Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:7]1
Reactant: N#Cc1ccc(Br)cn1
Reactant: C[C@@H]1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C#N)nc2)CCN1

Procedure:
A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98 mmol), 5-bromo 2-cyanopyridine (1.66 g, 9.08 mmol), tris(dibenzylidineacetone)dipalladium (0) (83.15 mg, 0.0908 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (169.37 mg, 0.272 mmol) and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield 5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile as brown color oil (1.15 g, 39.1% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(N=Cc2ccc(F)cc2)cc1

Procedure:
A mixture of 19.60 g (115 mmol) of 4-methylsulfonylaniline, 12.19 mL (115 mmol) of 4-fluorobenzaldehyde and 590 mL of toluene was refluxed in a Dean-Stark for 2 days. The solvent was removed and the crude product obtained was directly used in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([NH2:17])[CH:11]=1>O1CCOCC1>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([NH:17][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])[CH:11]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cc(Cl)cc(Cl)n1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1cc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethoxycarbonyl isothiocyanate (2 g, 16 mmol) was added to a solution of 4,6-dichloropyridin-2-amine (2.2 g, 13 mmol) in 1,4-dioxane (100 mL) and stirred at rt for 18 h. LCMS showed desired product. The reaction mixture was concentrated in vacuo and the residue azeotroped with EtOAc (3×20 mL) to give a cream solid, which was triturated with EtOAc to give the desired product as a white solid (2.9 g, 76%). 1H NMR (DMSO) δ 12.31 (s, 1H), 11.77 (s, 1H), 8.86 (d, J=1.1 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H). m/z [M+H]+=293.88
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:54]=[CH:55][N:56]=4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[N:42]=[CH:41][C:40]6[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=6)[C:34]5=[O:48])[C:28]=4[CH2:49][O:50][C:51](=[O:53])[CH3:52])[CH:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:43]([C:38]1[CH:39]=[C:40]2[C:35](=[C:36]([F:47])[CH:37]=1)[C:34](=[O:48])[N:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]3[CH:26]=[C:21]([NH:20][C:17]4[N:16]=[CH:15][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:19][CH:18]=4)[C:22]4[N:23]([CH:54]=[CH:55][N:56]=4)[CH:24]=3)[C:28]=1[CH2:49][O:50][C:51](=[O:53])[CH3:52])[N:42]=[CH:41]2)([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cn3)c3nccn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCNCC4)cn3)c3nccn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 6-{6-[2-acetoxymethyl-3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)phenyl]-imidazo[1,2-a]pyridin-8-ylamino}-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (280 mg, 0.3689 mmol) in DCM (8 mL) was added TFA (1.4 mL) and the solution was stirred at room temperature for one hour. TLC showed a complete reaction. The solution was poured onto water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product used directly to the next step (260 mg). LC-MS: 660 [M+1]+, tR=1.270 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH2:14][C:15]([OH:17])=O.C(C1C=C(OC)C=CC=1CC(O)=O)C1C=CC=CC=1>>[F:1][C:2]1[CH:20]=[CH:19][C:18]2[C:15](=[O:17])[CH2:14][C:7]3[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=3[CH2:5][C:4]=2[CH:3]=1
Reactant: COc1ccc(CC(=O)O)c(Cc2cccc(F)c2)c1
Agent: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Product: COc1ccc2c(c1)Cc1cc(F)ccc1C(=O)C2

