Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[K].Cl.Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C(O)=O>CS(C)=O.C(O)C.C(OCC)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[CH2:13][O:14][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCCCN1CCCCC1
Reactant: COc1ccc(C=CCO)cc1OC
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(/C=C/COCCCN2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)prop-2-en-1-ol (270 mg) in dimethyl-sulfoxyde (4 mL) are added successively powdered potassium hydroxyde (175 mg 85% wt) and, portionwise, 1-(3-chloropropyl)piperidine, hydrochloride (250 mg). The mixture is stirred overnight at room temperature, then hydrolysed with water (80 mL). The solution is extracted twice with ethyl acetate (20 mL). The combined extracts are washed twice with water (10 mL), dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with a gradient dichloromethane/methanol from 98/2 to 90/10. Fractions containing the expected product are pooled, concentrated under reduced pressure, dissolved in 10 mL of dichloromethane, filtered over Millipore membrane and concentrated under reduced pressure. The base thus obtained is dissolved in 2 mL of ethanol and 100 μL of diethyl oxide. A solution of 88 mg of oxalic acid in 2 mL of ethanol is added. The precipitate that appears is filtered, washed with diethyl oxide and dried under reduced pressure at a temperature close to 40 C to give 185 mg of trans-1-{3-[3-(3,4-dimethoxyphenyl)allyloxy]propyl}piperidine, oxalate as a white powder melting at 111-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(3-bromophenyl)butan-1-ol (5 g) (WO 0266422 A1) in dry DMF was treated with imidazole (1.8 g) and tert-butyldiphenylsilyl chloride (7.2 g) and stirred at room temperature for 16 h. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with 2M HCl, water, sat. NH4Cl(aq), water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, Gradient between cyclohexane and cyclohexane-EtOAc (5:1) to give the title compound. LCMS RT=4.82 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C=O

Procedure:
The sub-title compound was prepared by the method of Example 1 part d) using 5-chloro-2-hydroxybenzaldehyde (40 g), potassium carbonate (40 g), acetone (400 ml) and tert-butyl bromoacetate (37 ml) (yield=45.5 g).
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH:11]([CH3:1])[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:29])[CH3:30])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Yield: 99.2 %

Procedure:
A mixture of Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.98 g, 1.97 mmol) and 20% palladium hydroxide/carbon (0.10 g) in methanol (20 ml) was stirred at room temperature in a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=100:10:1) to give N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.71 g, 99%).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH2:28][CH2:29][CH2:30][OH:31]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:28][CH2:29][CH2:30][OH:31])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CNCCO)CO2

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), 2-aminoethanol (0.5 ml), ACN (2.5 ml). 1H-NMR (400 MHz, MeOD): δ 7.36 (2H, m), δ 4.54 (1H, dd, J 12, 2.4), δ 4.44 (1H, m), δ 4.18 (1H, dd, J 12, 7.2), δ 3.71 (2H, t, J 5.6), δ 3.13 (3H, s), δ 2.98 (2H, m), 2.81 (2H, m) ppm (J-values are in Hz and shifts relative to solvent-peak at 3.31 ppm).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH2:8][C:9](OC)=[O:10])=[CH:4][CH:3]=1.[NH2:15][OH:16]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH2:8][C:9]([NH:15][OH:16])=[O:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)CSCc1ccc(Cl)cc1
Solvent: CO
Product: O=C(CSCc1ccc(Cl)cc1)NO

Procedure:
A solution of 0.15 mol of methyl 2-(4-chlorobenzylmercapto)-acetate in 50 ml of methanol is mixed with a solution of 0.225 mol of hydroxylamine (base) and 0.15 mol of NaOH3 in 150 ml of methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+].[NH2:21][C:22]1[C:39]([CH2:40][N:41]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH3:43])=[CH:38][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33]Cl)=[O:27])=[CH:24][C:23]=1[Br:50]>>[NH2:21][C:22]1[C:39]([CH2:40][N:41]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH3:43])=[CH:38][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][O:18][C:17](=[O:19])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[O:27])=[CH:24][C:23]=1[Br:50]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CCCN(CCCl)CCOC(=O)c1cc(Br)c(N)c(CN(CC)C2CCCCC2)c1
Agent: [Na+]
Product: CCCN(CCOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)CCOC(=O)c1cc(Br)c(N)c(CN(CC)C2CCCCC2)c1

