Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH3:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C@H:12](CO)[CH:13]([CH3:15])[CH3:14]>[Zn].ClC1C=CC=CC=1>[CH:13]([C@H:12]1[CH2:10][O:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11]1)([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccccc1
Reactant: CC(C)[C@H](N)CO
Agent: [Zn]
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(c2ccccc2)=N1
Yield: 86 %

Procedure:
Under a nitrogen atmosphere, a mixture of methyl benzoate (1.5 mmol), (S)-valinol (1.8 mmol), the zinc cluster obtained in the above-described Example 5 (0.0375 mmol), and chlorobenzene (2.5 ml) was refluxed for 12 hours. As a result, (S)-4-isopropyl-2-phenyloxazoline was obtained in a yield of 86%.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:15](=[O:49])[CH:16]([C:21]1[CH:48]=[CH:47][C:24]([C:25]([NH:27][C:28]2[CH:33]=[C:32]([C:34]3[CH:38]=[CH:37][S:36][CH:35]=3)[CH:31]=[CH:30][C:29]=2[NH:39]C(=O)OC(C)(C)C)=[O:26])=[CH:23][CH:22]=1)[CH2:17][N:18]([CH3:20])[CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:39][C:29]1[CH:30]=[CH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[CH:33][C:28]=1[NH:27][C:25](=[O:26])[C:24]1[CH:47]=[CH:48][C:21]([CH:16]([CH2:17][N:18]([CH3:20])[CH3:19])[C:15]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:49])=[CH:22][CH:23]=1
Reactant: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the trifluoroacetic acid salt of tert-butyl [2-[(4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzoyl)amino]-4-(3-thienyl)phenyl]carbamate (374 mg, 0.54 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 1 h. Concentration yielded a yellow residue that was purified by reverse phase HPLC (10-70% MeCN/water). The resulting solid was dissolved in CH2Cl2 (with a small amount of MeOH), neutralized with sat. NaHCO3, washed with brine, dried (MgSO4), and evaporated to yield N-[2-amino-5-(3-thienyl)phenyl]-4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzamide as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1cc(F)ccc1F
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A suspension of 2,5-difluorobenzaldehyde (291.5 mg, 2.05 mmol), 2-methyl-2-nitropropane (427.3 mg, 4.14 mmol) and zinc (407.3 mg, 6.23 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.69 ml, 12.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature, stirred for 2 hours and let stand overnight. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (393 mg; 90%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:13].[ClH:14]>CN(C)C=O>[Cl:14][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1Br
Reactant: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)cc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500 mL round bottom flask 4.50 g of 2-bromo-5-tert-butyl-1,3-dimethylbenzene (18.6 mmol) and 9.50 g of NiCl2.6H2O (40.0 mmol) were added. Then 30 mL of N,N-dimethylformamide was added to the flask, giving a blue-green solution. The flask was fitted with a condenser and was left to reflux with stirring. After 0.5 hours the solution was dark blue. After refluxing for 5 days the mixture was cooled to rt and then diluted with 25 mL of 2 M HCl. The aqueous phase was extracted with 40 mL of ethyl acetate. The volatiles were removed from the extract by evaporation to give a white solid. (91% conversion to the title product) All of the solids were dissolved in 25 mL of N,N-dimethylformamide and the solution was placed in a 125 mL round bottom flask. Then 5.1 g of NiCl2.6H2O (21.5 mmol) was added to the flask. The flask was fitted with a condenser and was left to reflux with stirring. After 0.5 hours the solution was dark blue. After refluxing for 5 days the mixture was cooled to rt and then diluted with 25 mL of 2 M HCl. The aqueous phase was extracted with 40 mL of ethyl acetate. The volatiles were removed from the extract by evaporation to give a white solid. C12H17Cl, fw=196.72. Yield 3.51 g, 95.6%. Mp: 39° C. (melt). 1H NMR (300 MHz, CDCl3): δ 7.01(s, 2H), 2.30 (s, 6H), 1.22 (s, Rf=0.69 (cyclohexane/silica).
