Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].[C:3]12([CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]1)[CH2:7][CH2:6][CH2:5][CH2:4]2>>[OH:2][N:1]=[C:9]([OH:10])[CH2:8][C:3]1([CH2:13][C:12]([OH:11])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NO
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Product: O=C(O)CC1(CC(O)=NO)CCCC1

Procedure:
In a manner analogous to that described in Example 1, by the reaction of hydroxylamine with 1,1-cyclopentane-diacetic anhydride, there was obtained 1,1-cyclopentane-diacetic acid N-hydroxyimide (m.p. 70°-74° C.) which, by acylation with benzene-sulphonyl chloride, was converted into benzene-sulphonyloxy-1,1-cyclopentane-diacetic acid imide (m.p. 133°-136° C.).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[S:22][CH:23]([CH3:25])[CH3:24].C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:26][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[S:22]([CH:23]([CH3:25])[CH3:24])=[O:35]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SC(C)C)c1CC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)C(C)C)c1CC(C)C

Procedure:
Prepared from product of Example 12 (5.97 g, 14.95 mmol) and MCPBA (3.03 g of an 85% mixture with MCBA, 14.95 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (4.03 g).
Reaction SMILES: [CH3:1]O.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)[C:14]#[N:15].C[O-].[Na+].CI>O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)([CH3:1])[C:14]#[N:15]
Reactant: N#CC(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(C#N)(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reaction time: 2.5 h
Yield: 77 %

Procedure:
Methanol (5 ml) was added to 945 mg of alpha-(2-benzothiazolylthio)(m-phenoxyphenyl)acetonitrile, and the mixture was stirred under ice cooling in an argon atmosphere. Then, 1.0 ml of a 2.7 M methanol solution of sodium methoxide was added, and the mixture was stirred under ice cooling for 10 minutes. Methyl iodide (0.25 ml) was then added. The mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 2.5 hours. Then, 30 ml of water was added, and the reaction mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene and methylene chloride) to afford 752 mg (yield 77%) of alpha-(2-benzothiazolylthio)-alpha-(m-phenoxyphenyl)propionitrile as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][CH2:12][OH:13].[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCl
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(OCCCO)c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A stirred solution of 25 grams (0.23 mole) of 3-methylphenol and 18.8 grams (0.20 mole) of 3-chloropropan-1-ol in 100 mL of aqueous 10% sodium hydroxide was heated at reflux for about 40 minutes. After this time, the reaction mixture was cooled to ambient temperature and extracted with three 100 mL portions of diethyl ether. The combined extracts were then washed with three 50 mL portions of an aqueous dilute sodium hydroxide solution and dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 29 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([N:26]2[CH2:41][CH2:40][C:28]3([CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)[CH2:27]2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:20]1([C:17]2[O:16][C:15]([C:14]3[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([N:26]4[CH2:41][CH2:40][C:28]5([CH2:32][CH2:31][NH:30][CH2:29]5)[CH2:27]4)[N:13]=3)=[N:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccccc5)o4)n3)C2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(N2CCC3(CCNC3)C2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 7-[5-[bis(tert-butoxycarbonyl)amino]-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-3,7-diazaspiro[4.4]nonane-3-carboxylate (50.9 mg, 0.07668 mmol) was treated with a solution of hydrogen chloride (192 μL, of 4 M, 0.77 mmol) in dioxane. The reaction mixture was stirred for 2 h at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in DMF and purified by reverse phase HPLC using (1-99% ACN/H2O (5 mM HCl)) to yield 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(2,7-diazaspiro[4.4]nonan-2-yl)pyrazin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 2H), 8.25-7.99 (m, 2H), 7.89 (s, 1H), 7.66 (d, J=6.6 Hz, 3H), 3.60-3.47 (m, 4H); 3.36-3:25 (m, 2H), 3.18 (tt, J=12.1, 6.0 Hz, 2H), 2.19-1.83 (m, J=17.8, 12.7, 5.9 Hz, 4H); LC/MS m/z 364.1 [M+H]+.
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]O.C(N(CC)CC)C.C1(C(Cl)=O)CCC=1>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][O:6][C:5]([C:1]1[CH2:4][CH2:3][CH:2]=1)=[O:7]
Reactant: OCCCCCl
Reactant: O=C(O)C1=CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C1=CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCCCl)C1=CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 38.2 %

