Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>CC(C)=O>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1cccc(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(-c2ccc(OCc3ccccc3F)cc2)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-pyridinecarboxylate (D80, 650 mg, 2.84 mmol) in acetone (8 ml) were added K2CO3 (780 mg, 5.67 mmol) and 1-(bromomethyl)-2-fluorobenzene (805 mg, 4.26 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 6 h. Solvent was removed under reduced pressure and the residue was dissolved in AcOEt. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude compound was purified by flash chromatography on 25 g silica gel cartridge, using a gradient of cyclohexane/ethylacetate 10/0 to 8/2 as eluent, to give the title compound (700 mg, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH:13]=[N:14][OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([OH:21])[C:19]#[CH:20].[O-]Cl.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[CH:20]=[C:19]([CH2:18][OH:21])[O:15][N:14]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: ON=Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-benzyloxy-benzaldehyde oxime (2.27 g, 10 mmol-a compound of 92% purity) was dissolved in methylene chloride (40 ml, 0.25 M), to which solution was added propargyl alcohol (1.77 ml, 30 mmol). To the resulting solution was very slowly dropwise added 10% NaOCl (13.7 ml, 20 mmol) at 0° C., using a dropping funnel. After the addition of NaOCl was completed, the mixture was stirred for about 5 hours while increasing the temperature slowly to room temperature. The completion of the reaction was confirmed by liquid chromatography, and the mixture was distilled under reduced pressure to remove the methylene chloride. Water (200 ml) was added to the residue and the resulting solid was filtered off. The filtered compound was washed with excess of water and finally washed with diethyl ether. The thus-obtained solid compound was recrystallized from ethyl acetate/hexane (1:2) to obtain 2.50 g of [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:14])[CH3:13])=[C:4]([OH:15])[CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.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:15][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([OH:16])=[CH:18][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12](=[O:14])[CH3:13]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(=O)c1c(O)cc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1c(O)cc(-c2ccc(O)cc2)c2ccccc12
Temperature: 100 °C
Yield: 83.5 %

Procedure:
A mixture of 1-(4-bromo-2-hydroxynapthalen-1-yl)ethanone (0.255 g, 0.96 mmol), (4-hydroxyphenyl)boronic acid (0.140 g, 1.06 mmol), Pd(PPh3)4 (0.056 g, 0.048 mmol) and potassium carbonate (0.4 g, 2.88 mmol) in water (9.7 mL) in dioxane (32.0 mL) was flushed with nitrogen, sealed and heated for 2 h in a 100° C. oil bath. The solution was cooled to room temperature and partitioned between 200 mL of 10% methanol in ethyl acetate and 100 mL saturated aqueous sodium chloride. The layers were separated and the aqueous layer was extracted (2×50 mL 10% methanol in ethyl acetate). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 5:1 hexanes/ethyl acetate) gave 0.223 g (83%) of 1-[2-hydroxy-4-(4-hydroxyphenyl)napthalen-1-yl]ethanone. 1H NMR (400 MHz, d6-DMSO): 8.11 (d, 1H), 7.87 (d, 1H), 7.56 (dt, 1H), 7.33 (m, 3H), 7.07 (s, 1H), 6.99 (d, 2H), 2.89 (s, 3H); MS (EI) for C18H14O3: 279 (MH+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:53])C(=O)C1>C(O)(=O)C.C(Cl)Cl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[C:32]=2[Cl:53])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(Cl)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reaction time: 18 h
Yield: 52.5 %