Reaction SMILES: O[Li].O.CO.[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:9]([NH:11][C@H:12]([C:14]([O:16]C)=[O:15])[CH3:13])=[O:10])[CH3:8].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[NH:6]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@H:7]([C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH3:8]
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of LiOH.H2O (275 mg, 6.56 mmol) in a mixture of solvents MeOH: H2O (10.9 mL: 3.6 mL) was added Boc-Ala-Ala-OMe (1.2 g, 4.38 mmol) and stirred for 4 hours at r.t. The solution was acidified to pH 2 with saturated aqueous solution of citric acid and the mixture was extracted with EtOAc (3×20 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to give the desired product Boc-Ala-Ala-OH as a highly viscous and hygroscopic oil in quantitative yields (1.14 g). The product was taken for further reactions directly without any purification.
Reaction SMILES: [SH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C.Br[C:61]1[CH:68]=[C:67]([N:69]2[C:73]3=[N:74][CH:75]=[CH:76][C:77]([C:78]4[CH:79]=[N:80][C:81]5[C:86]([CH:87]=4)=[CH:85][CH:84]=[CH:83][CH:82]=5)=[C:72]3[C:71]([CH3:88])=[CH:70]2)[CH:66]=[CH:65][C:62]=1[C:63]#[N:64]>O1CCOCC1.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].O.C(OCC)(=O)C>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([S:1][C:65]2[CH:66]=[C:67]([N:69]3[C:73]4=[N:74][CH:75]=[CH:76][C:77]([C:78]5[CH:79]=[N:80][C:81]6[C:86]([CH:87]=5)=[CH:85][CH:84]=[CH:83][CH:82]=6)=[C:72]4[C:71]([CH3:88])=[CH:70]3)[CH:68]=[CH:61][C:62]=2[C:63]#[N:64])[CH2:3][CH2:4]1
Reactant: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: O[C@H]1CC[C@H](S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1cn(-c2ccc(C#N)c(S[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 120 °C
Reaction time: 6 h

Procedure:
Trans-4-mercaptocyclohexanol (0.050 g), tris(dibenzylideneacetone)dipalladium(0) (0.008 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.010 g), and N,N-diisopropylethylamine (0.116 mL) were added to a solution of compound (40f) (0.150 g) prepared in Example 40(6) in 1,4-dioxane (1.71 mL), followed by stirring under nitrogen flow at 120° C. for 6 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain a crude product of 2-(trans-4-hydroxycyclohexylthio)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile. Subsequently, an aqueous sodium hydroxide solution (4 M, 0.851 mL) and a 30% hydrogen peroxide solution (0.193 mL) were added to a solution of this 2-(trans-4-hydroxycyclohexylthio)-4-{(3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile in DMSO (0.4 mL) and ethanol (1.6 mL) at room temperature, followed by stirring for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed by sprinkling water and ether, and then dried under reduced pressure to obtain compound (67) (0.023 g, the second stage yield: 13%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[C:24]3[C:23]([C:25]([OH:27])=O)=[CH:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:27]=[C:25]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:18][CH:17]=[C:16]([C:24]=23)[CH2:15][N:14]1[CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2c[nH]c3nccc(C(=O)O)c23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N2Cc3c[nH]c4nccc(c34)C2=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-((1-(tert-butoxycarbonyl)piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid was dissolved in DMF (5 mL). HATU (914 mg, 2.4 mmol) and DMAP (196 mg, 1.6 mmol) were added, and the reaction stirred at rt for 2 h. The solution was concentrated in vacuo and purified by preparative HPLC eluting with a gradient of 30% to 50% Solvent B in Solvent A to give 123 mg of the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD) δ 1.48 (s, 9 H) 1.59-1.70 (m, 1 H) 1.88 (d, J=13.39 Hz, 1 H) 1.95-2.02 (m, 1 H) 2.06 (dd, J=12.25, 3.92 Hz, 1 H) 2.75 (br. s., 1 H) 3.15 (t, J=11.62 Hz, 1 H) 4.04-4.20 (m, 2 H) 4.51 (br. s., 1 H) 4.93-5.14 (m, 2 H) 7.44 (s, 1 H) 7.58 (d, J=5.31 Hz, 1 H) 8.43 (d, J=5.56 Hz, 1 H). [M+H] found 357.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=1.[C:44](O)(=[S:46])[CH3:45]>O1CCCC1>[C:44]([O:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([Br:34])=[CH:36][CH:37]=1)(=[S:46])[CH3:45]
Reactant: CC(O)=S
Reactant: OCCc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OCCc1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
5 mmol (1 ml) of DIAD are added to a solution, cooled to 0° C., of 5 mmol (1.32 g) of triphenylphosphine in 16 ml of tetrahydrofuran. After stirring the mixture cold for 15 minutes, there is added dropwise thereto a mixture of 2.5 mmol (0.5 g) of 2-(4-bromophenyl)-1-ethanol and 5 mmol (0.83 ml) of thioacetic acid diluted with 5 ml of tetrahydrofuran. The mixture is stirred cold for a further 10 minutes and then the temperature is brought to ambient temperature for 18 hours. The solvents are evaporated off. The residue is taken up in diisopropyl ether and the precipitate formed is filtered off. The filtrate is concentrated and then purified by chromatography on silica gel. using petroleum ether as eluant, to yield the expected product.
