Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[S:23][CH:24]=[C:25]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[N:26]=3)[CH:15]=2)=[O:12])=[CH:6][CH:5]=1.O1CCCCC1.CO.O.[OH-].[Li+]>O>[CH:27]1([C:25]2[N:26]=[C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=4)[CH:19]=[CH:18][CH:17]=3)[S:23][CH:24]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOCC1
Solvent: CO
Product: O=C(Cc1ccc(C(=O)O)cc1)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A solution composed of 0.5 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester, 20 ml of tetrahydropyran, 3 ml of methanol, 3 ml of water and 0.35 g of lithium hydroxide monohydrate was allowed to stand at room temperature for 20 hr. The solvents were removed by rotary evaporation and the residual materials were taken up in 30 ml of water. Addition of an excess of acetic acid caused the precipitation of 0.5 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 262°-263° C. after recrystallization from 2-propanol.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:49]=[CH:48][C:25]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:28][C:24]=3[CH:23]=2)[CH:17]=1)[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O1CCOCC1.Cl>[NH:26]1[C:25]2[CH:48]=[CH:49][C:22]([C:18]3[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=3)[CH2:15][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:23][C:24]=2[N:28]=[N:27]1
Reactant: CN(C)CCCN(Cc1ccccc1)Cc1cccc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)CCCN(Cc1ccccc1)Cc1cccc(-c2ccc3[nH]nnc3c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
N-Benzyl-N′,N′-dimethyl-N-[3-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-propane-1,3-diamine (60 mg, 0.093 mmol) was dissolved in a mixture of 5 mL of ethanol, 5 mL of dioxane and 8 mL of 2M aqueous hydrochloric acid solution, and the resulting mixture was stirred at room temperature for 6 h. The volatiles were removed in vacuo and the residue partitioned between diethyl ether and 1M HCl solution. The aqueous phase was washed with diethyl ether and the combined organic phases were concentrated in vacuo to obtain the crude product, which was dissolved in small amount of 1M HCl solution and freeze dried. Purification by HPLC (elution with 30% acetonitrile/70% water (containing 0.1% trifluoroacetic acid)) afforded 30 mg of the title compound. LC/MS (short method): Retention time 1.19 min; (M+H)=400.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOC(=O)CCc1cccc(N)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-2-furoic acid (247 mg, 1.29 mmol) was coupled to aniline (124) (250 mg, 1.29 mmol) using Method C to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=O)[CH:3]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[N:9][CH:8]=[C:4]2[CH:3]=1
Reactant: O=CNCc1cc(Br)ccn1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccn2cncc2c1
Temperature: 25 °C

Procedure:
A solution of 10.75 g of N-(4-bromopyridin-2-ylmethyl)formamide in 100 ml of benzene is admixed with 8.43 g of phosphorus oxychloride. The reaction mixture is heated to reflux over 4 hours. The reaction mixture is subsequently cooled to room temperature and concentrated by evaporation, and the residue is admixed with 200 ml of water. The aqueous solution is basified with 1M NaOH and extracted with dichloromethane (3×300 ml). The combined organic phases are washed with 300 ml of water, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([CH:10]([NH:27][C:28]3[N:36]=[CH:35][N:34]=[C:33]4[C:29]=3[NH:30][CH:31]=[N:32]4)[CH2:9][OH:8])[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]=2[CH:22]=1
Reactant: Fc1ccc2nc([C@H](COCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: OCC(Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of [(R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-(7H-purin-6-yl)amine (124 mg, 0.26 mmol) in anhydrous DCM (3 mL) at 0° C. under a nitrogen atmosphere was added boron tribromide (1.0M in DCM, 0.3 mL, 0.26 mmol) dropwise. The reaction mixture was slowly warmed to RT and stirred at RT for 1 h. Additional BBr3 (0.3 mL) was added and stirring continued for 1 h. MeOH was added then the volatiles removed under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 172 (60 mg, 59%). LCMS (Method K): RT 3.11 min [M+H]+ 390.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.93 (0.8H, s), 12.17 (0.2H, s), 8.27-8.01 (2H, m), 7.74-7.43 (6H, m), 7.16-7.01 (1H, m), 6.93-6.79 (1H, m), 5.56-5.31 (1H, m), 5.21-5.02 (1H, m), 3.95-3.74 (2H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:42])([C:18]2[N:19]=[CH:20][N:21]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:22]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11](F)[CH:10]=2)=[CH:4][CH:3]=1.[Cl:43][C:44]1[CH:45]=[C:46]([OH:50])[CH:47]=[CH:48][CH:49]=1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[Cl:43][C:44]1[CH:45]=[C:46]([CH:47]=[CH:48][CH:49]=1)[O:50][C:11]1[CH:10]=[C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:42])[C:18]2[N:19]=[CH:20][N:21]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:22]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Oc1cccc(Cl)c1
Reactant: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1Oc1cccc(Cl)c1