Procedure:
This compound was prepared from sodium 2-[(2,6-dichlorophenyl)-amino]-phenyl-acetate and N-{2-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyloxy]-ethyl}N-(2-chloroethyl)-n-propylamine analogous to Example 8. Oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[Cl:18][C:19]1[CH:28]=[CH:27][C:26]2[N:25]=[C:24]3[C:29]([CH3:33])([CH3:32])[CH2:30][CH2:31][C:23]3=[C:22](Cl)[C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:19]1[CH:28]=[CH:27][C:26]2[N:25]=[C:24]3[C:29]([CH3:33])([CH3:32])[CH2:30][CH2:31][C:23]3=[C:22]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([N:11]5[CH2:16][CH2:15][O:14][CH2:13][CH2:12]5)[CH:6]=4)[C:2]([CH3:17])([CH3:1])[CH2:3]3)[C:21]=2[CH:20]=1
Reactant: CC1(C)CCc2c1nc1ccc(Cl)cc1c2Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)CN(c2c3c(nc4ccc(Cl)cc24)C(C)(C)CC3)c2cc(N3CCOCC3)ccc21

Procedure:
Prepared according to procedure T using 4-(3,3-dimethylindolin-6-yl)morpholine (0.2 g, 0.86 mmol), 7,9-dichloro-3,3-dimethyl-2,3-dihydro-1H-cyclopenta[b]-quinoline (0.434 g, 1.72 mmol), cesium carbonate (0.561 g, 1.72 mmol), Pd2(dba)3 (0.079 g, 0.086 mmol) and (±) BINAP (0.084 g, 0.129 mmol) in 1,4-dioxane (2 mL). After HPLC purification 7-chloro-9-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-3,3-dimethyl-2,3-dihydro-1H-cyclopenta[b]-quinoline was obtained. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.02 (1H, d, J=9.0 Hz), 7.86 (1H, m), 7.68 (1H, m), 7.06 (1H, m), 6.38 (1H, m), 5.73 (1H, s), 3.86 (2H, d, J=0.5 Hz), 3.73 (2H, s), 3.62 (4H, dd, J=5.4, 4.4 Hz), 3.06 (1H, m), 2.84-2.94 (4H, m), 1.96 (1H, m), 1.33 (12H, m). Mass Spectrum (ESI) m/e=463 (M+1).
Reaction SMILES: ClC1C2C(=CC=CC=2)N=CC=1.N1C2C(=CC=CC=2)C=NC=1.[N+:22]([C:25]1[CH:41]=[CH:40][CH:39]=[CH:38][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)([O-])=O.[H][H]>[OH-].[Pd+2].[OH-].[C].[C].[Pd].CN(C)C=O>[NH2:22][C:25]1[CH:41]=[CH:40][CH:39]=[CH:38][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccnc2ccccc12
Agent: [Pd+2]
Agent: [Pd]
Agent: Clc1ccnc2ccccc12
Solvent: CN(C)C=O
Product: Nc1ccccc1Oc1ccnc2ccccc12

Procedure:
Next, 4-chloroquinoline derivative or a corresponding quinazoline derivative is allowed to act on nitrophenol in the presence of a suitable solvent or in the absence of a solvent to synthesize a 4-(nitrophenoxy)quinoline derivative or a corresponding quinazoline derivative which is then stirred in a suitable solvent, for example, N,N-dimethylformamide, in the presence of a catalyst, for example, palladium hydroxide-carbon or palladium-carbon, in a hydrogen atmosphere to give a 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative. Alternatively, a 4-chloroquinoline derivative or a corresponding quinazoline derivative may be allowed to act on aminophenol in the presence of a base, for example, sodium hydride, to give a 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([C:9]([O:11]C)=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1.[OH-].[K+]>C(O)C.O>[F:14][C:2]([F:1])([F:13])[C:3]1[C:4]([C:9]([OH:11])=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: COC(=O)c1nccnc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nccnc1C(F)(F)F
Yield: 62.6 %

Procedure:
Methyl 3-trifluoromethylpyrazine-2-carboxylate (700 mg, 3.4 mmol) was dissolved in ethanol-water (1:1, 10 ml), followed by adding potassium hydroxide (300 mg) and refluxing under heating for 1 hour. The reaction solution was concentrated under reduced pressure, followed by dilution of residue with water and washing with ethyl acetate. The water layer was acidified with HCl, followed by extracting with ethyl acetate, washing with a saturated brine. The solution was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 409 mg of the desired compound as crystal.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11]/[CH:12]=[CH:13]/[C:14](Cl)=[O:15])[CH3:10].O>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])/[CH:13]=[CH:12]/[O:11][CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCO/C=C/C(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
26.63 g (0.155 mol) of 4-bromoaniline are dissolved in 120 ml of pyridine and 23.14 g (0.172 mol) (E)-3-ethoxy-acrylic acid chloride are added dropwise at a temperature between 0° C. and 5° C. and the mixture is stirred for one hour at 0° C. Then the reaction mixture is allowed to warm up to RT and stirred for 14 h. The reaction mixture is combined with water, the precipitate formed is filtered off and washed with water. The solid is dried at 65° C. in the drying cupboard.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C@@H:9]2[CH2:11][C@H:10]2[NH:12][CH:13]=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.II.CO>O1CCCC1>[CH3:13][NH:12][C@@H:10]1[CH2:11][C@H:9]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CN[C@@H]1C[C@H]1c1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN[C@@H]1C[C@H]1c1ccccc1
Yield: 57.1 %