Procedure:
To a solution of (2S)-ethyl 2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (40 mg, 0.064 mmol, 1 equiv) in acetic acid (0.64 mL) was added NCS (10 mg, 0.077 mmol, 1.2 equiv). After stirring 18 h, reaction is pale yellow solution. LCMS indicated complete conversion. The reaction was diluted with DCM and washed with saturated aqueous bicarbonate. The DCM layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-10% EtOAc in hexane) to provide desired product as a viscous yellow oil (22 mg, 52% yield). 1H NMR (500 MHz, CDCl3) δ 7.16 (s, 1H), 7.12 (d, J=5.7 Hz, 2H), 6.97 (d, J=9.1 Hz, 1H), 6.83 (d, J=10.6 Hz, 1H), 4.97 (s, 1H), 4.62-4.50 (m, 2H), 4.35 (t, J=5.3 Hz, 2H), 4.19-4.11 (m, 2H), 2.84 (s, 3H), 2.75 (s, 2H), 2.27 (d, J=1.7 Hz, 3H), 2.23-2.13 (m, 2H), 1.80 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.17 (s, 9H); 19F NMR (471 MHz, CDCl3) δ −119.48 (s, 1F), −139.47 (s, 1F); LCMS (ESI, M+1): 655.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[C:15](Cl)[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.CC#N.C(O)(C(F)(F)F)=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[C:15]([C:31]3[CH:32]=[CH:33][O:29][CH:30]=3)[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1cccc([N+](=O)[O-])c1
Reactant: OB(O)c1ccoc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(Nc1nc(-c2ccoc2)cc(-n2cnc3ccccc32)n1)c1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-[1-(3-nitrophenyl)ethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine and furan-3-boronic acid according to the precedure described in EXAMPLE 306, Step C and using [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(H) as catalyst. Mass spectrum (CH3CN/TFA/NH4O2CH/ESI) 427.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]2[N:9]=[C:10]([CH3:18])[S:11][C:12]=2[C:13]([O:15]CC)=[O:14])[CH:7]=1.[OH-].[K+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]2[N:9]=[C:10]([CH3:18])[S:11][C:12]=2[C:13]([OH:15])=[O:14])[CH:7]=1
Reactant: CCOC(=O)c1sc(C)nc1-c1cc(Cl)ccc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-c1nc(C)sc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylate (520 mg, 1.67 mmol) and potassium hydroxide (125 mg) in THF (18 mL) and water (4.5 mL) was stirred for 20 hours at room temperature and then at 75° C. for a further 8 hours. The solution was treated with 1M HCl aq. (pH 2) and extracted with DCM. The organics were evaporated to dryness to give 450 mg (95%) of 4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylic acid as a white solid. LCMS (ESI) m+H=284.3; 1H NMR (400 MHz, DMSO-d6): δ 7.43 (dd, 1H); 7.31 (d, 1H); 7.10 (d, 1H); 3.71 (s, 3H); 2.69 (s, 3H).
Reaction SMILES: [Br:1]Br.[BrH:3].[C:4]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:6])[CH3:5].CCOCC>C(Cl)Cl>[BrH:1].[Br:3][CH2:5][C:4]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: BrBr
Agent: Br
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CBr)C1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
7.9 g of bromine are added rapidly at RT to a suspension of 14 g of 4-acetyl-4-phenylpiperidine hydrobromide in 200 ml of DCM and the reaction mixture is stirred overnight at RT. It is diluted by the addition of 200 ml of ether and the precipitate formed is wrung and washed with ether to give 16.7 g of the expected product after drying under vacuum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:21][NH2:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Solvent: ClCCl
Product: CC(=O)NCc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a suspension of C-[1-(3-thiazol-2-yl-phenyl)-1H-benzoimidazol-5-yl]-methylamine (0.70 g, 2.3 mmol) in dichloromethane (30 ml) was added acetic anhydride (2.4 ml, 2.5 mmol) dropwise with stirring. After the addition, stirring was continued for 30 min and the reaction mixture was washed twice with saturated, aqueous sodium bicarbonate and once with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The concentrate was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (9:1:0.1 v/v/v). This afforded the desired product (0.52 g, 65%). Mp. 156.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>S(=O)(=O)(O)O.O>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: Oc1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1cccc(Cl)c1
Reaction time: 18 h

Procedure:
Concentrated sulphuric acid (5 drops) was added cautiously to a stirred mixture of 3-chlorophenol (74 g) and acetic anhydride (64.6 g) at ambient temperature. The mixture was left to stand for 18 hours and then added to water (300 ml). The mixture was extracted with dichloromethane and the combined extracts washed with sodium bicarbonate solution, dried and evaporated under reduced pressure. The oil obtained was distilled under vacuum to give 3-chlorophenyl acetate b.p. 116°-118° C. (2 mmHg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH2:4][NH2:5].F[C:8]1[C:25](F)=[CH:24][C:23]([I:27])=[CH:22][C:9]=1[C:10]([C:12](=[CH:18]OCC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11].[H-].[Na+]>CN1C(=O)CCC1>[I:27][C:23]1[CH:22]=[C:9]2[C:10](=[O:11])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][N:5]3[CH2:4][C:3](=[O:6])[N:2]([CH3:1])[C:25]([CH:24]=1)=[C:8]23
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(I)cc(F)c1F
Reactant: CNC(=O)CN
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)N(C)C(=O)C2
Temperature: 100 °C
Yield: 60.7 %