Reaction SMILES: C(O[CH:4]=[C:5]([C:19]#[N:20])[CH2:6][CH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:24][C:23]1[N:25]=[C:19]([NH2:20])[C:5]([CH2:6][CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:4][N:22]=1
Reactant: CCOC=C(C#N)CCCc1cccc2ccccc12
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(CCCc2cccc3ccccc23)c(N)n1
Temperature: 125 °C
Reaction time: 6 h
Yield: 35.9 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 0.85 gram (0.003 mole) of 1-ethoxy-2-cyano-5-(naphth-1-yl)-1-pentene, 1.22 grams (0.013 mole) of guanidine hydrochloride, and 2.65 grams (0.01 9 mole) of potassium carbonate in 20 mL of N,N-dimethylformamide was heated at 110° C. for 20 hours. After this time the reaction mixture was analyzed by thin layer chromatography (TLC) which indicated the reaction was not complete. The reaction mixture was warmed to 125° C. where it was stirred for six hours. TLC analysis of the reaction mixture after this time indicated that the reaction was still not complete. An additional 10 mL of dimethylformamide was added, and the reaction mixture was stirred at 125° C. for an additional 64 hours. The reaction mixture was then poured into water, and the mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were concentrated under reduced pressure, yielding a yellow solid. The solid was triturated with dichloromethane. The solid was collected by filtration and subjected to column chromatography on silica gel. Elution was accomplished with 10:1 methylene chloride and methanol. The eluate was concentrated under reduced pressure, yielding 0.30 gram of 2,4-diamino-5-[3-(naphth-1-yl)propyl]pyrimidine, mp 179°-181° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C.O>C(#N)C>[Br:19][C:20]1[CH:21]=[C:22]([C:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)=[O:24])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (300 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (12 mL) were added 3-bromobenzoyl chloride (191 μL) and triethylamine (202 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (407 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](B2OC(C)(C)C(C)(C)O2)=[N:24]1>>[NH:23]1[C:31]2[C:26](=[C:27]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=4)[N:3]=3)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1
Reactant: CC(=O)Nc1ccc(Nc2nc(Cl)nc3c2cnn3C)cc1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: CC(=O)Nc1ccc(Nc2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)cc1

Procedure:
N-[4-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-phenyl]-acetamide was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica and trituration yielded 157. NMR: (CDCl3): 2.08 (s, 3H, CH3), 4.17 (s, 3H, CH3), 7.51 (t, H, ArH, J=7.77 Hz), 7.69 (m, 3H, 3×ArH), 7.78 (m, 2H, 2×ArH), 8.28 (d, H, ArH, J=7.26 Hz), 8.17 (sbr, H, NH), 8.93 (s, H, ArH), 9.98 (s, H, ArH), 10.07 (s, H, ArH), 13.18 (s, H, ArH). MS: (ESI+) MH+=399.13
Reaction SMILES: N1([C:6]2C[CH2:8][C:9]3[C:14]([CH:15]=2)=[C:13]([Cl:16])[CH:12]=[CH:11][CH:10]=3)CCCC1.CI.O.[C:20]([OH:23])(=O)[CH3:21]>O1CCOCC1.CCOCC>[CH3:6][CH:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:16])[CH2:8][CH2:21][C:20]1=[O:23]
Reactant: Clc1cccc2c1C=C(N1CCCC1)CC2
Reactant: CC(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CC1C(=O)CCc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The dihydronaphthalene was dissolved in 30 ml of p-dioxane. To the solution were added 10 ml of methyl iodide, and the mixture was heated to reflux for 18 hours under nitrogen. To the reaction mixture then were added 25 ml of water and 1 ml of acetic acid, and the heating was continued for four hours. The reaction mixture then was cooled to room temperature, and the solvent was removed in vacuo. The resulting residue was suspended in water, and the aqueous mixture was extracted with ether. The organic extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated in vacuo to give a dark oil. The oil was dissolved in ether and placed on a flash silica column. The column was eluted with a 1:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The eluate was evaporated in vacuo to give 3.14 g of 1-methyl-8-chloro-2-tetralone as a mobile, orange liquid.
