Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1)([CH3:10])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21](N=C=NCCCN(C)C)C.CO>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:21][O:18][C:17]([C:15]1[N:16]=[C:12]([S:11][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:10])[CH3:9])[S:13][CH:14]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)O)cs1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-tert-Butoxycarbonyl-1-methyl-ethylsulfanyl)-thiazole-4-carboxylic acid was dissolved in methylene chloride (1200 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191.70 g), 4-dimethylaminopyridine (5.86 g) and methanol (19.47 mL) were added and the mixture was stirred at room temperature overnight. The mixture was washed with dilute hydrochloric acid (about 0.5 mol/L), saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 500 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved again in ethyl acetate (700 mL), washed successively with dilute hydrochloric acid (about 0.2 mol/L), saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 300 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained solid was washed with a mixed solvent (10:1, about 500 mL) of hexane and ethyl acetate, and the solid was collected by filtration. The solvent was evaporated from the filtrate and the residue was purified by silica gel column chromatography (using 500 g of Fuji Silysia BW-300, elution solvent: hexane/ethyl acetate=3/1). The obtained solid was washed with hexane and combined with the solid obtained earlier to give 2-(1-tert-butoxycarbonyl-1-methyl-ethylsulfanyl)-thiazole-4-carboxylic acid methyl ester (94.6 g).
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:15]([CH2:17][NH2:18])[OH:16]>C(O)C>[OH:16][CH2:15][CH2:17][NH:18][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:18][CH2:17][CH2:15][OH:16])=[O:13])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: NCCO
Solvent: CCO
Product: O=C(NCCO)c1ccc(C(=O)NCCO)cc1

Procedure:
A mixture of 194 g (1.0 mole) of dimethyl terephthalate, 150 ml (2.46 mole) ethanolamine and 300 ml ethanol was refluxed for 7 hours. On cooling the title product separated. It was filtered and then washed with ethanol. After drying, it melted at 227°-229° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.C(N(CC)CC)C.[CH2:28]([OH:31])[C:29]#[CH:30]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:13]=2)[O:9][N:8]=1
Reactant: C#CCO
Reactant: N#Cc1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of the 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (140 mg, 0.374 mmol), Pd(PPh3)4 (10 mg, 0.009), and Cul (30 mg, 0.158 mmol) in N,N-dimethylformamide (3 mL) was treated with triethylamine (1 mL, 726 mg, 7 mmol). The reaction mixture was cooled to 0° C. and treated with propargyl alcohol (56 mg, 1 mmol). The mixture was stirred at ambient temperature 5 hours and then filtered through a short plug of silica gel, washing with ethyl acetate. The organic solution was concentrated in vacuo. Silica gel chromatography afforded 20 mg (18%) of 3-(2-pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole: 1H-NMR (MeOH-d4), δ ppm: 8.80 (d, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.30 (d, 1H), 8.10 (m, 2H), 7.60 (m, 1H), 4.5 (s, 2H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][NH2:19])[CH:14]=[CH:15][C:16]=1[F:17].C(N(C(C)C)CC)(C)C>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][NH:19][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCC(=O)NCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of glutaric anhydride (342 mg, 3 mmol), [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride salt (721.5 mg, 3 mmol), and diisopropyl ethyl amine (2 mL) in THF (50 mL) was stirred at room temperature for 1 hour. It was concentrated, mixed with 4% HCl (50 mL) and extracted with EtOAc (50 mL, 2×). The combined organic extracts were dried and concentrated to provide the captioned product (920 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH3:7])[O:5][CH:4]([CH3:8])[C:3]1=NO.[OH:11]S(O)(=O)=O>>[O:1]=[C:2]1[CH:6]([CH3:7])[O:5][C:4]([CH3:8])=[C:3]1[OH:11]
Reactant: CC1OC(C)C(=NO)C1=O
Reactant: O=S(=O)(O)O
Product: CC1=C(O)C(=O)C(C)O1