Procedure:
Glycine methylamide (1.0 g) is added at room temperature to a solution of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-2-propenoate (Preparation 21, 2.0 g) in NMP (20 mL). Sodium hydride (400 mg, 60% dispersion in mineral oil) is added in two portions to the solution, and the solution is heated at 100° C. for 30 min. The product is partitioned between chloroform and water, the chloroform phase is concentrated and applied to a silica gel column with 1-2% methanol chloroform as the eluant. The purified fractions are triturated with ether to give 1.22 g of the title compound. Physical characteristics: M.p. 278-283° C.; 1H NMR (DMSO-d6) δ1.29, 3.63, 4.23, 5.10, 7.65, 8.09, 8.55. Anal. Found: C, 43.49; H, 3.18; N, 6.75.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]([CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:13].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:16][O:15][CH:14]([O:17][CH3:18])[C:12]1([CH3:11])[CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:13]1
Reactant: O=C(CO)c1ccccc1
Reactant: COC(OC)C(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(OC)C1(C)CC(=O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In 250 ml of toluene were dissolved 30 g (0.22 mmole) of 2-hydroxy acetophenone and 33.8(0.29 mmole) of pyruvic aldehyde dimethyl acetal; and, 6.3 ml (0.09 mmole) of pyridine was added thereto. After stirring at room temperature 30 minutes, the reactants were heated to reflux for 5 hours using Dean-Stark apparatus. The solvent was removed under reduced pressure and 100 ml of 2N HCl aqueous solution was added. The resultant solution was stirred for 1 hour at room temperature, extracted with ethyl acetate (20 ml×2), washed with 100 ml of water and then with 50 ml of saturated sodium chloride aqueous solution and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) to obtain 39 g (0.16 mmole, yield 75%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][O:28][C:29]1[C:37]2[N:36]=[C:35]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[N:34]([CH3:44])[C:33]=2[CH:32]=[CH:31][CH:30]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:35]3[N:34]([CH3:44])[C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[C:37]=4[N:36]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: COc1cccc2c1nc(N1CCNCC1)n2C
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1cccc2c1nc(N1CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC1)n2C

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 4-methoxy-1-methyl-2-piperazin-1-yl-1H-benzimidazole
Reaction SMILES: [CH:1]([C:3]1(O)[CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C[O:10][C:11]([CH3:13])=[CH2:12].OP(O)(O)=O.N#N>CC(OC)(C)C.C(N(CC)CC)C>[C:3]1(=[CH:1][CH2:2][CH2:12][C:11](=[O:10])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=CC1(O)CCCC1
Reactant: C=C(C)OC
Agent: N#N
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)CCC=C1CCCC1
Temperature: 125 °C
Reaction time: 14 h
Yield: 68.8 %

