Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C[N+](C)=CS(Cl)(=O)=O.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=1.[CH2:20]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=O)=[CH:26][CH:25]=1)[CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]2[O:17][C:28]([C:27]3[CH:32]=[CH:33][C:24]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=3)=[N:30][N:31]=2)=[CH:13][N:12]=1
Reactant: CC(C)Cc1ccc(C(=O)NN)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: C[N+](C)=CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cc1ccc(-c2nnc(-c3ccc(Cl)nc3)o2)cc1
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
N,N-Dimethyl(chlorosulphonyl)methaniminium chloride (1.57 g, 0.01 mol) was added to a solution of 6-chloronicotinic acid (1.58 g, 0.01 mol) and dichloromethane (20 mL) at 0° C. and stirred for 10 minutes. 4-isobutylbenzohydrazide (5.29 g, 0.03 mol) was added to the reaction mixture, followed by the dropwise addition of a solution of triethylamine (12.3 mL, 0.09 mol) in dichloromethane (30 mL). The resulting mixture was stirred at room temperature for 12 hours, quenched with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was recrystallized from methanol:acetone (10:1) to give the title compound (2.57 g, 82% yield) as a white solid.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH:30]2[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]2)[CH2:26][CH2:25]1)[CH3:23]>C(#N)C>[Br:1][CH:33]1[CH2:34][CH2:35][CH:30]([CH:27]2[CH2:28][CH2:29][CH:24]([CH2:22][CH3:23])[CH2:25][CH2:26]2)[CH2:31][CH2:32]1
Reactant: CC[C@H]1CC[C@H](C2CCC(O)CC2)CC1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCC1CCC(C2CCC(Br)CC2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
102 ml of bromine are added dropwise over the course of 2 hours at 5-15° C. to 536 g of triphenylphosphine in 2000 ml of acetonitrile, the mixture is subsequently stirred at 5° C. for 1 hour, 422 g of 4-(trans-4-ethyl-cyclohexyl)cyclohexanol are added, and the mixture is stirred at RT for 24 hours. Conventional work-up gives 4′-bromo-4-ethylbicyclohexane, GC 94.7%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C(=O)([O-])[O-].[Na+].[Na+]>>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Product: O=C1CCCCC1
Product: OC1CCCCC1
Reaction time: 2.5 h
Yield: 91.5 %
Yield: 8 %

Procedure:
A reduction of phenol was performed at 215° C. and 70 psig, with 0.03 gm. sodium as sodium carbonate per 1000 gm. phenol. After 150 minutes, the reaction yielded 91.5% cyclohexanone and 8% cyclohexanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:30].O>CN(C)C(=O)C.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>[ClH:1].[CH2:21]([N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:35]4[CH:36]=[CH:37][C:32]([CH2:31][C:29]#[N:30])=[CH:33][CH:34]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1)[CH3:22]
Reactant: CCn1ncc(CN2CCN(c3nccnc3Cl)CC2)c1C
Reactant: N#CCc1ccc(B(O)O)cc1
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: O
Solvent: CC(=O)N(C)C
Product: CCn1ncc(CN2CCN(c3nccnc3-c3ccc(CC#N)cc3)CC2)c1C
Product: Cl
Temperature: 70 °C
Yield: 47.9 %