Procedure:
To a suspension of sodium borohydride (0.66 g, 17.57 mmol) in tetrahydrofuran (55 ml) was added dropwise at room temperature a solution of the compound (2.36 g, 14.64 mmol) obtained in step A in tetrahydrofuran (32 ml). Then, a solution of iodine (1.86 g, 7.33 mmol) in tetrahydrofuran (63 ml) was added dropwise, and the mixture was heated under reflux overnight. The reaction mixture was ice-cooled, methanol (125 ml) was added, and the mixture was concentrated under reduced pressure. To the residue was added 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (chloroform-methanol) to give the title compound (1.23 g, yield 57%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16]CC)=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:21])=[N-]>CC([O-])=O.CC([O-])=O.[Pd+2].CCOCC>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=[O:15])[CH2:11][C@H:10]1[CH:12]1[CH2:13][CH2:21]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1C1CC1
Temperature: -15 °C
Yield: 106.3 %

Procedure:
A 30 mL ether solution of (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate (1.0 g, 3.9 mmol, prepared as described in WO2005037214) in a 500 mL round-bottomed flask equipped with a stir bar was first cooled in an acetone-ice bath to approx. −15° C., then an ether solution of diazomethane (33 ml, 20 mmol) was added in one portion to the above solution. While stirring vigorously and keeping the reaction open to air, Pd(OAc)2 (0.088 g, 0.39 mmol) was added to in one portion to the reaction at −15° C. After the active effervescence subsided, the reaction was allowed to stir for another 5 min at −15° C. and concentrated down to fairly clean crude product. The crude could be further purified with flash chromatography on silica (eluent=hexanes/EtOAc 5:1), giving the titled compound as a colorless thick oil (1.0 g, 95% yield). 1H-NMR (400 MHz, CDCl3) δ 5.10 (br s, 1 H), 4.18-4.24 (m, 2 H), 1.60-1.64 (m, 2 H), 1.44 (s, 9 H), 1.27 (t, 3 H), 1.05-1.11 (m, 1 H), 0.83-0.89 (m, 1H), 0.47-0.58 (m, 2 H), 0.30-0.34 (m, 2 H). LCMS (APCI+) 170.0 (MH+−Boc).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].Br[C:23]1[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]([C:23]2[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNC(=O)Nc1ccc(-c2ncc(C(=O)OC)s2)cn1

Procedure:
N-Ethyl-N′-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]urea (Intermediate 1, 0.20 g, 0.69 mmol), methyl 2-bromo-1,3-thiazole-5-carboxylate (0.152 g, 0.69 mmol), tetrakis triphenyl phosphine palladium (0.08 g, 0.069 mmol), and cesium carbonate (0.245 mg, 0.754 mmol) were taken in a microwave vial and degassed with argon. Then dioxane:water (4:1, 3 mL) was added to it and microwaved at 110° C. for half an hour. The reaction mixture was partitioned between water and EtOAc and layers separated. The organic layer was washed with sat. sodium bicarbonate solution, water, brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by flash chromatography eluting with 2% MeOH in DCM to 3% MeOH in DCM. MS (ESP): 307 (M+H+) for C13H14N4O3S; NMR: 1.09 (t, 3H), 3.16-3.22 (m, 2H), 3.86 (s, 3H), 7.60 (d, 1H), 7.79 (t, 1H), 8.27 (dd, 1H), 8.49 (s, 1H), 8.83 (s, 1H), 9.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][C@@H:17]([CH3:19])[C@@H:16]([NH2:20])[CH2:15][C@H:14]3[CH3:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(NC3CCC(N)CC3)=CC=N2)=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([F:51])[CH:50]=1)[C:45](O)=[O:46].N1C2C(=CC=C(C(O)=O)C=2)C=C1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@@H:13]3[C@H:14]([CH3:21])[CH2:15][C@H:16]([NH:20][C:45](=[O:46])[C:44]4[CH:43]=[C:42]([F:41])[CH:50]=[C:49]([F:51])[CH:48]=4)[C@H:17]([CH3:19])[CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: C[C@@H]1C[C@H](N)[C@H](C)C[C@@H]1Nc1ccnc2cc(Cl)ccc12
Agent: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Agent: O=C(O)c1ccc2cc[nH]c2c1
Product: C[C@@H]1C[C@H](Nc2ccnc3cc(Cl)ccc23)[C@H](C)C[C@@H]1NC(=O)c1cc(F)cc(F)c1