Procedure:
A 600 ml autoclave containing a mixture of 1-ethenyl-cyclopentanol (172.0 g; 1.54 mol), isopropenyl methyl ether (218.8 g; 3.04 mol), triethylamine (1.65 ml) and 85% H3PO4 (0.72 ml) was pressurized with N2 at 2 bar and heated up to 125° C. An increase of the pressure to 7 bar was observed. After 14 hours stirring, the autoclave was cooled down to room temperature and depressurized. MTBE (1.5 l) was added to the mixture, washed with H2O (4×25 ml) until neutral pH, dried (MgSO4) and concentrated. Distillation (61° C./0.1 torr) yielded 161.3 g (69% yield) of 5-cyclopentylidenepentan-2-one.
Reaction SMILES: [CH3:1][C:2]([NH2:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.C(O)(C)C>C1(C)C=CC=CC=1.[Pt]>[NH2:19][C:2]([CH3:18])([CH3:1])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(N)CNc1c(N)cnc2ccccc12
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 2-methyl-N1-(3-nitroquinolin-4-yl)propane-1,2-diamine (2.45 g, 9.42 mmol), in 100 mL of toluene and 50 mL of isopropanol was treated with 0.5 g of 5% Pt on carbon and shaken under H2 (3 atm, 3 Kg/cm2) for 3 h. The solution was then filtered through a Celite pad and concentrated to give 2.17 g of crude N4-(2-amino-2-methylpropyl)quinoline-3,4-diamine as a light brown foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][OH:15])[N:10]=2)=[CH:5][CH:4]=1)#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.OP(O)(O)=O.O>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH:14]=[O:15])[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2nc(CO)no2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-c2nc(C=O)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A mixture of 5-(4-cyanophenyl)-3-hydroxymethyl-1,2,4-oxadiazole (4.08 g), N,N'-dicyclohexylcarbodiimide (20.92 g) and o-phosphoric acid (9.94 g) in dimethyl sulfoxide (80 ml) was stirred at ambient temperature. After 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ether to give 5-(4-cyanophenyl)-3-formyl-1,2,4-oxadiazole (2.17 g).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[C:41]([C:42]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 617.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[N:3]1.P(Br)(Br)[Br:13]>C(Cl)(Cl)Cl>[Br:13][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: BrP(Br)Br
Reactant: Cn1nc([N+](=O)[O-])cc1CO
Solvent: ClC(Cl)Cl
Product: Cn1nc([N+](=O)[O-])cc1CBr
Temperature: 0 °C
Yield: 99.7 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 156c (0.56 g, 3.6 mmol) and chloroform (10 mL). The reaction was cooled to 0° C. using an ice bath and phosphorous tribromide (0.98 g, 3.6 mmol) was added dropwise. The cooling bath was removed and the reaction stirred at reflux for 3 h. After this time, the reaction was cooled to 0° C. and diluted with methylene chloride (25 mL). Saturated aqueous sodium bicarbonate was added until a pH of 8.5 was reached. The layers were separated, and the aqueous layer was extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford a quantitative yield (0.79 g) of 156d as an off-white solid: MS (ESI+) m/z 222.1 (M+H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[S:22][CH2:23][C:24]([OH:26])=O.[NH2:27][C@@H:28]1[C:35](=[O:36])[N:34]2[C@@H:29]1[S:30][CH2:31][C:32](/[CH:40]=[C:41]1/[C:42](=[O:50])[N:43]([CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH2:44][CH2:45]/1)=[C:33]2[C:37]([OH:39])=[O:38]>CN(C)C=O>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[S:22][CH2:23][C:24]([NH:27][C@@H:28]1[C:35](=[O:36])[N:34]2[C@@H:29]1[S:30][CH2:31][C:32](/[CH:40]=[C:41]1/[C:42](=[O:50])[N:43]([CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH2:44][CH2:45]/1)=[C:33]2[C:37]([OH:39])=[O:38])=[O:26]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CSc1nc2ccccc2s1)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12

Procedure:
With 220.0 mg (1.35 mmol) 1,1′-carbonyldiimidazole, 304.1 mg (1.35 mmol) (benzothiazol-2-ylsulfanyl)-acetic acid and 394.8 mg (1.13 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 7 ml N,N-dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][NH:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][N:26]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCNC1
Reactant: NC(=O)CBr
Product: NC(=O)CN1CC[C@@H](CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
2-[(3R)-3-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidin-1-yl]acetamide was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R)-pyrrolidin-3-ylmethyl]-1,3-thiazolidine-2,4-dione and 2-bromoacetamide following General Procedure H.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])=[CH:9][CH:8]=[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]=2.[CH2:28]([O:30][CH2:31][C:32](Cl)=O)[CH3:29].C(N(CC)CC)C>>[CH2:28]([O:30][CH2:31][C:32]1[N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:29]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2cc(-c3ccccc3)ccc2c1NCCCN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCN1CCCC1=O
Yield: 56.7 %

Procedure:
1-[3-(3-Amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (2.21 g, 6.13 mmol) was treated with ethoxyacetyl chloride (0.95 mL, 8.76 mmol) according to the methods described in Parts C and D of Examples 152–156. Triethylamine (8.6 mmol) was added in Part C. The product from Part D was purified by column chromatography on silica gel (eluting with acetone and then chloroform:methanol in a gradient from 95:5 to 90:10) to provide 1.49 g of 1-[3-(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a brown solid.