Procedure:
Combine 3′-chloro-4-(1-ethyl-5-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.300 g, 0.935 mmol), potassium carbonate (0.310 g, 2.24 mmol), (4-Cyanomethylphenyl)boronic acid (0.180 g, 1.12 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol) in N,N-dimethylacetamide (1.9 mL). Add water (940 μL), and reflux reaction for 6 hr. Continue to heat at 70° C. for 18 hr. Add DCM and wash with water. Extract water layer three times with DCM. Dry combined organics (magnesium sulfate) and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 to 20:80 methanol:ethyl acetate), to give the free base of the title compound (196 mg, 52%). Dissolve the free base (0.194 g, 0.482 mmol) in acetonitrile (579 μL) and add aq. 1 N HCl solution (579 μL, 0.579 mmol). Shake for 15 min. at ambient temperature. Freeze dry to give the title compound (201 mg, 95%). MS (ES): m/z=402 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22]([OH:29])[C:23]([O:27][CH3:28])=[C:24]([OH:26])[CH:25]=1.CCN(CC)CC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[C:23]([O:27][CH3:28])=[C:22]([OH:29])[CH:21]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: COc1c(O)cc(CN)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(O)cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Yield: 107.3 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (89 mg, 0.32 mmol), 5-aminomethyl-2-methoxy-benzene-1,3-diol hydrochloride salt (66 mg, 0.32 mmol) and Et3N (111 μL, 0.8 mmol) in N,N-dimethylformamide (DMF) (2 mL) is stirred at 25° C. for 24 hours. H2O (10 mL) is added to the reaction mixture. The resulting precipitate is filtered, washed with H2O and dried in vacuo to give 144 mg of the title compound as a beige powder. HRMS (ESI) m/z calcd for C18H15BrN2O5 (M+H)+1 419.02371. found: 419.02294.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:33])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([C:28]5[O:29][CH:30]=[CH:31][CH:32]=5)[CH2:23]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.CS(O)(=O)=O.O>[OH-].[K+].C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)[CH2:23]2)=[CH:17][C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:33])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccco5)C4)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccco5)C4)cc3nc21
Temperature: 80 °C
Yield: 46.8 %

Procedure:
A suspension of (RS)-3-ethoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.3 g) in 0.5 N aqueous potassium hydroxide (12 cc) and ethanol (12 cc) is heated for 1 hour to a temperature in the region of 80° C. and then treated at the same temperature with an N aqueous solution (6 cc) of methanesulphonic acid. After cooling to approximately 20° C., the insoluble water is drained, washed with water (3×10 cc), ethanol (3×10 cc) and ethyl ether (3×10 cc) and recrystallized in a mixture of ethanol (13 cc) and dimethylformamide (27 cc). (RS)-7-Fluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.570 g) obtained in the form of a yellow solid, m.p. 258°-260° C.
Reaction SMILES: Cl.[NH:2]1[C:6]([CH2:7][CH:8]=[O:9])=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[S:23]([N:2]1[C:6]([CH2:7][CH:8]=[O:9])=[CH:5][N:4]=[CH:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: O=CCc1cnc[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cncc2CC=O)cc1

Procedure:
A solution of 1.46 g (10 mM) of 2-(5-imidazolyl)-acetaldehyde HCl in 20 ml of dichloromethane is treated with 2.01 g (20 mM) of triethylamine and 1.9 g of p-toluenesulfonyl chloride at 25° C for about 16 hours after which the solution is washed with 3 N hydrochloric acid, water, sodium bicarbonate and water then dried and evaporated to afford 2-(1-tosylimidazol-5-yl)acetaldehyde upon recrystallization from ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Cl.[CH3:16][CH:17]1[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1>>[CH3:16][CH:17]1[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CC1CCN=C(N)N1
Agent: Cl
Product: CC1CCn2c(nc(-c3ccncn3)cc2=O)N1