Procedure:
Cyclobut-1-enecarboxylic acid (2.04 mmol, 200 mg) was dissolved in 1.5 mL dry CH2Cl2. The solution was cooled to 0° C. and oxalyl dichloride (4.08 mmol, 345 μL) was added. The temperature of the solution was raised to rt, and the mixture was allowed to react for 1 h. The solvent was evaporated to generate a viscous oil. 4-chlorobutanol (1.36 mmol, 148 mg) and triethylamine (2.72 mmol, 379 μL) were dissolved in 1.0 mL dry CH2Cl2, and the solution was stirred at 0° C. for 45 min before being added to a vial containing cyclobut-1-enecarboxylic chloride. The reaction mixture was stirred for 16 h at rt. The CH2Cl2 solution was concentrated by rotary evaporation, and then purified by flash column chromatography (60% CH2Cl2/pentane) to yield 21 as a colorless oil (98 mg, 38%). 1H-NMR (500 MHz, CDCl3) δ 6.73 (s, 1H), 4.11 (t, J=6.0 Hz, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.43 (m, 2H), 1.81 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 162.27, 146.69, 138.71, 63.31, 44.58, 29.31, 29.20, 27.20, 26.20.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][C:10]=2[N+:22]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[NH2:22][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH:13]=[CH:14][C:9]=1[NH:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Nc1ccc(NCC2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-{4-[(Cyclohexylmethyl)amino]-3-nitrophenyl}-2,2-dimethylpropanamide (215 mg, 0.645 mmol) was dissolved in 20 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken in a Parr hydrogenation apparatus under H2 atmosphere (45 psi) at RT for 24 h. The solution was filtered through Celite and the solvent evaporated to give the desired product. Yield: 175 mg (89%); MS (ESI) (M+H)+304.04.
Reaction SMILES: O[CH:2]([C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=[CH2:4].S(Cl)([Cl:13])=O>CCCCCC.CN(C)C=O>[Cl:13][CH2:4][CH:3]=[CH:2][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CC(O)C#CC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)C#CC=CCCl
Yield: 88.7 %

Procedure:
Ten grams (0.072 mole) of 3-hydroxy-6,6-dimethyl-hept-1-ene-4-yne was dissolved in 100 ml of hexane, and to the resulting solution were added 50 mg (6.8×10-4 mole) of N,N-dimethylformamide and 12.80 g (0.108 mole) of thionyl chloride. The mixture was reacted overnight at room temperature with stirring with a hydrogen chloride gas trap mounted on the reactor. The reaction mixture was concentrated under reduced pressure to obtain 10 g of a crude 1-chloro-6,6-dimethylhept-2-ene-4-yne.
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([CH2:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:20]([OH:22])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:47][OH:48]>C(OCC)(=O)C>[OH:48][NH:47][C:20](=[O:22])[CH:19]([CH2:18][S:15]([C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=1)(=[O:17])=[O:16])[CH2:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(C)cc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-methylpyrrolidinone (20 mL) cooled in an ice bath, is added 2-[(4-methylbenzenesulfonyl)methyl]-3-(4-methylbenzenesulfonyl)-propionoic acid (4.4 g, 11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.2 g, 22 mmol), and hydroxylamine hydrochloride (1.5 g, 22 mmol). After stirring overnight at ambient temperature, the mixture is transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The organic phase is concentrated in vacuo and triturated from hexane to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:43][C:44]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:61][C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[NH:54][C:53]3=[O:62])[CH2:48][CH2:47]2)=[O:45])[C:13]([NH:15][C@H:16]([C:29](=[O:42])[N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.NCCCC[C@H](NC(=O)[C@H](NC(N1CCC(C2C(=O)NC3C(C=2)=CC=CC=3)CC1)=O)CC1C=C2C(=C(C)C=1)NN=C2)C(=O)N1CCN(C2C=CN=CC=2)CC1>>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:15][C:13](=[O:14])[C@H:12]([NH:43][C:44]([N:46]1[CH2:51][CH2:50][CH:49]([N:52]2[CH2:61][C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[NH:54][C:53]2=[O:62])[CH2:48][CH2:47]1)=[O:45])[CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)[C:29](=[O:42])[N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH2:32][CH2:31]1
Reactant: Cc1cc(C[C@@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Agent: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCN)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N[C@@H](CCCCN)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12

