Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C(#N)C>[CH3:2][N:3]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1)[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: CNC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CN(CCOc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
2-Methylamino-5-nitroindane hydrochloride (0.46 g), 2-bromoethoxy-4-nitrobenzene (0.49 g) [see C.A., (1960), 54, 11046a] and potassium carbonate (2 g) were heated under reflux in acetonitrile (50 ml)/ethanol (20 ml) for 20 hours. The solvent was then removed by evaporation in vacuo and the residue diluted with water and extracted with methylene chloride. The organic layer was dried (MgSO4) and evaporated to give an oil which was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated to give the title compound as an oil, yield 0.28 g.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]#[N:7])[CH2:2][CH3:3].[NH2:8][OH:9]>C(Cl)Cl>[OH:9]/[N:8]=[C:6](\[NH2:7])/[CH2:5][O:4][CH2:1][CH2:2][CH3:3]
Reactant: NO
Reactant: CCCOCC#N
Solvent: ClCCl
Product: CCCOC/C(N)=N/O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of propoxyacetonitrile (3.03 g) and hydroxylamine (2.01 g, 50 wt % in water) is stirred for 2 h at 100° C. At RT DCM is added, the organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[H][H]>CCO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Yield: 99 %

Procedure:
A solution of 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone (20a) in 10 mL of EtOH was hydrogenated with a balloon filled with hydrogen in the presence of palladium (10 wt. % on activated carbon, 0.61 g, 0.57 mmol) for 18 h at RT. It was filtered through a pad of Celite and rinsed with EtOAc (2×20 mL). The filtrate was concentrated. The brown residue was triturated with 10 mL of hexanes. The liquid was decanted. The solid was dried in a vacuum oven at 40° C. for 1 h to give 1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (20b; 1.42 g, 5.70 mmol, 99% yield) as a brown solid. Crude material used in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.54 (2H, m), 6.32 (1H, dd, J=8.3, 2.4 Hz), 4.63 (2H, br.), 3.76 (3H, s), 3.54 (4H, m), 2.95 (2H, m), 2.89 (2H, m), 2.02 (3H, s). m/z (ESI, +ve ion) 250.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:32][C:33]([NH:35][CH3:36])=[O:34]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:32][C:33]([NH:35][CH3:36])=[O:34])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: COc1cc(CCNCC2CC2)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CN(CCc1ccc(OCc2ccccc2)c(OC)c1)CC1CC1
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 0.5 g (1.6 mmol) of [2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)-amine, 0.27 ml (1.92 mmol) of triethylamine, 0.207 g (1.92 mmol) of 2-chloro-N-methyl-acetamide in 4 ml of dimethylformamide was heated with microwaves to 120° C. for 2 hours. The solvent was removed under vacuum and the crude was purified by flash chromatography (ethyl acetate/hexane 0:10→9:1 gradient). 0.52 g (84% yield) of the title compound was isolated as a yellow solid.
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([NH:24][C:22](=[O:23])[C:21]3[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:20]=3[F:19])=[O:26])=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(Oc2cccc3ccccc23)nc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Oc2cccc3ccccc23)nc1

Procedure:
A mixture of 2.5 g. of 2-(1-naphthoxy)-5-amino pyridine and 8.13 ml. of toluene was heated up to 50° C. To this resulting homgeneous solution was added a solution of 3.1 g. of 2,6-difluorobenzoyl isocyanate in 2 ml. of toluene. The resulting mixture was heated at 80° for 1.5 hours, cooled, and filtered to give 4.7 g. of white crystals; mp. 223.5°-224.0°.
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][C:15]2[N:19]=[C:20]4[CH2:25][CH2:24][CH2:23][CH2:22][N:21]4[C:14]3=2)C=CC=CC=1.[OH-].[Na+]>C(O)=O.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH:12]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:18]2[C:13]=1[C:14]1[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]3=[N:19][C:15]=1[CH:16]=[N:17]2
Reactant: c1ccc(CN(Cc2ccccc2)c2cccc3c2ncc2nc4n(c23)CCCC4)cc1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: ClCCl
Product: Nc1cccc2c1ncc1nc3n(c12)CCCC3
Yield: 32.6 %