Procedure:
A mixture of 7.76 g (40.0 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705582), 6.0 g (40.0 mmol) 6-methyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrochloride
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH2:11][CH:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:21][O:22]3)=[CH:17][C:16]=2[F:28])[CH2:13][OH:14])=[C:6](F)[CH:5]=1.C(O)C>C1COCC1.CCOCC>[Br:3][C:4]1[CH:5]=[C:6]2[C:7]([CH2:11][CH:12]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:21][O:22]4)=[CH:17][C:16]=3[F:28])[CH2:13][O:14]2)=[CH:8][C:9]=1[F:10]
Reactant: CCCC1COc2cc(C(CO)Cc3cc(F)c(Br)cc3F)c(F)cc2C1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: CCCC1COc2cc(C3COc4cc(Br)c(F)cc4C3)c(F)cc2C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
1.2 g (10.5 mmol) of potassium hydride (35 percent in paraffin oil) are initially introduced in 40 ml of THF, and a solution of 4.50 g (8.12 mmol) of 3-(4-bromo-2,5-difluorophenyl)-2-(6-fluoro-3-propylchroman-7-yl)propan-1-ol in 20 ml of THF is added dropwise at 30° C. The batch is subsequently stirred at 60° C. for 4 h, a little ethanol is added, and the batch is diluted with MTB ether and washed with sat. sodium chloride soln. The org. phase is dried over sodium sulfate, the solvent is removed in vacuo, and the crude product is filtered through silica gel with toluene and recrystallised from heptane/ethyl acetate, giving 7-bromo-6,6′-difluoro-3′-propyl-3,4,3′,4′-tetrahydro-2H,2′H-[3,7′]-bichromenyl as colourless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:44]=[CH:43][C:11]([CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]([N:20]([C:22]2[C:23]([Cl:42])=[C:24]([C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[N:35]=[C:34]([CH3:37])[CH:33]=[CH:32]3)[CH3:21])=[O:19])=[O:15])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:42][C:23]1[C:22]([N:20]([CH3:21])[C:18](=[O:19])[CH2:17][NH:16][C:14](=[O:15])[CH:13]=[CH:12][C:11]2[CH:43]=[CH:44][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:9][CH:10]=2)=[CH:40][CH:39]=[C:38]([Cl:41])[C:24]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([CH3:37])[CH:33]=[CH:32]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCCBr)cc4)c3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N5CCCC5=O)cc4)c3Cl)c2n1
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a stirred solution of 8-[3-[N-[4-(bromobutyramido)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (50 mg) in N,N-dimethylformamide was added potassium carbonate (30 mg) at ambient temperature and the resulting mixture was stirred at the same temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (methanol-ethyl acetate=1:12, V/V) to afford 8-[2,6-dichloro-3-[N-methyl-N-[4-(2-oxo-1-pyrrolidinyl)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (33.4 mg) as an amorphous solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.O.[NH2:21][NH2:22].[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C(O)C>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([NH:21][NH:22][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([CH3:23])[CH:25]=2)[C:8]([F:12])=[CH:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: NN
Reactant: C=CCOc1ncc(F)c(Cl)n1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCOc1ncc(F)c(NNC(=O)c2cccc(C)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
A 25 mL vial was charged with 2-(allyloxy)-4-chloro-5-fluoropyrimidine (72.5% pure, 175 mg, 0.673 mmol), ethanol (4 mL), triethylamine (234 μL, 1.68 mmol), and hydrazine monohydrate (34 μL, 0.706 mmol). The resulting solution was then agitated on an orbital shaker at room temperature for 90 min. 3-Methylbenzoyl chloride (93 μL, 0.706 mmol) was then added, and the reaction was further agitated for 16 h. The crude reaction mixture was concentrated under reduced pressure, and then purified by flash column chromatography (EtOAc/hexane gradient) to afford the title compound (95.8 mg, 47%) as a pale yellow solid: mp 181-185° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.44 (bs, 1H), 9.75 (bs, 1H), 8.10 (d, J=3.5 Hz, 1H), 7.65-7.75 (m, 2H), 7.37-7.43 (m, 2H), 5.95 (m, 1H). 5.25 (m, 1H), 5.15 (m, 1H), 4.63 (m, 2H), 2.37 (s, 3H); MS (ESI) m/z 303 (M+H)+, 301 (M−H)−.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:19])[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:19])[CH:10]=1
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1sc(N)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of ethyl 5-(tert-butoxycarbonylamino)-3-methylthiophene-2-carboxylate (25.00 g, 87.61 mmol) and trifluoroacetic acid (50 mL) in dichloromethane (100 mL) was stirred at 0° C. for 2 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate (300 mL) and 1 N aqueous sodium hydroxide (300 mL). The aqueous layer was extracted with ethyl acetate (200 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 40% ethyl acetate in hexanes to afford ethyl 5-amino-3-methylthiophene-2-carboxylate as a beige solid (14.44 g, 89%): 1H NMR (300 MHz, CDCl3) δ 5.95 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.41 (s, 3H), 1.32 (t, J=7.1 Hz, 3H); MS (ES+) m/z 186.2 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]#[N:15])[C:8]=3[CH:16]=2)[CH2:3][CH2:2]1.[CH:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[O:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][NH:15][C:23]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:24])[C:8]=3[CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N#CCN1CCOc2ccc(C3CC3)cc21
Product: O=C(NCCN1CCOc2ccc(C3CC3)cc21)C1CCCCC1