Procedure:
4-[(4-Chloro-phenyl)-hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-2-fluoro-benzonitrile (0.337 g, 0.591 mmol), 3-chlorophenol (0.074 mL, 0.709 mmol), 40% KF on alumina (0.182 g), and 18-Crown-6 ether (0.018 g, 0.068 mmol) were refluxed in CH3CN for 40 hr under Ar. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with satd. NaHCO3 solution, water, brine and dried (MgSO4). Filtration and concentration gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[CH3:36][N:34]([CH3:35])[C:32]([C:17]1[CH:18]=[C:19]2[C:24](=[C:15]([CH:13]([NH:4][C:3]3[C:5]([F:10])=[CH:6][CH:7]=[C:8]([F:9])[C:2]=3[F:1])[CH3:14])[CH:16]=1)[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])=[O:33]
Reactant: Nc1c(F)ccc(F)c1F
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1c(F)ccc(F)c1F)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 44.2 %

Procedure:
2,3,6-trifluoroaniline (0.086 mL, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-2-morpholino-4-oxo-8-(1-(2,3,6-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide (42 mg, 43%) as a white solid. Mass Spectrum: M+H+ 476. NMR Spectrum (DMSOd6): 1.56 (d, 3H), 2.75 (bs, 3H), 2.97 (bs, 3H), 3.50-3.59 (m, 4H), 3.69-3.80 (m, 4H), 5.38-5.47 (m, 1H), 5.57 (s, 1H), 6.05 (d, 1H), 6.60-6.70 (m, 1H), 6.86-6.96 (m, 1H), 7.73 (d, 1H), 7.76 (d, 1H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[CH:24]=[O:25])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[CH:24]=[O:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Yield: 96.7 %

Procedure:
A solution of (R/S) 5-(tert-butyldimethylsilyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (150 mg, 0.42 mmol, 1.00 equiv) and TBAF (800 mg, 800.00 mmol, 1922.79 equiv) in THF (5 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with 10 mL of H2O and then extracted with 3×20 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 10-20% of ethyl acetate in petroleum ether to give 0.1 g (98%) of (R/S) 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as an off-white solid. LCMS (method A, ESI): RT=1.33 min, m/z=246.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:32][CH3:33])=[C:16]([CH:22]4[CH2:25][N:24]([C@H:26]([CH3:31])[C:27]([O:29]C)=[O:28])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[OH-].[Li+]>C(#N)C.O.C(OCC)(=O)C.Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:32][CH3:33])=[C:16]([CH:22]4[CH2:25][N:24]([C@H:26]([CH3:31])[C:27]([OH:29])=[O:28])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COC(=O)[C@@H](C)N1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN([C@H](C)C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of methyl (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoate (chiral intermediate from example 156 step 2) (13 mg, 0.027 mmol) in acetonitrile (0.6 mL) and water (0.2 mL) was added lithium hydroxide (2.4 mg, 0.10 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and 1 M HCl solution. The organic layer was separated and dried over Na2SO4, filtered and concentrated to give the desired product (10.2 mg, 83%). LCMS calculated for C22H28ClN6O3 (M+H)+: m/z=459.2; Found: 459.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([NH:13]C(=O)C)=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2.[NH4+].[OH-]>O>[Br:1][C:2]1[C:11]2[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]([NH2:13])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CCN(C)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2c(N)c([N+](=O)[O-])cc(Br)c2C1
Yield: 98.9 %