Procedure:
Palladium hydroxide on carbon (0.35 g) was added to a solution of N,N-bis(phenylmethyl)-8,9,10,11 tetrahydropyrido[1',2':1,2]imidazo[4,5-c]quinolin-4-amine (0.38 g, 0.9 mmole) in formic acid (about 15 mL). The reaction mixture was heated at reflux for 3 days then diluted with methylene chloride and made basic (about pH 9) with 10% sodium hydroxide. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated under vacuum to provide a white solid. The material was purified by column chromatography (silica gel eluting with 4-10% methanol in methylene chloride v/v) to provide a solid. The solid was suspended in methylene chloride (20 mL) then isolated by filtration and dried to provide 70 mg of 8,9,10,11 tetrahydropyrido[1',2':1,2]imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 275°-278° C. Calculated for C14H14N4 +0.2 CH2Cl2 : %C, 66.81; %H, 5.69; %N, 21.95; Found: %C, 67.06; %H, 5.60; %N, 22.18.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:29]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)([CH3:31])[CH3:30]>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:33]2[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]2[CH:29]([CH3:31])[CH3:30])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
4-(8-((4-tert-Butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (80 mg) was reacted with 2-isopropylbenzimidazole via General Procedure I for Buchwald coupling to give 31.4 mg 471 following reverse phase purification. MS (Q1) 532.4 (M)+
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[F:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]=[C:54]=[O:55])=[C:49]([C:56]([F:59])([F:58])[F:57])[CH:48]=1>O1CCCC1>[C:37]([CH2:36][C:12]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][N:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:54]([NH:53][C:50]3[CH:51]=[CH:52][C:47]([F:46])=[CH:48][C:49]=3[C:56]([F:58])([F:57])[F:59])=[O:55])[CH2:5][CH2:6]2)[CH2:13]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C=Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)Nc6ccc(F)cc6C(F)(F)F)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (500 mg, 1 mmol) in tetrahydrofuran (30 mL) were added triethylamine (0.29 g, 2.8 mmol) and 4-fluoro-1-isocyanato-2-(trifluoromethyl)benzene (190 mg, 0.95 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Purification by combi-flash using 30-100% EtOAc/hexanes gave 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide as a powder. LC-MS: 698.1 (M+H)+.
Reaction SMILES: [C:1]([C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH:19]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>CO>[C:1]([C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH:19]=[CH:22][C:23]([OH:25])=[O:24])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccoc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: CO
Product: CCCCCCCCCCCC#Cc1ccoc1C=CC(=O)O
Yield: 96 %

Procedure:
Reaction of 3-(1-tridecynyl)furan-2-carboxaldehyde (700 mg, 2.56 mmole from Example 6) with malonic acid (535 mg, 5.12 mmole) as described in Example 2 gave 0.778 g (98%) of the title compound, mp (methanol) 71°-72° C. νmax (mull) 3140, 2600 (broad), 1680, 1630, 1465 cm-1 ; δ(DMSO) 0.80 (3H, distorted t, terminal CH3), 1.09-1.60 (18H, m, alkylene chain), 2.42 (2H, t, CH2C≡C), 6.25 (1H, d, J 15.3 Hz, C=CH--CO2H), 6.62 (1H, d, J 2 Hz, C-4H), 7.33 (1H, d, J 15.3 Hz, Ar CH=C), 7.79 (1H, d, J 2 Hz, C-5H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[S:7].C(=O)([O-])[O-].[Na+].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]([CH2:33][C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[O:35])[N:22]=2)=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[N:23]([CH2:33][C:34]([N:36]3[CH2:37][CH2:38][N:39]([C:6]4[S:7][CH2:2][CH2:3][CH2:4][N:5]=4)[CH2:40][CH2:41]3)=[O:35])[N:22]=2)=[CH:19][CH:20]=1
Reactant: S=C=NCCCBr
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(C2=NCCCS2)CC1
Temperature: 60 °C

