution is cooled to 0° C. and iodine (5.2 g, 20.5 mmol) is added in 2 portions. The mixture is allowed to warm to RT then 4-benzenesulfonylbutan-1-ol is added and the mixture is stirred at RT for 24 h. The mixture is diluted with water and extracted with EtOAc (3×). The organic layer is washed with a 20% solution of Na2S2O3 and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using hexane/EtOAc (1:1) as eluent to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J28) (271 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (355 mg, 79%).
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[O:54][CH:53]=[N:52][C:51]=2[C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:46][CH:45]=1.[N:60]1([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:58]([O:57][C:55]([C:51]1[N:52]=[CH:53][O:54][C:50]=1[C:47]1[CH:48]=[CH:49][C:44]([N:63]2[CH2:62][CH2:61][N:60]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:65][CH2:64]2)=[CH:45][CH:46]=1)=[O:56])[CH3:59]
Reactant: CCOC(=O)c1ncoc1-c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: CCOC(=O)c1ncoc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 50.3 %

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium(0) (0.079 g, 0.09 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.100 g, 0.17 mmol), ethyl 5-(4-bromophenyl)oxazole-4-carboxylate (0.500 g, 1.69 mmol), tert-butyl 1-piperazinecarboxylate (0.409 g, 2.20 mmol) and cesium carbonate (0.786 g, 2.41 mmol) in dioxane (25 ml) and t-butanol (25 ml) was degassed, placed under a nitrogen atmosphere and heated under reflux overnight. The solvent was removed in vacuo and the residue partitioned between water and DCM. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 50% EtOAc in hexane as eluant to afford tert-butyl 4-(4-(4-(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.340 g, 0.85 mmol, 50%) of a yellow solid. 1H NMR (CDCl3) δ 1.42 (3H, t), 1.49 (9H, s), 3.28 (4H, br. t), 3.59 (4H, br. t), 4.42 (2H, q), 6.95 (2H, d), 7.83 (1H, s), 8.05 (2H, d). LCMS (1) Rt: 2.37 min; m/z (ES+) 402.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[O:15][C:14]([CH3:16])=[N:13][C:12]=2[C:17]([O:19]CC)=[O:18])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[O:15][C:14]([CH3:16])=[N:13][C:12]=2[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1nc(C)oc1CCc1cccc(CC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc(CCc2oc(C)nc2C(=O)O)c1

Procedure:
A solution of the product from step (vi) (19.0 g) and lithium hydroxide (5.6 g) in tetrahydrofuran (200 ml) and water (100 ml) was heated at reflux for 4 hours and concentrated under reduced pressure. The residue was suspended in water, acidified with 2N HCl and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine. The organic phase was collected, dried (MgSO4) and solvent evaporated to give a brown solid. Purification was by flash chromatography, eluting with 50% ethyl acetate in dichloromethane with 0.5% acetic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13].[CH2:14]([O:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13])[C:19](=[O:21])[CH3:20])[CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Product: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2-chloro-4-methanesulfonylbenzene and 3-oxobutyric acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.O>CCO.CC(O)=O.[Fe]>[CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2ncccc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC=C(c2ncccc2N)CC1
Temperature: 70 °C
Yield: 102.2 %

Procedure:
A solution of 90.0 mg (0.387 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-3-nitro-pyridine (as prepared in the previous step) in EtOH (10 mL) and water (5 mL) was treated with AcOH (3 drops) and 121 mg (2.17 mmol) of Fe powder then heated to 70° C. for 1.5 h. The mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 80.0 mg (100%) of the title product as a tan glass: Mass spectrum (ESI, m/z): Calcd. for C13H18N2, 203.2 (M+H), found 203.2.