Procedure:
10 g of 4-oxo-3-oximino-2,5-dimethyl-tetrahydrofuran and 50 ml of 10% strength H2SO4 are heated at 80° C and the hydrolysis is followed by thin layer chromatography. The oxime has been converted after 3 hours. In its place, 4-oxo-3-hydroxy-2,5-dimethyl-4,5-dihydrofuran has been formed, as established by isolating the product and comparing the chromatographic and spectroscopic data with those of a comparative substance.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.[OH-].[K+].[CH2:19](O)C>O>[Br:1][C:2]1[C:10]([O:11][CH3:19])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[NH:6]2
Reactant: CCOC(=O)c1cc2c(Br)c(O)ccc2[nH]1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]c(C(=O)O)cc2c1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Ethyl 4-bromo-5-hydroxyindole-2-carboxylate (1.49 g, 5 mmol.), (Jnl. Org. Chem. 1984, 49, 4761), was dissolved in ethanol (10 ml) and water (3.5 ml). Potassium hydroxide (840 mg) was added and the mixture stirred at 50° C. under an atmosphere of nitrogen for 1 hour then cooled to ambient temperature. The solvent was evaporated and the residue redissolved in water (25 ml). 2M Aqueous hydrochloric acid was added until the reaction mixture was at pH4, giving a precipitate which was filtered off, washed with water and dried under vacuum to give 4-bromo-5-methoxyindole-2-carboxylic acid (1.30, 96%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[N:3]=1.[C:23]1([NH:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([NH:32][CH2:31][CH2:30][NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1
Reactant: NCCNc1ccccc1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1C1=CCCO1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1C1=CCCO1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-(4,5-dihydro-furan-2-yl)-pyrimidin-4-yl ester and N-phenylethylenediamine in DME. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]O)[CH2:14][C@@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:29])(=O)=O.C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O.[Cl-]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][Cl:29])[CH2:14][C@@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CCCl)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
Methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate (Intermediate 37) (650 mg, 1.93 mmol) was reacted with methanesulfonyl chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mmol) as described for Intermediate 6. The crude chloride was used without delay for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[C:18]([CH2:27][C:28]([OH:30])=[O:29])=[C:17]2[CH3:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](OC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)[CH3:33].[H-].[Na+].C(OC1C=CC(CCl)=CC=1)C1C=CC=CC=1>>[CH2:32]([O:29][C:28](=[O:30])[CH2:27][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:17]=1[CH3:31])[CH3:33]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2ccc(OCc3ccccc3)cc2)c2ccc(OC)cc12

Procedure:
1-[(4-Benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid. Using the method described in Example 6, Part A, 2.0 g (8.12 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester, 0.325 g (8.12 mmol) of 60% NaH/mineral oil, and 1.88 g (8.12 mmol) of 4-benzyloxy-1-chloromethylbenzene were reacted to give on workup 800 mg of crude 1-[(4-benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester. The crude ester in 50 mL of MeOH and 15 mL of 1N NaOH was heated at reflux temperature for 3 hours and left standing for 16 hours. After diluting with water, the mixture was made acidic with 1N HCl and extracted with EtOAc. The EtOAc solution was dried (Na2SO4) and concentrated. The residue was crystallized from MeOH to give 280 mg (32% yield) of 1-[(4-benzyloxyphenyl)-methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid, mp, 175-179° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:21][CH2:20]2)[CH:11]=1.O1CCCC1.N>O>[NH2:16][C:15]1[C:10]([Cl:9])=[CH:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:21][CH2:20]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)C(=O)N1CCN(c2cc(Cl)c([N+](=O)[O-])cn2)CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1CCN(c2cc(Cl)c(N)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add (4.5 mmol, 0.8 g) of sodium dithionite, over 1-[4-(4-chloro-5-nitro-pyridin-2-yl)-piperazin-1-yl]-2,2-dimethyl-propan-1-one (0.9 mmol, 0.3 g) in 22 mL of 1:1 mixture of tetrahydrofuran and water and 4 mL of ammonia. Stir the solution for 2 hours at room temperature. Concentrate under reduce pressure and extract the residue in ethyl acetate. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue that is used without further purification. MS(ES): m/z=297 [M+H].
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl[CH2:39][C:40]1[NH:44][C:43]2[C:45]([F:49])=[CH:46][CH:47]=[CH:48][C:42]=2[N:41]=1>C(#N)C>[F:49][C:45]1[C:43]2[N:44]=[C:40]([CH2:39][N:11]([CH:9]3[C:10]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][CH2:8]3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[NH:41][C:42]=2[CH:48]=[CH:47][CH:46]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: Fc1cccc2nc(CCl)[nH]c12
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c(F)cccc2[nH]1)C1CCCc2cccnc21
Temperature: 60 °C
Yield: 41 %