Procedure:
0.08 mL 1-bromo-3-isothiocyanato-propane and 305 mg sodium carbonate were added to 250 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-piperazin-1-yl-ethanone in 5 mL chloroform. The reaction was stirred over night at 60° C. The reaction was filtered over silicagel and the solvent was evaporated. The residue was crystallized from diethylether to yield 206 mg of the desired compound. Rt: 1.17 min (method B), (M+H)+: 483
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[Br:14])=[N+]=[N-].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[Br:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a mixture of 2-azidomethyl-1-bromo-4-nitrobenzene (6.57 g) and THF (50 mL) there was added triphenylphosphine (7.05 g) at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours, after which water (10 mL) was added and the mixture was heated to reflux for 15 hours. The solvent in the mixture was distilled off under reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (5.64 g) as a colorless solid.
Reaction SMILES: CON(C)[C:4](=[O:19])[CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[C:24]([CH3:29])[N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:4](=[O:19])[CH2:5][CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:25]=[C:24]([CH3:29])[N:23]=1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Reactant: Cc1cc(I)cc(F)n1
Product: Cc1cc(C(=O)CC(c2ccccc2)c2ccccc2)cc(F)n1

Procedure:
In analogy to example 55, step 2, from N-methoxy-N-methyl-3,3-diphenyl-propionamide and 2-fluoro-4-iodo-6-picoline was prepared the title compound as an off-white solid, MS (ESI+): m/z=320.1449 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH2:11][CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[CH:3][CH:4]=[CH:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9].P(=O)(O)(O)O.O>C1C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[CH2:13][CH2:12][CH2:11][CH:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][CH:6]([OH:10])[CH2:7][CH2:8][CH3:9]
Reactant: C=C(C)CCCC(C)=CC=CC(=O)CCC
Agent: O=P(O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCC(O)CCC1C(C)CCCC1(C)C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
1.66 kilograms of 8,12-dimethyltrideca-5,7,12-tri-en-4-on dissolved in 3 kilograms benzene are dropped while stirring at 10°-15° C. into 1.66 kilograms phosphoric acid and the reaction mixture is stirred for 2 hours at 20° C. and thereafter for 3 hours at 30° C. Thereupon water is added, the aqueous phase is extracted twice with benzene, the benzene extract is neutrally washed with sodium carbonate solution, and the benzene is then removed by distillation. The reaction product is purified by distillation. The yield is 1.3 kilograms 1-(2',6',6'-trimethylcyclohex-2'-enyl)-hex-1-en-3-on.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:33]=[CH:32][C:10]([CH2:11][N:12]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[N:3]=1.CC(C)([O-])C.[K+].[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C1COCC1>[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([NH:1][C:2]2[O:6][N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([CH2:11][N:12]([CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:13](=[O:23])[C:14]4[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=4)=[CH:32][CH:33]=3)[N:3]=2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(-c2noc(N)n2)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc([N+](=O)[O-])cc4)cc3)no2)cc1
Yield: 10 %

Procedure:
Prepared using General Procedure 10. To a stirring solution of tert-butyl 2-(N-(4-(5-amino-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-67 (150 mg, 0.331 mmol) in THF (3 mL) was added potassium tert-butoxide (599 μL, 0.992 mmol) at room temperature. After 15 mins a solution of 4-methylbenzene-1-sulfonyl chloride (63.1 mg, 0.331 mmol) in THF (1 mL) was added. After 1 h the reaction mixture quenched with 1 M HCl (30 mL) and then extracted with EA (50 mL). The organic layer was concentrated in vacuo and purified by chromatography (EA/hexanes) to provide 20 mg (10%) of tert-butyl 2-(N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-68. LCMS-ESI (m/z) calculated for C29H29N5O8S: 607; found 608 [M+H]+, tR=2.50 min (Method 10).
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([CH3:32])([CH3:31])[CH3:30])[C:17](OCC)=[O:18])(=O)[CH3:14]>>[CH3:32][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][C:16]1[C:13]([CH3:14])=[N:2][N:1]([C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=3[N:4]=2)[C:17]=1[OH:18])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccccc1C(C)(C)C)C(C)=O
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccccc4C(C)(C)C)c3O)nc2c1