Procedure:
The procedure is as in Example 2, starting from the compound obtained in Step A and with the replacement of butyryl chloride with cyclohexylcarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](O)([CH3:14])[CH3:13]>>[CH:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1)([CH3:14])[CH3:13]
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Reactant: CC(C)O
Product: CC(C)OC(=O)c1ccc(Cl)c(O)c1
Temperature: 85 °C
Yield: 75 %

Procedure:
4-Chloro-3-hydroxy-benzoic acid (100 mg, 0.58 mmol) and 1 mL of isopropanol were mixed and then heated to 85° C. for overnight. The mixture was then concentrated in vacuum and the resulting residue was purified by flash chromatography (8–20% EtOAc/Hex) to give the desired ester (94 mg, 75%). MS (DCI) m/z 215 (M+H)+, 232 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[C:11]([C:12]#[C:13][Si](C)(C)C)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4].C1COCC1.[OH-].[Na+].Cl>CCOC(C)=O.CCCCCC>[C:12]([C:11]1[C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[N:7][CH:8]=[CH:9][CH:10]=1)#[CH:13]
Reactant: CC(C)(C#N)c1ncccc1C#C[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cccnc1C(C)(C)C#N
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
To a solution of 2-methyl-2-(3-(2-(trimethylsilyl)ethynyl)pyridin-2-yl)propanenitrile (1.6 g, 6.6 mmol) and THF (20 mL, 244 mmol), was added NaOH (13 mL, 66 mmol). After 1.5 hours, TLC (30% EtOAc/hexane) showed complete reaction to provide a product with a lower spot. The reaction was acidified with 5N HCl (pH=2) and then was extracted with EtOAc. The organic layer was washed with water and brine (3× each) and then dried over MgSO4 and concentrated in vacuo to give a yellow oil. The crude product was purified by silica flash chromatography (0-75% EtOAc/hexane) to give the desired product as a light-orange crystalline solid (0.93 g, 83%). MS (m/z)=171 (M+H)+. Calculated for C11H10N2 170.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:12]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][C:6]2[CH:17]=[CH:18][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[NH:11]1
Reactant: O=C1Nc2cc(CO)ccc2Oc2ccccc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc2c(c1)NC(=O)c1ccccc1O2
Reaction time: 0.17 h
Yield: 83 %

Procedure:
8-(hydroxymethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (0.241 g, 1 mmole) in acetonitrile was added to the molecular sieves (1 g) under N2 at room temperature then 4-methylmorpholine N-oxide (0.175 g, 1.5 mmole) was also added into the reaction mixture. After stirring the mixture for 10 minutes, tetrapropylammonium perruthenate (0.0176 g, 0.05 mmole) was added and the reaction followed by t.l.c. until complete. Dilute the reaction mixture with 10 ml of ethyl acetate and flashed it through a small silica gel column. Collected all the ethyl acetate that contains desired material, extracted the organic layer with 1N HCl and also washed it with brine. Dried the organic layer over sodium sulfate and filtered and concentrated. Obtained the desired compound (white solid) in 83% yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:12]#[N:13].N>[Ni].CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][NH2:13]
Reactant: N#Cc1cc2cccnc2cc1F
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc2cccnc2cc1F
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To 7-fluoroquinoline-6-carbonitrile (1.00 g, 5.813 mmol), methanol saturated with ammonia (13.5 ml) and Raney-Ni (1.27 g) were added and hydrogenated at 50-60 psi for 4 h. The reaction mixture was filtered and concentrated to afford the title compound as a brown oil (0.80 g, 78%), 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.85 (d, J=2.3 Hz, 1H), 8.35 (d68.0 Hz, 1H), 8.06 (d, J=9.5 Hz, 1H), 7.68 (d, J=11.8 Hz, 1H), 7.49 (t, J=3.8 Hz, 1H), 3.92 is, 2H), 1.90 (brs, 2H)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:15][NH2:16])[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:15][NH:16][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:21]5[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=5)[CH:25]=4)[CH2:13][CH2:14]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CC1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 49 %