Procedure:
The title compound was prepared from tert-Butyl (S)-5-((R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinazolin-3 (4H)-yl)piperidine-1-carboxamido)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate using the same procedure as described for N-((R)-1-((S)-6-amino-1-oxo-1-(4-(pyridin-4-yl)piperazin-1-yl)hexan-2-ylamino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide. The title compound was obtained in 70% yield. MS (ESI) 750 (M+H) ; Rf=1.58.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Clc1cc(-c2cccs2)ncn1
Temperature: 100 °C

Procedure:
To a flask fitted with a condenser was added 4,6-dichloro-pyrimidine (500 mg, 3.36 mmol), thiophene-2-boronic acid (429 mg, 3.36 mmol), Pd(OAc)2 (38 mg, 0.17 mmol), Ph3P (88 mg, 0.34 mmol), 1 M Na2CO3 (10.4 mL, 10.4 mmol), and DME (20 mL). The resulting mixture was heated at 100° C. for 18 h. After cooling, the resulting mixture was partitioned between CHCl3 (30 mL) and water (30 mL). The organic layer was dried and concentrated to yield a crude residue which was purified on SiO2 (0-30% EtOAc/hexanes) to yield 4-chloro-6-thiophen-2-yl-pyrimidine.
Reaction SMILES: C([O:4][CH:5]([CH3:24])[C:6]([NH:8][CH2:9][CH2:10][CH:11]1[C:22]2[C:21]3[O:20][C:19]([CH3:23])=[N:18][C:17]=3[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12]1)=[O:7])(=O)C.[OH-].[Na+]>O1CCCC1>[OH:4][CH:5]([CH3:24])[C:6]([NH:8][CH2:9][CH2:10][CH:11]1[C:22]2[C:21]3[O:20][C:19]([CH3:23])=[N:18][C:17]=3[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12]1)=[O:7]
Reactant: CC(=O)OC(C)C(=O)NCCC1CCc2ccc3nc(C)oc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2ccc3c(c2o1)C(CCNC(=O)C(C)O)CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 1-methyl-2-{[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]amino}-2-oxoethyl acetate (70 mg, 0.212 mmol) in tetrahydrofuran (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (52.4 mg, yield 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.Br[CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:34]1[CH2:35][CH2:36][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([N:8]7[CH2:12][CH2:11][CH2:10][C:9]7=[O:13])=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:32][CH2:33]1)[CH2:41][CH2:42][CH3:43]
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Reactant: CCCCBr
Product: CCCCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(N4CCCC4=O)cc2C)cc1)CC3

Procedure:
The title compound was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and 1-bromobutane using a similar procedure to Example 19, as a yellow oil (55%). This was converted to its hydrochloride salt and crystallised from acetone as a white solid.
Reaction SMILES: O[C:2]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3].O.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[CH:2]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3]
Reactant: COc1cccc(O)c1C(C)(C)O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(O)c1C(C)C
Yield: 92 %

Procedure:
To a solution of 2-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-phenol dissolved in acetic acid (50 mL) was added 10% palladium on charcoal (500 mg), water (6 mL), and ammonium formate (7.82 g, 124 mmol). After refluxing for 1 hour, the reaction was cooled and filtered through celite. The celite pad was washed with ethyl acetate (500 mL). Water (300 mL) was added to the filtrate, and the mixture was basified (pH=8) using solid sodium bicarbonate. The ethyl acetate layer was collected and washed with water, brine, dried using anhydrous sodium sulfate and concentrated to yield 2-Isopropyl-3-methoxy-phenol (3.68 g, 92%) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>>[CH2:28]([N:12]1[C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[C:19]2[C:14]([C:15]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:17]=[CH:18]2)=[N:13]1)[CH:27]=[CH2:26]
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1OC
Yield: 34.9 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-(trifluoro-methyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.7 mmol) to give the title compound (0.062 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].C(Cl)CCl.C1C=CC2N(O)N=[N:39]C=2C=1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C.O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([NH2:39])=[O:23])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.3 %

