Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:43])[N:9]=[C:10](SC)[C:11]([C:28]1[CH:37]=[C:36]([O:38][CH3:39])[C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[C:29]=1[F:40])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[NH:54][NH2:55])=[O:48])[CH3:45]>C(N(CC)CC)C>[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[N:54]1[C:8](=[O:43])[NH:9][C:10]([CH:11]([C:28]2[CH:37]=[C:36]([O:38][CH3:39])[C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[C:29]=2[F:40])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[O:21][N:20]=3)=[CH:15][CH:14]=2)=[N:55]1)=[O:48])[CH3:45]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1cc(OC)c2c(c1F)OCCO2
Reactant: CCOC(=O)c1scnc1NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To 5 ml of a DMF solution containing 113 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester, 40 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester (Example (185c)) and 0.030 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol and 0.035 ml of acetic acid, and 103 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give the title compound (57 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C>[N+:13]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([OH:12])[C:2]([OH:1])=[CH:3]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc2ccccc2cc1O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cccc2cc(O)c(O)cc12
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A suspension of 5.0 g of 2,3-Dihydroxynaphthalene dimesitylate in 50 ml of acetic anhydride was treated with 12 ml of 70% HNO3 at such a rate as to keep the temperature between 37-40° C. A cooling bath should be kept under the flask, ready to be raised if necessary, as the temperature should not be allowed to exceed 45° C. The 12.0 ml of nitric acid was added to the reaction mixture over a period of 1-2 h. After 2 h, the reaction mixture was cooled to 5° C. in an ice bath and the precipitate was collected by filtration and washed with ether. Yield 5-Nitro-2,3-dihydroxynaphthalene dimesitylate 70%; mp 199-201° C., 1H NMR (DMSO-d6) δ 3.58 (s, 6H), 7.76 (t, J=8.0 Hz, 1H), 8.25-8.65 (m, 4H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[CH:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[O:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1cnc(Cl)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Copper (I) iodide (25 mg) and bis-(triphenylphosphin)-palladium(II)-chloride (30 mg) are added to 6-chloro-4-iodo-pyridin-3-ol (200 mg) in N,N-dimethylformamide (3 mL) under an argon atmosphere. Triethylamine (110 μL) is added and the resulting mixture is stirred at room temperature for 1 h. A solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (175 mg) in N,N-dimethylformamide (2 mL) is added dropwise and the reaction mixture is stirred at 55° C. for 3 h. The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30) to give the title compound. LC (method 2): tR=1.40 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[N:20][N:21]=2)[N:18]=1)(=O)=O.[C:22]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:35]1([CH:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]2[CH2:30][CH2:31][N:32]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[N:20][N:21]=4)[N:18]=3)[CH2:33][CH2:34]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCCCCNc1ccc2nncn2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CCN(CCCCCCNc3ccc4nncn4n3)CC2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.6 %

Procedure:
796 mg of 6-[6-(methanesulfonyloxy)hexylamino][1,2,4]triazolo[4,3-b]pyridazine was dissolved in 15 ml of N,N-dimethylformamide; 769 mg of 1-(diphenylmethyl)piperazine, 422 mg of potassium carbonate, and 506 mg of potassium iodide were added, followed by stirring at 60° C. for 4 hours. After cooling, saline was added; the reaction mixture was extracted with ethyl acetate and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized from ethyl acetate, washed with diethyl ether, recrystallized in the same manner, and dried, to yield 353 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21](=[O:23])[CH3:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine (10.30 g, 36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid (10 drops) and the mixture was stirred and heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into ice water (300 mL). 2N Aqueous sodium hydroxide solution was added to raise the pH of the solution to about 10 and the resulting orange precipitate was collected by filtration. The solid was washed with water, air-dried, and then dried under vacuum to afford the title compound as an orange solid, 11.87 g (quant.). 1H NMR (DMSO-d6): δ 9.58 (s, 1H), 8.41 (d, 1H. J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s, 3H). MS (ES) 323 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OCC(=O)N2
Reaction time: 16 h