Procedure:
This compound was synthesized from (1-(4-phenylthiazol-2-yl)cyclopropyl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (47 mg, yield 49%). 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.25-8.23 (m, 2H), 8.09-8.07 (m, 1H), 7.90-7.88 (m, 2H), 7.63-7.59 (t, J=7.9 Hz, 1H), 7.41-7.38 (m, 2H), 7.35-7.33 (m, 1H), 7.32 (s, 1H), 3.93 (d, J=5.5 Hz, 2H), 1.42-1.39 (m, 2H), 1.23-1.20 (m, 2H). MS (ESI) m/z: Calculated for C23H17F3N4O2S: 470.10. found: 471.0 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[NH2:22])C(OC(C)(C)C)=O)C.Cl.CCOCC>CO.O1CCOCC1>[C:20]([C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][CH:17]=1)[NH:22][C:4](=[O:3])[CH2:5][NH:6]2)#[N:21]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)NCC(=O)N2
Yield: 99 %

Procedure:
N-Boc-2-amino-5-cyanophenylglycin ethyl ester (2.6 g, 8.17 mmol) in MeOH (20 mL) was treated with 4M HCl in dioxane (20 mL) at rt for 16 hours. To the mixture was added Et2O until no more solid appeared. The solid was collected, washed with Et2O, and dried by air to give the product (1.4 g, 82%). 1H NMR (CD3COCD3) δ 7.02 (d, J=8.4 Hz, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 3.89 (s, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Br:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH:53]=2)[NH:48][C:47]=1[C:63](O)=[O:64].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56](=[O:57])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])[CH:53]=2)[NH:48][C:47]=1[C:63]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:64]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Br)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Br)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
HATU (0.231 g, 0.608 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.126 g, 0.405 mmol), 3-bromo-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.144 g, 0.405 mmol) and diisopropylethylamine (0.106 mL, 0.608 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.086 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (br. s., 1H), 9.27 (br. s., 1H), 8.45 (br. s., 1H), 7.66-7.84 (m, 2H), 7.38-7.56 (m, 4H), 7.17-7.34 (m, 2H), 4.57 (d, 2H), 1.14-1.62 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=O)[CH3:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:12][NH2:13]>CCOC(C)=O.O>[Cl:1][C:2]1[C:7]2[C:8]([CH3:9])=[N:12][NH:13][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: CC(=O)c1c(Cl)ccnc1Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]c2ccnc(Cl)c12
Yield: 64 %

Procedure:
1-(2,4-Dichloro-pyridin-3-yl)-ethanone (6.2 g, 32.6 mmol) in 65% aqueous hydrazine (45 ml) was stirred at rt overnight. The mixture was diluted with EtOAc and water. The organic extract was washed with brine, dried and concentrated to give a white solid. The crude product was purified by flash column chromatography over silica gel (200 g) eluting with 1:1 petroleum ether:EtOAc to give an off-white solid (3.5 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s, 3 H), 7.47 (d, J=5.95 Hz, 1 H), 8.06 (d, J=5.95 Hz, 1 H). m/z (ES+APCI)+: 168/170 [M+H]+.