Procedure:
A solution of the product from Example 7 (3.68 g, 11.2 mmol) and 80 mL of 3:2H2SO4:H2O was heated at 90° C. for 1 hour. The reaction mixture was cooled and poured onto ice, and the resulting solution was made basic with concentrated aqueous NH4OH solution. The solid that formed was collected by suction filtration and dried under vacuum to give the title compound as a yellow solid (3.17 g, 99%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[C:28]([O:27][C:25](=[O:26])[CH2:24][O:20][C:4]1[CH:5]=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)[CH:18]=[CH:19][C:3]=1[C:1]#[N:2])([CH3:31])([CH3:30])[CH3:29]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.6 %

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (200 mg, 0.75 mmol) in THF (50 mL) was added NaH (43 mg, 95%, 1.81 mmol) portion-wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of t-butyl bromoacetate (0.25 mL, 1.65 mmol). The reaction was heated at 70° C. for 24 hours. After the cooling of the reaction solution to room temperature, the mixture was filtered. The filtrate was evaporated under vacuum. The residue was purified using reverse phase chromatography, eluting from 5% MeOH/H2O to 90% MeOH/H2O, afforded 36 mg of the title compound in 12.6% yield. 1H NMR 400 MHz (DMSO-d6) δ: 9.26 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.14 (s, 1H), 7.09 (dd, J=2.3, 8.2 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.68 (dd, J=2.0, 8.6 Hz, 1H), 4.96 (s, 2H), 4.86 (s, 2H), 1.37 (s, 9H); MS (ES) m/z: 380 (M−H)−; HPLC purity: 99.11% (220 nm), 98.48% (254 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:14][CH:13]2[CH2:12][O:11][C:10]3=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClCCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:10][OH:15])[CH2:14][CH:13]2[CH2:12][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1OCC2C[C@]12c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC1C[C@@]1(CO)c1ccc(Cl)c(Cl)c1
Yield: 98.4 %

Procedure:
BMS (10.9 mL, 115 mmol) was added to (1S)-1-(3,4-dichloro-phenyl)-3-oxabicyclo[3.1.0]hexan-2-one (14 g, 57.6 mmol) in dry tetrahydrofuran (140 mL), under nitrogen atmosphere. The reaction mass was refluxed for 5 hours and monitored by TLC (dichloromethane (100%)). The reaction was quenched with 10% potassium carbonate solution. The aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 14 g (98.5%) of desired product. 1H NMR δ(300 MHz,CDCl3): 0.9-0.98 (1H,m), 1.17 (1H,m), 1.48 (1H,m), 3.23-3.42 (2H,m) 3.92-4.03 (2H,m) 7.10-7.13 (1H,m), 7.24-7.27 (1H,m), 7.38 (1H,m,).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1cccc(CBr)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.[Br:26]N1C(=O)CCC1=O>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Br:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1Br
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.600 g) in tetrahydrofuran (20 ml) was added N-bromosuccinimide (0.288 g). The mixture was left at room temperature for 2 hours and then poured onto a column of silica gel (30 g) and eluted with hexane:dichloromethane (1:1). Combination and evaporation of suitable fractions gave a red oil which was further purified by column chromatography on silica gel (30 g) eluted with hexane:dichloromethane (1:1), then dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH3:24])=[CH:16][CH:15]=2)[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[N:26]1C(=O)CC[C:27]1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH2:24][C:27]#[N:26])=[CH:16][CH:15]=2)[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cccc(NC(=O)C(C)(C)C)n2)c2ccccc12
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)Nc1cccc(-c2ccc(CC#N)c3ccccc23)n1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 1.21 g (3.795 mmol) N-t-butylcarbonyl-6-(4-methylnaphthalen-1-yl)-pyridin-2-ylamine, 810 mg (4.554 mmol) N-bromosuccinimide, 35 mL carbon tetrachloride, and 10 mg bis-(1-cyano-1-azo)-cyclohexane. The reaction was heated at reflux for a total of 8 hours as additional portions of initiator were added at 1, 2, and 4 hours. The reaction was cooled, filtered with carbon tetrachloride, and evaporated. The red oil, 2.5 g, was used directly.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)C(OCC)=O)C.O.Cl.[OH-].[Na+]>[OH-].[Na+].C1COCC1>[CH3:18][O:17][C:14]1[N:13]=[CH:12][C:11]([CH2:5][C:4]([OH:19])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(6-Methoxy-pyridin-3-yl)-malonic acid diethyl ester (5.6 g, 21.0 mmoL) prepared in Example 3 was dissolved in 2N NaOH/THF:H2O (1:1) (20 mL). The resulting mixture was heated to reflux for 3 hours. The reaction mixture was then adjusted to pH=1 by concentrated HCl and stirred at room temperature for another 1 hour. The solution was then adjusted to pH=13 by 1N NaOH and extracted with ether. The aqueous phase was acidified to pH=5 by 1N HCl and extracted 3× by ethyl acetate. The combined organic phase was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound a white solid (2.45, 70%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=O)=[CH:5][NH:6]2.[CH3:13][N:14]1C2C(=CC=CC=2)C(C)=C1C=O>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][NH:14][CH3:13])=[CH:5][NH:6]2
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: O=Cc1c[nH]c2cccc(F)c12
Product: CNCc1c[nH]c2cccc(F)c12