Procedure:
According to the procedure of Preparation 10(d), except substituting 2-(3-fluorobenzyl)-4-methoxyphenylacetic acid for the 2-benzyl-4-methoxyphenylacetic acid, the title compound was obtained as a white solid: Mp 129-130° C.; MS (ES) m/e 279.2 (M+Na)+.
Reaction SMILES: [PH4+].[CH3:2]C([O-])(C)C.[K+].[Cl:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=[CH2:2]
Reactant: COc1ccc(C=O)c(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a suspension of phosphonium salt (2.05 g, 5 mmol) in THF (50 mL), was added t-BuOK (0.84 g, 7.5 mmol). The mixture turned to yellow and was kept stirring at RT for 1 h. 2-Chloro-4-methoxybenzaldehyde (0.85 g, 5 mmol) was added to the mixture. The mixture was stirred for 24 h, diluted with sat. NaHCO3 and then extracted with hexane. Organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Isolera One (100% hexanes to afford the desired product (0.45 g, 53% yield). 1H NMR (CDCl3, δ): 7.49 (d, J=6.8 Hz, 1H), 7.03 (dd, J=8.8, 14.0 Hz, 1H), 6.90 (d, J=2.0, 1H), 6.79 (dd, J=2.0, 6.8 Hz, 1H), 5.62 (d, J=14.0 Hz, 1H), 5.26 (d, J=8.8 Hz, 1H), 3.80 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][N:14]([CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:15]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.Cl[C:49]1[C:50]2[C@H:57]([CH3:58])[CH2:56][CH:55]([OH:59])[C:51]=2[N:52]=[CH:53][N:54]=1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:30][CH2:31][N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:49]3[C:50]4[C@H:57]([CH3:58])[CH2:56][CH:55]([OH:59])[C:51]=4[N:52]=[CH:53][N:54]=3)[CH2:21][CH2:22]2)=[O:16])=[CH:37][CH:38]=1
Reactant: CCN(CC)CCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[C@@H]1CC(O)c2ncnc(Cl)c21
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-(N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (88 mg, 0.19 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 3 hours, and then concentrated in vacuo. The residue was dissolved in n-butanol (1 mL). N,N-diisopropylethylamine (0.11 mL, 0.6 mmol) was added to the solution. Then, (5R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopenta[d]pyrimidin-7-ol (37 mg, 0.20 mmol) was added to the solution. The reaction mixture was heated at 80° C. for 16 hours. The mixture was then diluted with H2O (1 mL), and extracted with DCM (2×5 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by preparative HPLC to give N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)-4-((5R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide (19.9 mg, 21%). MS (APCI+) [M+H]+ 501.3. 1H NMR (CDCl3, 400 MHz) δ□ 8.46 (s, 1 H), 7.34 (d, J=8.4 Hz, 4 H), 7.13 (d, J=8.4 Hz, 4 H), 5.50 (t, J=8 Hz, 1 H), 5.28 (dd, J=3.6, 8.4 Hz, 1 H), 4.45 (s, 4 H), 4.14-4.04 (m, 4 H), 3.94-3.81 (m, 4 H), 3.51-3.42 (m, 8 H), 3.20-3.00 (m, 16 H), 2.73-2.64 (m, 2 H), 2.40-2.20 (m, 4 H), 2.05-1.98 (m, 1H), 1.86-1.78 (m, 1 H), 1.33 (d, J=7.2 Hz, 3 Hz), 1.28 (t, J=7.2 Hz, 12 H), 1.21 (d, J=6.8 Hz, 3 Hz).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14]N)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].N([O-])=[O:17].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14][OH:17])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nccc2c(CN)cccc12
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1nccc2c(CO)cccc12
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
1-iso-Propyl-5-aminomethylisoquinoline (8.7 g) was dissolved in 20 ml of acetic acid and 20 ml of water, and with ice cooling, 9 g of sodium nitrite was added. The mixture was stirred for 30 minutes. Then, 30 ml of a 10 N aqueous solution of sodium hydroxide was added, and the mixture was heated for 1 hour. The product was extracted with ethyl acetate, washed in water, and dried, followed by distilling off the solvent. Recrystallization of the residue from methylene chloride/n-hexane afforded 7.1 g of 1-isopropyl-5-hydroxymethylisoquinoline as colorless needles having a melting point of 119.9° to 120.9° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([S:14][CH2:15][CH2:16][C@@H:17]([C:19](O)=[O:20])[NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([S:14][CH2:15][CH2:16][C@@H:17]([CH2:19][OH:20])[NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@@H](CCSCc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: N[C@H](CO)CCSCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 43 g of LiAlH4 (4 times the theoretical amount) in 1000 ml of anhydrous ether brought to reflux under mechanical agitation, there is added a solution of 144 g of the ethyl ester of the S-benzylhomocysteine in 600 ml of anhydrous ether at a speed such that the reaction mixture continues to boil. After the end of the addition, refluxing is continued for 1 hour.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH3:11])[CH2:13][CH2:14]1)[C:6]#[N:7]
Reactant: CN1CCCNCC1
Reactant: Cc1cc(C#N)ccc1F
Product: Cc1cc(C#N)ccc1N1CCCN(C)CC1