Procedure:
To a stirred solution of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (146 mg, 0.418 mmol), diisopropylethylamine (0.15 mL, 0.861 mmol) and potassium iodide (14 mg, 0.084 mmol) in acetonitrile (2.5 mL) was added 2-chloromethyl-7-fluoro-1H-benzimidazole (prepared according to the procedures described in Bridger et al. U.S. Provisional Application No. 60/232,891 filed Sep. 15, 2000 and from Application No. 60/234,510 filed Sep. 22, 2000) (80 mg, 0.433 mmol) and the mixture heated at 60° C. for 18 hours. The mixture was then concentrated and the residue diluted with CH2Cl2 (30 mL). The solution was washed with brine (3×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give a crude brown foam. The foam was purified by flash chromatography (1.75 cm ID, 12 g silica, 50:1:1 CH2Cl2: MeOH: NH4OH) to give pure 2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (86 mg, 41%). 1H NMR (CDCl3) δ 1.33-1.76 (m, 5H), 1.85-2.10 (m, 3H), 2.14-2.25 (m, 1H), 2.54-2919 (m, 4H), 3.45-3.55 (m, 2H), 3.98-4.24 (m, 3H), 7.29-7.45 (m, 2H), 7.63-7.69 (m, 2H), 7.72-7.77 (m, 2H), 8.56-8.63 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2C=CC=C[C:4]=2[N:3]=[C:2]1[NH2:10].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[CH3:15][C:13]1[N:10]=[C:2]2[S:1][CH:5]=[CH:4][N:3]2[C:11](=[O:16])[CH:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nc2ccccc2s1
Solvent: CC(=O)O
Product: Cc1cc(=O)n2ccsc2n1
Yield: 40715.4 %

Procedure:
A solution of 1,3-benzothiazol-2-amine (20 g, 0.133 mmol), ethyl acetoacetate (25.96 g, 0.199 mmol) and acetic acid (150 ml) was reacted together according to the procedure described in Intermediate 3, Step 1 to afford 9 g of the desired product as a pale yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[CH:20][CH:21]=1
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Reactant: ClCCCCSc1ccc(Cl)cc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 5 from 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-chlorophenylmercapto)-butylchloride.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].S([O:20][CH2:21][C:22]1([CH:28]=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(C)(=O)=O.C(N(CC)CC)C.Cl>COCCOCCOC>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][CH2:28][C:22]1([CH:21]=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)OCC1(C=O)CCCCC1
Reactant: O=C(c1ccccc1)c1ccccc1S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: O=CC1(CSc2ccccc2C(=O)c2ccccc2)CCCCC1
Yield: 18.1 %

Procedure:
A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HCl and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc:Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([Br:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:35][C:34]1[C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ncccc2Br)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncccc2Br)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-bromo-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CN(C)[C:18](=[O:21])[CH:19]=[CH2:20].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>ClC(Cl)C>[CH2:25]1[C:26]2=[C:31]3[C:30](=[CH:29][CH:28]=[CH:27]2)[C:18](=[O:21])[CH2:19][CH2:20][N:23]3[CH2:24]1
Reactant: c1ccc2c(c1)CCN2
Reactant: C=CC(=O)N(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C1CCN2CCc3cccc1c32
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
Add trifluoromethanesulfonic anhydride (10.5 mL, 63 mmol) in dichloroethane (30 mL) to N,N-dimethylacrylamide (6.4 mL, 63 mmol) in dichloroethane (100 mL) at 0° C. dropwise with vigorous stirring over 5 minutes. Add indoline (5.6 mL, 50 mmol) in dichloroethane (30 mL) dropwise over 5 minutes. Remove from cooling bath and heat at reflux for 3.5 hours. Cool to room temperature. Dilute with diethyl ether (600 mL). Wash with aqueous potassium carbonate (400 mL), dilute aqueous sodium bicarbonate (2×300 mL) and saturated aqueous sodium chloride (300 mL). Dry over sodium sulfate and concentrate under reduced pressure. Subject the residue to chromatography (pre-packed silica gel), eluting with 19:1 dichloromethane/ethyl acetate to provide the desired compound (2.65 g, 31%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([CH:14]=[O:15])[CH2:8][CH2:7]2)=[O:5])[CH3:2].CC(C)=[O:18].OS(O)(=O)=O.O=[Cr](=O)=O>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([C:14]([OH:18])=[O:15])[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(C=O)C(CC1)C2
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C12CCC(C1)C(C(=O)O)CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To an ice-cold solution of 4-formyl-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (3.85 mmol, 0.81 g) was added slowly Jones reagent (2.7 M, 1.43 mL). The reaction was stirred at ice temperature 20 min, then quenched by addition of iPrOH. diluted with H2O and extracted with Et2O (3×). The combined organic extracts were washed with H2O (2×), brine (1×), and dried (MgSO4). Filtration and evaporation provided the viscous oily bicyclo[3.2.1]octane-1,4-dicarboxylic acid 1-ethyl ester (0.76 g, 87%) as a mixture of axial and equatorial acids. 13C NMR (100 MHz, CDCl3): 14.16 (q), 19.86 (t), 21.07 (t), 25.98 (t), 29.20 (t), 31.52 (t), 31.87 (t), 32.27 (t), 33.39 (t), 37.80 (d), 38.07 (t), 38.10 (d), 42.06 (t), 44.80 (d), 45.78 (d), 49.38 (s), 49.60 (s), 60.31 (t), 60.36 (t), 177.08 (s), 180.01 (s).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].CO[C:13]1[C:14](=O)[C:15](=[O:19])[C:16]=1[O:17]C>CO>[CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:13]2[C:16](=[O:17])[C:15](=[O:19])[C:14]=2[N:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CCCN1CCCNCC1
Solvent: CO
Product: CCCN1CCCN(c2c(N3CCCN(CCC)CC3)c(=O)c2=O)CC1

