Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Br:14][C:15]1[C:16](Cl)=[N:17][CH:18]=[C:19]([CH:34]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[O:21]>CN(C=O)C>[Br:14][C:15]1[C:16]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:17][CH:18]=[C:19]([CH:34]=1)[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:31])[F:33])=[CH:27][CH:28]=1)=[O:21]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OC2CCOCC2)c(Br)c1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
Tetrahydro-2h-pyran-4-ol (0.361 mL, 3.79 mmol) and K2CO3 (314 mg, 2.275 mmol) were added to a suspension of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 300 mg, 0.758 mmol) in DMF (2 mL) and the RM was stirred at 120° C. for 3.5 h. The solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, 40 g, EtOAc/n-hexane, isocratic 2:8) to afford 5-bromo-6-(tetrahydro-2h-pyran-4-yloxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (25 mg, 0.054 mmol) together with pyrimidin-5-ylboronic acid (30 mg, 0.160 mmol), Pd(Ph3P)4 (10 mg, 8.13 μmol) K3PO4 (35 mg, 0.163 mmol) and toluene (0.4 mL) was stirred at 110° C. for 10 h under an argon atmosphere. The cooled RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative SFC (Column 4-EP; gradient 7% to 12% in 6 min.) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.06 min, m/z=461.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.61-1.75 (m, 2H) 2.04 (m, J=10.00 Hz, 2H) 3.54 (m, J=8.80, 8.80 Hz, 2H) 3.70-3.80 (m, 2H) 5.37-5.47 (m, 1H) 7.39 (d, J=8.47 Hz, 2H) 7.87 (d, J=9.03 Hz, 2H) 8.50 (s, 1H) 8.82 (s, 1H) 9.15 (s, 2H) 9.22 (s, 1H) 10.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([O:8][C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A solution of 2-chloro-5-hydroxy pyridine (5.00 g, 38.60 mmol), 1-Boc-4-hydroxypiperidine (9.32 g, 46.31 mmol) and triphenyl phosphine (15.19 g, 57.90 mmol) in THF (200 mL) at 0° C. was treated dropwise with diisopropylazodicarboxylate (11.14 mL, 57.90 mmol). The mixture was stirred at room temperature for 18 hours, diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (25-40% EtOAc in petrol (40-60° C.)) gave 4-(6-chloro-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.70 g, 47%) as a pale yellow residue. 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=2.8 Hz, 1H), 7.23-7.16 (m, 2H), 4.51-4.41 (m, 1H), 3.75-3.64 (m, 2H), 3.40-3.29 (m, 2H), 1.99-1.86 (m, 2H), 1.83-1.67 (m, 2H), 1.47 (s, 9H). LCMS (m/z, Method A) ES+ 311.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][NH:7][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[Cl:11])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCCc1cccc(Br)c1
Solvent: O
Solvent: ClCCl
Product: O=C(NCCc1cccc(Br)c1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromophenethylamine (10.0 g, 50 mmol) in DCM (100 ml) containing TEA (8.36 g, 60 mmol, 1.2 eq.) cooled to 0° C. is added 2-chlorobenzoylchloride (8.75 g, 50 mmol, 1.0 eq.) portionwise. The resulting mixture is stirred at rt for 1 hr. Water (100 ml) is added to quench the reaction. The organic layer is collected, washed with water and brine, dried over sodium sulfate, and concentrated to give the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[C:8](Cl)([O:10][CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O>[NH2:7][C:5](=[O:6])[C@H:3]([NH:2][C:8](=[O:9])[O:10][CH2:11][CH:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:4]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Reaction time: 8 h
Yield: 120.4 %

Procedure:
A solution of D-Alaninamide hydrochloride (3 g) in 10% sodium carbonate solution (50 ml) and dioxan (50 ml) was treated with FMOC chloride (6.24 g) in dioxane (40 ml) and allowed to stir overnight. The mixture was diluted with water (500 ml) and the product collected by filtration and dried in vacuo to give 9.0 g of the subtitle compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Cl-].[Li+].[CH2:14](C([Sn])=C(CCCC)CCCC)[CH2:15]CC>C1(C)C=CC=CC=1.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>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2)=[CH2:15]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Brc1ccc2nccnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc2nccnc2c1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A mixture of 6-Bromoquinoxaline (1.05 g, 5.02 mMol), tetrakis(triphenylphosphine)palladium (0.232 g, 0.2 mMol), and lithium chloride (0.639 g, 15.1 mMol) in dry toluene (50 mL) under nitrogen was treated with tributylvinyl tin (4.4 mL, 15.1 mMol) and heated to one hundred degrees for three hours. After cooling to room temperature the mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was discarded and the organics washed with brine (2×100 mL), dried with magnesium sulfate, filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 10% ethyl acetate in dichloromethane as eluant yielded 680 mg (87% yield) of 6-vinylquinoxaline as a light orange solid. 1H NMR (DMSO-d6): δ=8.92 (dd, 2H, J=14.1, 1.9 Hz), 8.10 (m, 3H), 7.03 (dd, 1H, J=17.7, 10.9 Hz), 6.15 (dd, 1H, J=17.7, 0.4Hz), 5.52 (d, 1H, J=11.1 Hz). LC/MS (Method A), rt=1.14 mins., purity=99%, calculated mass=156, [M+H]+=157.
Reaction SMILES: C[O:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][C:6]1[C:10]2[C:11](=[O:25])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8][N:7]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][C:6]1[C:10]2[C:11](=[O:25])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8][N:7]=1
Reactant: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c(Cc3ccccc3O)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 64.7 %