Procedure:
According to the procedure of Preparation 13 (c),except substituting 4-fluoro-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound was prepared as a viscous oil: MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28]C(C#N)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[C:31]([OH:34])(=[O:33])[CH3:32]>OS(O)(=O)=O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][C:32]([C:31]([OH:34])=[O:33])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)O
Reactant: CCCCCCCCOc1ccc(N2CCN(c3ccc(C#N)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
A solution of 4-[4-(4-Octyloxyphenyl)piperazin-1-yl]benzonitrile (0.5 g) in 20% H2SO4 aqueous solution (30 ml) and acetic acid (20 ml) was refluxed for 9 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration, and added to a mixture of water, tetrahydrofuran and ethyl acetate, and adjusted to pH 2.5 with 1N NaOH aqueous solution. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-(4-Octyloxyphenyl)piperazin-1-yl]benzoic acid (388 mg).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)[CH2:3][C:4]([OH:6])=[O:5].Cl>[OH-].[Na+].O.NN.[Ni]>[F:13][C:11]1[CH:12]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:14][N:1]=[C:2]2[CH2:3][C:4]([OH:6])=[O:5]
Reactant: NC(CC(=O)O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Product: O=C(O)Cc1n[nH]c2ccc(F)cc12
Temperature: 80 °C
Yield: 8.6 %

Procedure:
3-Amino-3-(5-fluoro-2-nitrophenyl)propionic acid (15.32 g, 67.1 mmol) was dissolved in a mixed solution of 5% sodium hydroxide solution (80 mL) and 85% hydrazine hydrate (5 mL). The reaction was heated to 80° C., and then Raney nickel (2×25 mg) was added carefully. After reacted for half an hour, it was cooled, and adjusted to pH=2 with 6 N hydrochloric acid. A solid precipitated, pumping filtered, dried in vacuum to obtain a yellow solid 1.12 g, at a yield of 8.6%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH3:10][O:11][Na]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:11][CH3:10])[CH:5]=[C:4]([Br:9])[CH:3]=1
Reactant: CO[Na]
Reactant: Fc1cc(Br)cc(Br)c1
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(Br)c1

Procedure:
step 1—A solution of 1,3-dibromo-5-fluoro-benzene (CASRN 1435-51-4), MeONa (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5% NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford 1,3-dibromo-5-methoxy-benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH:13]/[C:14](/[NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[N:15]\[C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.I(O)(=O)(=O)=[O:32]>CC(C)=O.C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH:13]/[C:14](/[NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[N:15]\[C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:24])=[O:32])[CH:18]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CSc1cccc(C(=O)/N=C(/NCC(C)C)Nc2cc(-c3ccc(F)cc3)n[nH]2)c1
Reactant: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)CN/C(=N/C(=O)c1cccc(S(C)=O)c1)Nc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 77 %

Procedure:
To an orange solution of (Z)—N-[[[3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino]-(isobutylamino)methylene]-3-methylsulfanyl-benzamide (500 mg, 1.175 mmol) and ferric chloride trihydrate (9.5 mg, 0.035 mmol) in acetone:acetonitrile (1:1) was added periodic acid (295 mg, 1.3 mmol) in one portion. After stirring the resulting mixture at room temperature for ca. 21 hr, the reaction was quenched by adding aqueous sodium thiosulfate. The product was extracted with DCM, and the organic layer was washed with brine and dried over MgSO4. The drying reagent was removed by filtration, and the filtrate was concentrated onto silica gel and purified by silica chromatography (50-90% EtOAc in hexanes) to provide the title compound (77% yield). MS (EI+) m/z: 442.17.