Procedure:
The titled compound was prepared according to the method described in Example 23 substituting (1S,2R,4S,5R)-N-(7-chloroquinolin-4-yl)-2,5-dimethylcyclohexane-1,4-diamine for N-(7-chloroquinolin-4-yl)cyclohexane-1,4-diamine and 3,5-difluorobenzoic acid for indole-6-carboxylic acid. 1H NMR (300 MHz, DMSO) δ ppm 8.87 (d, 1 H), 8.55 (t, 1 H), 8.07 (d, 1 H), 7.93 (d, 1 H), 7.83 (dd, 1 H), 7.42-7.64 (m, 4 H), 7.00 (d, 1 H), 4.00-4.20 (m, 2 H), 1.63-2.34 (m, 6 H), 1.03 (d, 3 H), 1.00 (d, 3 H). MS(ESI(+)Q1MS m/z 444 (M+H)+).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].[F-].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.O>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Yield: 77.9 %

Procedure:
Under an atmosphere of argon, 9-bromoanthracene (3.9 g, 15 mmole), 4-formylphenylboronic acid (2.5 g, 17 mmole, 1.1 eq), potassium fluoride (3.2 g, 56 mmole, 3 eq) and tris(dibenzylideneacetone)-dipalladium(0) (0.07 g, 76 mmole, 1% Pd) were suspended in anhydrous THF (25 ml). To the obtained suspension, a toluene solution of tri-t-butylphosphine (66%, 0.06 ml, 0.2 mmole, 1.3 eq to Pd) was added and the resultant mixture was heated under refluxing for 10 hours. To the reaction mixture, water (50 ml) and toluene (150 ml) were added. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with magnesium sulfate. Then, the solvent was removed by distillation and a light yellow solid was obtained. The obtained solid was purified by the column chromatography (silica gel/ hexane+50% dichloromethane) and a light yellow solid (3.3 g, 78%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:16](=[O:24])[C:17](=[N+]=[N-])[C:18](=[O:21])[CH2:19][CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1>ClCCl.Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[O:24]=[C:16]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[O:2][CH2:1][CH:17]1[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)C(=[N+]=[N-])C(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCC(=O)C1COC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Yield: 40.4 %

Procedure:
A solution of rhodium acetate dimer (0.002 g, 0.005 mmol) in dichloromethane (27 mL) was heated to 81° C. A solution of tert-butyl 4-methoxy-4-(2-diazo-1,3-dioxopent-1-yl)piperidine-1-carboxylate (0.092 g, 0.270 mmol) from Step D in dichloromethane (7 mL) was added slowly dropwise over 12 min. The reaction mixture was refluxed for 45 min then poured into IN hydrochloric acid, and extracted three times with dichloromethane. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfite, filtered, and concentrated. The residue was purified by flash chromatography eluting with 10% ethyl acetate/dichloromethane to afford the title compound (0.034 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.C(N(CC)CC)C>ClCCl>[NH2:1][C:2]1[C:9]([Cl:10])=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:13][CH2:12]2)[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1cc(N)c(Cl)c(N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
(I11C): To the stirred solution of 3-amino-4-chloro-5-(piperazin-1-yl)benzonitrile (1.0 g, 4.22 mmol) in dichloromethane (10 mL) was added BOC2O (0.981 mL, 4.22 mmol) at 0° C., drop wise over a period of 10 minutes followed by triethylamine (0.883 mL, 6.34 mmol). The reaction mixture was allowed to warm to room temperature, stirred it for 1 hour. The reaction mixture was diluted with methylene chloride (100 mL), washed with brine (30 mL), dried over Na2SO4 and concentrated at 45° C. to get tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.4 g) as a brown solid. The crude material was washed with diethyl ether four times and dried under vacuum to get tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.4 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:33](=O)[CH:34]([CH3:36])[CH3:35].C(O)(=O)C>ClCCl>[CH3:33][CH:34]([CH3:36])[CH2:35][NH:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: N#Cc1ccc(-n2cnc3c(N)cccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CNc1cccc2c1ncn2-c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a stirred solution of 4-(4-amino-1H-benzimidazol-1-yl)benzonitrile (246 mg, 1.05 mmol) in dichloromethane (10 mL) at rt was added sodium triacetoxy borohydride (311 mg, 1.47 mmol, 1.4 eq), isobutyraldehyde (91 mg, 1.26 mmol, 1.2 eq) and acetic acid (63 m g, 1.05 mmol, 1 eq) and the mixture was stirred for 2 h. The mixture was poured on water and extracted with DCM. After evaporation of the organic phase, purification of the residue by flash chromatography yielded 190 mg 4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzonitrile (62.3%).