Procedure:
To a solution of 3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (50 mg, 0.13 mmol, prepared in Example 22) in acetic acid (1 ml) was added 47% hydrogen bromide (0.5 ml), and the mixture was heated under reflux. After additional 47% hydrogen bromide (1 ml) and acetic acid (1 ml) was added, the mixture was heated under reflux for 2 days, then admixed with water, filtered to give precipitates which were dried to afford 3-(2-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (31 mg, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1)#[CH:2].[Br:13][C:14]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:17](I)=[CH:16][N:15]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:13][C:14]1[N:15]=[CH:16][C:17]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][N:6]([CH2:8][C:9]([F:11])([F:12])[F:10])[CH:7]=3)[N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]=2[CH:19]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(CC(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(-c2cnn(CC(F)(F)F)c2)cc2cnc(Br)cc21
Temperature: 60 °C
Yield: 47.3 %

Procedure:
4-Ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (Preparation 148, 326 mg 1.87 mmole) was dissolved in DMF (4.9 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 565 mg 1.50 mmole) was added. To the solution was added triethylamine (0.91 mL, 655 mg 6.5 mmole) and copper(I) iodide (10 mg 0.052 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (37 mg 0.052 mmole) was added and the reaction was again flushed with nitrogen, then heated at 60° C. for 110 minutes. The reaction was cooled and added to water (50 ml). The reaction were extracted with ethyl acetate thrice (3×20 ml). The combined organic extracts were washed with water (3×20 mL) and brine, dried and concentrated in vacuo. The residue was purified using column chromatography eluting with 100% dichloromethane, 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane to 30% ethyl acetate in dichloromethane to afford the title compound (300 mg, 47%). 1H-NMR (CDCl3, 500 MHz): δ 2.98 (s, 3H), 4.80 (q, J=8.20 Hz, 2H), 6.76 (d, J=0.95 Hz, 1H), 7.84 (d, J=0.63 Hz, 1H), 7.94 (s, 1H), 8.25 (t, J=0.95 Hz, 1H), 8.67 (d, J=0.95 Hz, 1H). 19F-NMR (CDCl3, 470.385 MHz): −71.56.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[N:9]=1)[C:2]([NH2:4])=[NH:3].[OH-].[Na+].[ClH:29]>CO>[ClH:29].[ClH:29].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CCCCCCN2C(=O)c3ccccc3C2=O)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)Nc1nc(CCCCCCN)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 2-guanidino-4-(6-phthalimidohexyl)thiazole (4.2 g.) in methanol (30 ml.) and 10% w/v aqueous NaOH (10 ml.) was heated under reflux for 15 minutes. The pH of the mixture was then adjusted to 1 with concentrated HCl and the mixture heated under reflux for 30 minutes. The pH of the mixture was then adjusted to 12 with 10% w/v aqueous NaOH and the mixture heated under reflux for 15 minutes. The pH of the mixture was then adjusted to pH 1 with concentrated HCl and the mixture was heated under reflux for 30 minutes and then stirred at room temperature for 16 hours. The mixture was then evaporated to dryness in vacuo and the residue suspended in water and filtered to remove solids which were further washed with water. The combined aqueous filtrates were extracted several times with ethyl acetate, then with ether. The aqueous layer was evaporated to dryness and the residue extracted several times with ethanol. The combined ethanol extracts were evaporated to dryness, reextracted with ethanol and this extract filtered and evaporated to dryness to give 2-guanidino-4-(6-aminohexyl)thiazole dihydrochloride as a yellow foam which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24]CC)=O)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:37][NH2:38]>C(O)C>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([NH:37][NH2:38])=[O:24])=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 80 °C
Yield: 103.9 %

Procedure:
To a solution of ethyl 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinate (Example 43) (0.2 g, 0.43 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.1 mL, 2.1 mmol). The reaction mixture was heated to reflux at 80° C. for 16 h. The ethanol was evaporated under reduced pressure and the residue was dissolved in DCM and washed with water. The organic layer was dried and concentrated to provide 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinohydrazide (0.2 g, crude), which was used without further purification. LCMS Method E: retention time 1.8 min; [M+1]=447.50.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]#[N:17])[CH2:12][CH2:11]1.[OH:26][NH:27][C:28](=N)[CH2:29][O:30][CH3:31]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][C@H:7]1[CH2:9][C@H:8]1[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[O:26][N:27]=[C:28]([CH2:29][O:30][CH3:31])[N:17]=2)[CH2:14][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)c(F)c1
Reactant: COCC(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCc1noc(N2CCC([C@@H]3C[C@@H]3CCOc3ccc(S(C)(=O)=O)cc3F)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-((1R,2S)-2-{2-{2-fluoro-4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidine-1-carbonitrile (Step D, Example 111; 100 mg, 0.27 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.8 mL, 0.5 M in tetrahydrofuran, 0.4 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound. MS (ESI) m/z 454 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1.Cl.[C:23](=O)([O-])[O-:24].[Na+].[Na+]>O.CO>[CH3:23][O:24][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)C2CCCN2Cc2cc(N)ccc21
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CN1CCCC1C(=O)N2C
Reaction time: 1 h