Procedure:
A solution of 3.1 grams of 1-propylhomopiperazine in 20 ml. of methanol is mixed with a solution of 1.6 grams of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 50 ml. of methanol and refluxed under nitrogen for 5 hours. The methanol solvent is evaporated by heating on a steam bath and the residual solid is dissolved in 70 ml. of anhydrous benzene at room temperature, treated with charcoal, and filtered. The resulting filtrate is diluted with 250 ml. of hexane and the precipitate which forms is separated by filtration and dried and then recrystallized from 1000 ml. of refluxing hexane to give 3,4-bis(4-propyl-1-homopiperazinyl)-3-cyclobutene-1,2-dione as white crystals melting at about 90°-92° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8][CH2:7][N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:4].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCCN1S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1CNCCCN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of 11.0 g (0.026 mol) of the product of Example 45 in 50 mL of ethanol was added 4.40 g of 20% palladium hydroxide on carbon (Pearlman's catalyst) and the resulting suspension was shaken at room temperature in a Parr reactor under 44 psi of hydrogen for 4 h. The reaction mixture was then filtered through Celite and the filter cake was washed with 100 mL of methanol. The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate. The solution was washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was pure enough for use in the next step. Electrospray Mass Spec: 328.9 (M+H)+
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:17]([CH3:18])[CH:16]=[CH:15][C:9]3=[N:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH2:3]1.[Cl:20][C:21]1[C:22]([NH2:29])=[N:23][C:24]([NH2:28])=[N:25][C:26]=1Cl.CCN(CC)CC>CN(C=O)C>[Cl:20][C:21]1[C:26]([NH:14][CH:12]([C:11]2[N:10]=[C:9]3[CH:15]=[CH:16][N:17]([CH3:18])[C:8]3=[CH:7][C:6]=2[N:4]2[CH2:5][C:2]([F:1])([F:19])[CH2:3]2)[CH3:13])=[N:25][C:24]([NH2:28])=[N:23][C:22]=1[NH2:29]
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Temperature: 90 °C
Reaction time: 48 h
Yield: 5.3 %

Procedure:
To a 10 mL vial were added 1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (61 mg, 0.23 mmol), 5,6-dichloropyrimidine-2,4-diamine (41.0 mg, 0.229 mmol) and Et3N (0.064 mL, 0.46 mmol) in DMF (2 mL). The resulting yellow solution was heated to 90° C. and stirred for 48 hours. The crude product was purified by preparative HPLC eluting with 30-55% ACN in water (with ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (5 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.41 (m, 3 H), 3.73-3.86 (m, 3 H), 4.17-4.35 (m, 2 H), 4.43-4.58 (m, 2 H), 5.33-5.48 (m, 1 H), 5.69-5.80 (m, 2 H), 5.89-6.01 (m, 2 H), 6.32-6.43 (m, 1 H), 6.45-6.54 (m, 1 H), 7.37-7.43 (m, 1 H), 7.45-7.51 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C17H19ClF2N8, 409; found 409.