Procedure:
Using 2-hydrazino-5-methyl-1H-benzimidazole (4) obtained in Example 1, step 3 and ethyl 2-acetyl-3-[(1,1-dimethylethyl)phenyl]propanoate (41), and by a method similar to that in Example 1, step 4, 4-[[(1,1-dimethylethyl)phenyl]methyl]-3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-5-ol (42) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9]Br.C(OC)(=O)[CH2:12][C:13]([O:15]C)=[O:14].[H-].[Na+].Cl>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CC(=O)OC
Reactant: Fc1cccc(CBr)c1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCc1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask charged with 2-bromo-1-(bromomethyl)-3-fluorobenzene (2.0 g, 7.5 mmol) and a stir bar was added dimethyl malonate (20.0 mL, 174 mmol). The solution was cooled to 0° C. in an ice bath. To this solution was carefully added sodium hydride (0.597 g, 14.9 mmol) in small portions. When the addition was done, the reaction was kept stirring for another 30 minutes. The reaction was quenched with NH4Cl, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The residue was dissolved in acetic acid (50 mL). To this solution was added HCl (50 ml, 330 mmol), and the reaction was heated to reflux for 16 hours. Analysis by LC showed formation of the desired acid. Most of the solvent was removed on a rotary evaporator. The remaining solution was diluted with 50 mL of water, and extracted with ether (50 mL×3). The extracts were combined, and washed with 1N NaOH (50 mL×2). At that point, all the acid was in the aqueous as the salt. The aqueous washes were combined, acidified, and back extracted with DCM (100 mL×2). The extracts were combined, dried over Na2SO4, and concentrated to afford 3-(2-bromo-3-fluorophenyl)propanoic acid.
Reaction SMILES: N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([C:42]#[C:43][C:44]3[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH2:52][OH:53])=[N:48][CH:49]=3)=[N:40][CH:41]=2)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([C:42]#[C:43][C:44]3[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH:52]=[O:53])=[N:48][CH:49]=3)=[N:40][CH:41]=2)=[CH:32][CH:31]=1
Reactant: OCCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.62 mL (20.07 mmol) of pyridine and 8.51 g (3.01 mmol) of Dess-Martin periodinane solution (15% in DCM) were added to a solution of 0.70 g (2.01 mmol) of 3-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]pyridin-2-yl}propan-1-ol in 50 mL of DCM and the mixture was stirred for 16 hours at RT. Semisaturated aqueous sodium bicarbonate solution was added and the aqueous phase was extracted with MTBE. The combined organic extracts were dried over magnesium sulfate and evaporated down in vacuo. The residue was purified by HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). Yield: 115 mg (17% of theoretical); C21H15ClN2O (M=346.809); calc.: molpeak (M+H)+: 347/349 (Cl); found: molpeak (M+H)+: 347/349 (Cl); HPLC-MS: 6.70 minutes (method A).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].[H][H]>CO.O.[Pd]>[NH2:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCc1cc(Cl)nc(Cl)c1N
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCc1ccnc(Cl)c1N

Procedure:
In a 1 liter stirred autoclave 150.0 g of 3-amino-2,6-dichloro-4-n-propylpyridine and 5.0 g of 10% palladium/carbon are suspended in a mixture of 450.0 ml of methanol and 150.0 ml of water and hydrogenated under 3 bars of hydrogen at 50°-70° C. until the uptake of gas has ceased.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]([O:32][CH2:33]I)(=[O:31])[CH:28]([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:33][O:32][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 92.8 %

Procedure:
In the same manner as in Example 81, 360 mg of the title compound was prepared from 325 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 220 mg of isobutyryloxymethyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2C(OC(C)(C)C)=O)=[O:26])[C:10](=[O:23])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][NH:28]2)=[O:26])[C:10](=[O:23])[N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2)CC1)[C@@H]1Cc2ccccc2CN1
Yield: 37.7 %

Procedure:
tert-Butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-phenylpiperazinyl)ethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step 2) (127 mg, 0.211 mmol) was treated with 10 mL of EtOAc satd with HCl in a 50 mL round bottomed flask equipped with magnetic stirring. The resulting solid was filtered, washed with hexane and dried in vacuo to yield N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-phenyl-piperazinyl)ethyl}((3S)(3-1,2,3,4-tetrahydro-isoquinolyl))carboxamide (40 mg). MS (ESI, pos. ion) m/z: 503 (M+H), (ESI, neg. ion) m/z: 501 (M−H). Calc'd for C29H31ClN4O2: 502.21.