Reaction SMILES: C([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[C@H:16]([CH2:27][CH:28](CC1C=CC=CC=1)[C:29](=[O:31])[OH:30])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H].C(OCC)(=O)C>CO.[C].[Pd].O>[C:21]1([S:18]([NH:17][C@H:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:40])=[O:8])=[O:39])[CH2:27][CH2:28][C:29](=[O:30])[OH:31])(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: O=C(O)C(Cc1ccccc1)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CC[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 76.9 %

Procedure:
N-benzenesulfonyl-γbenzyl-L-glutamyl-L-proline benzylester (2.61 g, 4.6 mmole) was dissolved in methanol (40 ml), and water (5 ml) suspension of sodium bicarbonate (0.84 g, 10 mmole) was added thereto. Hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 4 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure, and the residue thus obtained was dissolved in water (30 ml). The mixture was washed with two 30 ml portions of diethyl ether, to the water layer 1N aqueous hydrochloric acid (15 ml) was added, and the solution thus obtained was concentrated under reduced pressure. The white residue thus obtained was dispersed in a mixture (100 ml) of ethyl acetate and methanol (1:1), and the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain white solid. It was recrystallized from methanol, ethyl acetate and petroleum ether to obtain N-benzenesulfonyl-L-glutamyl-L-proline (yield: 1.36 g, 76.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][Si](C)(C)C)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C(NF)(C)(C)C.C1COCC1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[CH:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: C[Si](C)(C)C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: CC(C)(C)NF
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-chloro-2-(4-trifluoromethoxy-benzyl)-5-trimethylsilanylethynyl-2,3-dihydro-isoindol-1-one (0.100 g, 0.22 mmol) in THF (1 mL) was treated with a 1M solution of tertiary-butyl amino fluoride-THF (1 mL). The reaction mixture was stirred at ambient temperature for 2 h. After this time, GC-MS indicated that the reaction was completed. The reaction solution was poured into water (7 mL) and extracted with diethyl ether (2×20 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated to afford 7-chloro-5-ethynyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one. The material was used without purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15](N)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:19]C1C=CC(O)=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Nc1ccc(O)cc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Product: CNC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 3-aminophenol for 4-aminophenol. 1H-NMR (DMSO-d6) δ 8.75 (br q, J=4.8 Hz, 1H), 8.48 (d, J=6.3 Hz, 1H), 7.39 (d, J=2.1 Hz, 1H), 7.15 to 7.07 (m, 2H), 5.51 to 6.47 (m, 1H), 6.31 to 6.24 (m, 2H), 5.40 (s, 2H), 2.77 (d, J=5.1 Hz, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:31][C:30]3([F:33])[F:32])=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:31][C:30]3([F:33])[F:32])=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
TFA (0.1 mL, 1.587 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2,2-difluorocyclopropanecarboxamide (10 mg, 0.023 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg). 1H NMR (400 MHz, CD3OD): δ 8.69 (s, 1H), 7.82 (m, 2H), 7.70 (d, 1H, J=8.8 Hz), 7.56-7.50 (m, 3H), 2.82-2.73 (m, 1H), 2.21-2.12 (m, 1H), 1.94-1.85 (m, 1H); ESI-MS [M+H]+: 354.2.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[S:28])=[CH:25][CH:24]=1>>[Cl:15][C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:27](=[S:28])[C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:31][CH:30]=3)([C:3]#[N:4])[CH3:20])[N:7]=2)[CH:11]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:13]=1
Reactant: CC(N)(C#N)Cn1nc2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2cc(C(F)(F)F)cc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4-chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 19, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.45 g, 90%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=508. 1H NMR: (400 MHz, DMSO-d6): 1.77 (s, 3H), 5.49-5.65 (m, 2H), 7.84-7.93 (m, 5H), 8.56 (d, J=1.1 Hz, 1H) and 8.95 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −61.09 (s, 3F) and −42.03 (s, 3F).