Procedure:
7.00 g (51.8 mmol) 4-fluoro-3-methyl-benzonitrile are heated to 110° C. together with 1-N-methyl-[1,4]diazepan for 1 week with stirring. After evaporation i. vac. the residue is separated on aluminium oxide (eluant: dichloromethane) and the corresponding fractions are again purified on silica gel (eluting gradient: dichloromethane/methanol 100:1→9:1).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:13])[C:9](=[O:12])OC)=[CH:6][C:5]([F:14])=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C@H:25]1[CH2:28][C@H:27]([NH2:29])[CH2:26]1.CC(C)([O-])C.[Na+]>[Pd+2]>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C@H:25]1[CH2:26][C@H:27]([N:29]2[C:2]3=[N:3][CH:4]=[C:5]([F:14])[CH:6]=[C:7]3[N:8]([CH3:13])[C:9]2=[O:12])[CH2:28]1
Reactant: COC(=O)N(C)c1cc(F)cnc1Cl
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncc(F)cc21
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
Methyl (2-chloro-5-fluoropyridin-3-yl)(methyl)carbamate (intermediate 37, 0.310 g, 1.418 mmol), trans-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 0.311 g, 1.418 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-tri-1-1,1′-biphenyl)]2-(2-aminoethyl)phenyl)palladium(ii) (0.085 g, 0.106 mmol), and sodium t-butoxide (0.341 g, 3.55 mmol) were scaled in a microwave vial under argon. Dry, sparged dioxane (1.5 mL) was added and the suspension heated at 50° C. After 20 minutes the vial was opened and the crude partitioned between 10% saturated ammonium chloride (100 mL) and ethyl acetate (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (dichloromethane to ethyl acetate gradient) then triturated with diethyl ether. Filtration gave the desired 3-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-6-fluoro-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.295 g, 0.799 mmol, 56.3% yield) as a free flowing cream colored solid. M+1: 370.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44-2.59 (m, 2 H) 2.63 (s, 3 H) 3.46-3.56 (m, 2 H) 4.50-4.59 (m, 1 H) 5.31 (quin, J=8.20 Hz, 1 H) 7.03 (dd, J=8.02, 2.54 Hz, 1 H) 7.09 (td, J=7.58, 1.08 Hz, 1 H) 7.30 (td, J=7.73, 1.17 Hz, 1 H) 7.52 (dd, J=8.02, 0.39 Hz, 1 H) 7.60 (dd, J=7.82, 0.78 Hz, 1 H) 7.95 (t, J=2.15 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH2:19][CH2:18][C:17](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[CH:18][C:17](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1cc2c3c(c1)c1cc(Br)ccc1n3CCC2=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Yield: 81.1 %

Procedure:
10-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (3.6 g) obtained in Example 1, step 3 was dissolved in anhydrous dioxane (300 ml), and DDQ (3.0 g) was added at room temperature. The mixture was heated under reflux in an argon atmosphere for 5 hours. After allowing to cool, the reaction mixture was added to 1N aqueous solution of sodium hydroxide (500 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N aqueous solution of sodium hydroxide and saturated aqueous solution of sodium chloride in succession, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride containing 3% methanol) to obtain the title compound (2.9 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=1)=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]1[O:24][C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)ccc2Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Cl)ccc3Cl)o2)cc1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Into a 250 ml flask fitted with a mechanical stirrer and thermometer was introduced 30 g (0.0686 mol) 2,5-dichlor-N′-[4-(octyloxy)benzoyl]benzohydrazide and 181 ml phosphorus oxychloride. This was refluxed and stirred for 8 hrs. About 100 ml of phosphorus oxychloride was distilled off under reduced pressure. The cooled residue was poured onto water and crushed ice with manual stirring and allowed to stand until the ice had melted. The precipitated white solid was collected by filtration, dried and recrystallized from ethanol. There was obtained 25.7 g (89% yield, mp 86° C.) of 2-(2,5-dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole. The structure was confirmed unambiguously by 1D and 2D NMR techniques and gave the following: 1H-NMR (500 MHz, CDCl3) 0.89 (3H, t), 1.31 (8H, m), 1.46 (2H, q), 1.79 (2H, q), 6.97 (2H, d), 7.38 (1H, dd), 7.44 (1H, d), 8.01 (2H, d), 8.06 (1H, d); 13C-NMR (500 MHz, CDCl3) 13.90, 22.44, 25.79, 28.91, 29.01, 29.13, 31.59, 68.08, 114.78, 115.37, 124.27, 128.58, 130.23, 130.87, 131.75, 132.20, 132.87, 161.03, 161.98, 164.95.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]1[N:12]=[C:11]([NH:13][CH2:14][C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])[CH:10]=[CH:9][N:8]=1>Cl.CO>[Br:1][C:2]1[N:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=2)[NH:5][C:6]=1[C:7]1[N:12]=[C:11]([NH:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])[CH:10]=[CH:9][N:8]=1
Reactant: C[C@@H](CNc1ccnc(-c2c(Br)nc(-c3ccc(C(F)(F)F)cc3)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](N)CNc1ccnc(-c2[nH]c(-c3ccc(C(F)(F)F)cc3)nc2Br)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 129.5 %