Procedure:
Under argon, 10% palladium on carbon (350 mg, 5% w/w) was added to a suspension of 7-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine (7 g, 39.3 mmol) in 50 ml of MeOH. The reaction mixture was hydrogenated at 40 psi for 16 hours. The reaction mixture was then diluted with THF (-200 mls) and the reaction was filtered through celite. The solvent was evaporated, leaving a brown solid as the residue. Product was recrystallized from THF/Hexane (1:5). Collected 4.2 g (72%) of a tan solid: m.p. 213-215, 'H NMR (300 M Hz, DMSO) δ 4.410 (S, 2H), 4.869 (S, 2H) 6.141 (d, 1H, J=2.44) 6.176 (dd, 1H, J=2.25, 4.69), 6.563 (d, 1H, J=8.19), 9.535 (brs, 1H); 13C NMR (300 MHz, DMSO) δ 66.9496, 102.2081, 108.1369, 116.5779; 116.8982, 144.5502, 145.4287, 164.389; Mass spectrum M+ at m/z 164
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=3[C:12]3[CH2:13][N:14]([C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[OH:25])[C:15](=[O:18])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH3:30][N:31](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[OH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[N:14]1[CH2:13][C:12]2[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([C:30]#[N:31])=[N:7][CH:6]=3)=[CH:17][C:16]=2[C:15]1=[O:18]
Reactant: CN(C)C=O
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Temperature: 25 °C

Procedure:
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.022 g, 0.019 mmol) in 0.5 mL of N,N-dimethylformamide was added zinc cyanide (0.034 g, 0.29 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.039 g, 0.097 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 30 min, cooled to ambient temperature, and purified via preparative reverse phase HPLC and preparative thin layer chromatography, eluting with 50% ethyl acetate in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 398.2 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 7.64-7.58 (m, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.46-7.44 (m, 1H), 4.87-4.71 (m, 2H), 4.45 (s, 2H), 4.21-4.09 (m, 1H), 3.79-3.64 (m, 1H), 2.70-2.67 (m, 1H), 2.24-2.21 (m, 1H), 2.01-1.98 (m, 1H), 1.87-1.83 (m, 1H), 1.72-1.61 (m, 1H), 1.56-1.38 (m, 3H) ppm.
Reaction SMILES: C([N:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])C.[Li+].[OH-]>C1COCC1.O>[F:14][C:11]1[CH:10]=[CH:9][C:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CCN(CC(=O)O)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNc1ccc(F)cc1

Procedure:
To a solution of 21.3 g (108 mmole) of ethyl N-(4-fluorophenyl)glycine in THF (100 mL) under nitrogen was added LiOH (5.44 g (130 mmol) monohydrate in 25 mL water. After 15 h the mixture was concentrated to half the volume and acidified to pH 3 with HCl. The precipitated solid was collected and washed with water (100 mL) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 80.0 mg (0.173 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-(1,1-dimethylethyl)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 6) and 18.1 mg (0.432 mmol) of LiOH-H2O in 6 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the remaining aqueous layer acidified with 1M HCl, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.82 (2H, d, J=8.2 Hz), 7.44 (6H, m), 7.25 (2H, d, J=8.3 Hz), 7.02 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.32 (2H, d, J=4.7 Hz), 1.32 (9H, s), 1.29 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:18])[CH3:17])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[Cl:25]N1C(=O)CCC1=O.Cl>CC(C)=O>[Cl:25][C:3]1[C:4]2[N:10]3[CH2:11][CH2:12][CH2:13][C@@H:14]([NH:15][C:16](=[O:18])[CH3:17])[C@H:9]3[C:8]3[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=3[O:6][C:5]=2[CH:23]=[CH:24][C:2]=1[Cl:1]
Reactant: CC(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)N[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.4 %