Procedure:
To a mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-5-carboxylic acid (100 mg, 0.26 mmol), EDC (75 mg, 0.39 mmol) and HOBt (53 mg, 0.39 mmol) in DMF (1.5 ml) was successively added diisopropylethylamine (0.15 ml, 1.04 mmol) and ammonium chloride (28 mg, 0.52 mmol). The mixture was stirred at ambient temperature for 48 h and then reduced in vacuo. Water was added and the precipitate formed collected by filtration and dried through azeotrope with toluene to afford 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-5-carboxylic acid amide (49 mg, 49%) as a beige solid. (LC/MS: Rt 2.54, [M+H]+ 382.99).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:29](O)[CH2:30][OH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:31]1[C:2]2([CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]2)[O:1][CH2:29][CH2:30]1
Reactant: OCCO
Reactant: COC(=O)C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCC2(C1)OCCO2
Temperature: 25 °C

Procedure:
Methyl 3-oxocyclohexanecarboxylate (930 mg) and pyridinium p-toluenesulfonate (299 mg) were combined in toluene (29.8 mL) to give a colorless solution. Ethylene glycol (0.996 mL) was added and the reaction was refluxed under Dean-Stark conditions for 2 days. The reaction was cooled to room temperature, triethylamine was added, and then the mixture was concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix 0-40% hexane/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:10](=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>O>[NH2:22][CH2:21][CH2:20][N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:12][S:11][C:10]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A mixture of t-butyl 2-[4-(4-bromophenyl)-2-(phenylimino)-thiazol-3(2H)-yl]ethylcarbamate (1.5 g), trifluoroacetic acid (10 ml) and water (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was crystallized from n-hexane to give the title compound (937 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Br:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Br:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2
Reactant: COc1ccc2ncc(NC(=O)OC(C)(C)C)c(Br)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(N)c(Br)c2c1
Reaction time: 3.5 h
Yield: 101.1 %

Procedure:
(4-Bromo-6-methoxy-quinolin-3-yl)-carbamic acid tert-butyl ester (22.7 g, 0.0643 mole) was dissolved in CH2Cl2 (200 mL) and treated with trifluoroacetic acid (100 mL). After 3.5 hr at RT, the mixture was concentrated and the residue was dissolved in water. The solution was made basic with aqueous sodium carbonate. The precipitate was filtered off, washed with water, and dried at 40° C. in vacuo overnight, to give the title compound (16.46 g, 101%) as a white solid: MS (ES) m/e 254/256 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]3[C:20](=[O:23])[O:21][CH2:22][C:18]=3[C:17]=2I)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([CH:40]2[CH2:45][CH2:44]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]3[C:20](=[O:23])[O:21][CH2:22][C:18]=3[C:17]=2[CH:44]2[CH2:45][CH2:40]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2I)COC3=O)CC1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2C2CC2)COC3=O)CC1
Temperature: 100 °C

Procedure:
To a microwave tube charged with tert-butyl-4-[2-(4-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (100 mg, 0.21 mmol) and a stir bar was added palladium acetate (3.6 mg, 0.016 mmol), tricyclohexylphosphine (8.9 mg, 0.032 mmol), cyclopropyl boronic acid (27 mg, 0.32 mmol), and potassium phosphate (160 mg, 0.74 mmol). The tube was sealed, and injected toluene (2 mL) and water (100 uL). The mixture was purged three times with nitrogen, and heated to 100° C. for 30 minutes. LC showed formation of the desired product. The reaction was purified by silica gel chromatography to afford tert-butyl-4-[2-(4-cyclopropyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate. LC-MS (IE, m/z): 387 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH2:23])=[S:22])[CH:15]=1>C(O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]2[S:22][CH:2]=[C:3]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)[N:23]=2)[CH:15]=1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)Nc1cccnc1
Solvent: CCO
Product: O=C(O)c1ccc(-c2csc(Nc3cccnc3)n2)cc1
Yield: 739.9 %

Procedure:
A solution of 4-bromoacetylbenzoic acid (2.2 g, 10 mmol) in ethanol (50 mL) was treated with pyrid-3-ylthiourea (1.53 g, 1 mmol) and the mixture was refluxed for 3 hr. Solids were collected by filteration, washed with ether and dried to provide 4-(2-pyrid-3-ylaminothiazol-4-yl)benzoic acid (2.2 g, 74% yield). LC-MS: FAB LC-MS. 298.2 (M+H+).