Procedure:
The mixture of (S)-tert-butyl 1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamate (0.14 g, 0.21 mmol) in concentrated HCl (0.24 mL) and MeOH (5 mL) was heated at 80° C. for 3 hours, then stirred at room temperature overnight. The reaction mixture was concentrated to a yellow solid to afford crude (S)—N1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-4-yl)propane-1,2-diamine (0.12 g) as the HCl salt, which is used in next step without purification: LCMS (m/z) 441.0 (MH+), tR=0.68 minute.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:19][CH:20]=O)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].Cl.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:19][CH2:20][N:31]2[CH2:34][CH:33]([OH:35])[CH2:32]2)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: OC1CNC1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CC(O)C1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
3-Cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-1-naphthamide (see WO 00/02859; 1.0 g, 2.3 mmol) was dissolved in CH2Cl2 (10 mL) and to the resultant solution were added azetidin-3-ol hydrochloride (0.24 g, 2.2 mmol) and triethylamine (0.30 mL, 2.2 mmol). After stirring for 40 min, sodium triacetoxyborohydride (0.65 g, 3.1 mmol) was added and the solution was stirred at room temperature for 3 h. The solvent was removed by evaporation and the residue was partitioned between saturated aqueous NaHCO3 solution and ethyl acetate. The solvent was removed by evaporation and the residue was dissolved in hydrochloric acid (1M). The solution was washed with CH2Cl2, alkalised with aqueous NaOH (2M) and then extracted with CH2Cl2. The solvent was removed by evaporation and there was obtained 0.85 g (80%) of 3-cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-(3-hydroxyazetidin-1-yl)butyl]-N-methyl-1-naphthamide as a white solid. 1H NMR (400 MHz, DMSO-d6): 0.8-4.4 (cm, 16H), 6.4-8.2 (cm, 8H), 8.6 (d, 1H); LCMS: m/z 482 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:22])([O:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][C:19](O)=[O:20])[CH:14]=[CH:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[BH4-].[Na+]>O1CCCC1.O1CCCC1.O.O>[OH:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:8]([CH3:22])([CH3:9])[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCC(=O)O)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[3-(1-tert-Butoxycarbonyl-1-methylethoxy)phenyl]propionic acid (10.0 g, 32.4 mmol) was dissolved in tetrahydrofuran (50 mL). Subsequently, triethylamine (3.6 g, 35.6 mmol) was added dropwise thereto. Ethyl chlorocarbonate (3.87 g, 35.6 mmol) was added under ice-cooling, and the mixture was stirred for one hour at room temperature. Sodium borohydride (2.45 g, 64.8 mmol) in tetrahydrofuran-water solution was added dropwise under ice-cooling, and the mixture was stirred for two hours at room temperature. Water was added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with diluted hydrochloric acid and saturated brine. The resultant mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=7/3), whereby the target compound was obtained (9.8 g (q.)).
Reaction SMILES: [C:1](/[N:9]=[C:10]1/[N:11]([CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)[C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:15]=[CH:14][C:13]=2[NH:27]/1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C(/N=C2/N([C@H]3CC[C@@H](C(N4CCNC[C@H]4C)=O)CC3)C3C=C(OCCN4CCCCC4)N=CC=3N/2)=O)=CC=1)#N>>[N:21]1([CH2:20][CH2:19][O:18][C:16]2[N:15]=[CH:14][C:13]3[NH:27]/[C:10](=[N:9]\[C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)/[N:11]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[C:12]=3[CH:17]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2/c(=N/C(=O)c3ccccc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Agent: C[C@@H]1CNCCN1C(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(C#N)cc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1C1CCNCC1)c1ccccc1

Procedure:
The title compound was prepared from (E)-tert-butyl 4-(2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate using a method analogous to the preparation of (E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (1.9 g, 97%). MS m/z=449.2 [M+H]. Calc'd for C25H32N6O2: 448.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.29 (m, 2H) 1.31-1.42 (m, 2H) 1.41-1.55 (m, 4H) 1.60-1.77 (m, 2H) 2.26-2.37 (m, 1H) 2.37-2.45 (m, 4H) 2.58-2.70 (m, 4H) 3.04-3.17 (m, 2H) 4.29-4.39 (m, 2H) 4.72-4.89 (m, 1H) 7.04-7.06 (m, 1H) 7.47-7.51 (m, 2H) 7.51-7.54 (m, 1H) 8.19-8.20 (m, 1H) 8.21-8.22 (m, 1H) 8.22-8.24 (m, 1H).