Procedure:
To a solution of trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]-pyrido[1,2-d][1,4]oxazepin1-yl)acetamide (Structure 12 of Scheme II, where R1=H, R2=H, R3=Cl, R4=R5=H, R15=CH3, X=O) (0.63 g, 1.84 mmol) in acetone (15 mL) were added N-chlorosuccinimide (246 mg, 1.84 mmol) and 6N (aq) HCl (3.1 mL). The resulting suspension was stirred at room temperature for 20 h. A second amount of N-chlorosuccinimide (246 mg, 1.84 mmol) was added and subsequently the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with ethyl acetate (3×), washed with sat. (aq) NaHCO3 (3×), 10% (aq) NaCl (2×) and dried (Na2SO4). The solvents were removed under reduced pressure. The solid was purified by column chromatography (silicagel, toluene/ethanol=9/1). Subsequent purification by HPLC resulted in the title compound (137 mg, 36.4%). Data: 1H-NMR (400 MHz, CDCl3) 1.55 (m, 1H), 1.82 (m, 2H), 1.94-2.20 (m, 1H), 2.10 (s, 3H), 2.92 (m, 1H), 3.11 (td, J=12.6, 4.2, 1H), 4.39 (d, J=1.9, 1H), 4.86 (m, 1H), 7.02-7.36 (m, 6 ArH).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][CH2:33][C:31]3[CH:30]=[CH:29][C:26]4[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=4[N:32]=3)[CH2:4]2)=[CH:15][CH:16]=1
Reactant: NC[C@@H]1CCN(CCn2c(=O)ccc3ccc(F)cc32)C1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C1COc2ccc(CNC[C@@H]3CCN(CCn4c(=O)ccc5ccc(F)cc54)C3)nc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of 1-{2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (87 mg, 0.30 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (54 mg, 0.302 mmol) was added Na2SO4 (355 mg, 2.50 mmol) and the reaction was stirred at ambient temperature for 18 h. The intermediate imine was treated with sodium triacetoxyborohydride (160 mg, 0.75 mmol) and stirred for an additional 16 h). The solvents were removed under reduced pressure; the residue was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic layer was dried (Na2SO4). Purification by column chromatography on silica gel, (1% to 20% methanol:dichloromethane gradient) yielded the title compound as an amorphous off-white solid (69 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1.[H-].[Na+].[CH3:28][S:29][CH2:30]Cl>CN(P(N(C)C)(N(C)C)=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:28][S:29][CH3:30])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[O:11][C:10]2=[O:24])[CH:7]=1
Reactant: CSCCl
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSCOc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (6.0 g, 16.2 mmol) in dry HMPA (50 mL) was added dropwise under nitrogen to a stirred suspension of sodium hydride (0.77 g of 60% dispersion in mineral oil, 19.4 mmol) in HMPA (15 mL). The resultant yellow solution was stirred for 30 min and then neat chloromethyl methyl sulfide (1.49 mL, 17.8 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and the product was extracted with ethyl acetate (500 mL). The EtOAc layer was washed with satd. NaHCO3, water, brine and then dried (MgSO4). Rotary evaporation of EtOAc gave a yellow semi-solid which was recrystallized from ethyl acetate/hexanes to afford the title compound as white crystals (4.4 g, 70%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([C:15]#[N:16])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:23]([C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[CH2:26]([C:25]([C:23]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:10][C:11]([C:15]#[N:16])=[N:12]3)=[CH:7][CH:6]=2)[CH:24]=1)([OH:30])[CH2:28][CH3:29])[CH3:27]
Reactant: C#CC(O)(CC)CC
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CN=[N+]=[N-])cc2n1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cn(Cc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 7-(azidomethyl)-4-phenylquinoline-2-carbonitrile (100 mg, 0.35 mmol), 3-ethylpent-1-yn-3-ol (47 mg, 0.42 mmol), copper iodide (100 mg, 0.52 mmol) and diisopropylethylamine (305 μL, 1.75 mmol) in THF (4 mL) was stirred at rt for 6 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5](/[CH:6]=[N:7]/[S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C@@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7][S@:8]([C:10]([CH3:11])([CH3:12])[CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Temperature: -45 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
(R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide, 18-b, (10 g, 34.84 mmol) was dissolved in anhydrous THF (100 ml). The mixture was then cooled to −45° C. and PhMgBr (34.84 ml, 69.68 mmol) was added dropwise. After addition, the mixture was allowed to stir at −45° C. for additional 4 h and warm to room temperature for another 2 h. TLC monitored the reaction and the time was prolonged if necessary. The mixture was quenched with saturated NH4Cl followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to provide the product, 22-a, (8 g, 63%). HPLC indicated that the diastereomer ratio is 96:4 after recrystallization once in hexane/ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=O>>[CH:43]1([NH:42][CH2:40][CH2:39][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:45][CH2:44]1
Reactant: O=C(CCl)NC1CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCNC3CC3)c(F)c2)c1
Yield: 6.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (37 mg) and 2-chloro-N-cyclopropylacetamide (19 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:36]([C:37]#[N:38])=[C:35]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:34]=[C:33]([S:44][CH2:45][C:46]3[N:47]=[C:48]([C:51]4[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=4)[S:49][CH:50]=3)[C:32]=2[C:58]#[N:59])=[CH:27][CH:26]=1)=[O:20])[CH3:18])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:57].[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([C:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[C:36]([C:37]#[N:38])=[C:35]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43]3)[N:34]=[C:33]([S:44][CH2:45][C:46]3[N:47]=[C:48]([C:51]4[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=4)[S:49][CH:50]=3)[C:32]=2[C:58]#[N:59])=[CH:29][CH:30]=1)=[O:20])[CH3:18])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 6 h

Procedure:
414 mg (0.482 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-isoleucyl-L-alaninate were dissolved in 3 ml dichloromethane, and 4.822 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 6 hours of stirring, 2 ml of a 1N solution of hydrogen chloride in diethyl ether were added, and the mixture was stirred at room temperature for a further 24 hours. The precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. Since the reaction was still incomplete, the solid was stirred in 5 ml of a 1N solution of hydrogen chloride in diethyl ether for a further 24 h. The precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 312 mg (81% of theory) of the target compound were obtained.