Procedure:
A solution of 3.5 g. of sodium nitrite in 30 ml. of water is added over 1 hour at 48°-50°C. to a solution of 11.5 g. of 7-amino-1,2,3,5,10,11a-hexahydro-10-methyl-11H- pyrrolo[2,1-c] [1,4]benzodiazepin-11-one in 20 ml. of concentrated hydrochloric acid and 500 ml. of methanol. The reaction mixture is held at this temperature for 1 hour longer, diluted with an equal volume of water, neutralized with sodium carbonate and concentrated under reduced pressure to remove the methanol. The aqueous residue is extracted with benzene and the benzene layer is concentrated to remove the crude 1,2,3,5,10,11a-hexahydro-7-methoxy-10-methyl-11H- pyrrolo[2,1-c] [1,4]benzodiazepin-11-one. Further purification is by partition chromatography on a diatomaceous earth column using a heptane/methyl cellosolve solvent system.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:36][C:35](=[O:37])[S:34][N:33]=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[NH:36][C:35](=[O:37])[S:34][N:33]=4)=[CH:30][CH:31]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2nsc(=O)[nH]2)cc1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(-c2nsc(=O)[nH]2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
65 mg (0.19 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 54 mg (0.28 mmol, 1.5 eq.) of 3-(4-aminophenyl)-1,2,4-thiadiazol-5(4H)-one were reacted according to General Method 7. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 45 mg (46% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCn4ccnn4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (54 mg, 45%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:5][C:4]=1[C:28]1[NH:32][C:31]2[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:30]=2[N:29]=1>O1CCOCC1>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:30]2[N:29]=[C:28]([C:4]3[CH:5]=[C:6]([C:9]4[CH:10]=[N:11][C:12]([N:15]5[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]5)=[CH:13][CH:14]=4)[CH:7]=[N:8][C:3]=3[NH2:2])[NH:32][C:31]=2[CH:33]=1
Reactant: COc1ccc2nc(-c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc3N)[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2nc(-c3cc(-c4ccc(N5CCNCC5)nc4)cnc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3 ml of 4M HCl in dioxane are added to tert-butyl 4-[6′-amino-5′-(6-methoxy-1 H-benzimidazol-2-yl)-[3,3′]bipyridinyl-6-yl]piperazine-1-carboxylate, and the mixture is stirred at room temperature for 14 h. The reaction mixture is evaporated to dryness, and water is added. The aqueous phase is adjusted to pH>10 using 2N NaOH and extracted 3× with ethyl acetate. The organic phases are dried using sodium sulfate, filtered and evaporated. The residue is purified by means of RP-HPLC and lyophilised, giving 5-(6-methoxy-1H-benzimidazol-2-yl)-6′-piperazin-1-yl-[3,3′]bipyridinyl-6-ylamine as free base; HPLC-MS [M+H]+ 402.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.C([N-]C(C)C)(C)C.[Li+].[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>C1COCC1>[Cl:19][CH2:9][C:4]1[O:3][C:2]([CH3:10])([CH3:1])[O:7][C:6](=[O:8])[CH:5]=1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C=C(CCl)O1
Temperature: -25 °C
Yield: 81.9 %

Procedure:
A solution of 2,2,6-trimethyl-1,3-dioxin-4-one (16.0 g, 0.11 mol) in THF (50 ml) was added dropwise over 20 min to a solution of lithium diisopropylamide (75 ml, 2.0 M solution in heptane/THF/ethylbenzene, 0.15 mol) at the temperature of −78° C. During the addition, a fine yellow suspension formed. Subsequently, the enolate solution was stirred at −78° C. for another 1 h and then cannulated to a solution of hexachloroethane (39 g, 0.16 mol) in THF (200 ml) at −50° C. over 30 min. The resulting reaction mixture was then allowed to warm slowly to −25° C., and poured into ice-cold aqueous 10% hydrochloric acid (200 ml). The organic layer extracted with ether was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 15.9 g of yellow oil. The product was used without further purification. 1H NMR (CDCl3, ppm): δ 5.57 (s, 1H), 4.00 (s, 2H), 1.96 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.P(Cl)(Cl)(Cl)=O.O.CN([CH:21]=[O:22])C>>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Cn1nc(C(F)(F)F)cc1O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
Into 16.6 g (100.0 mmol) of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole in 15.4 g of N,N-dimethylformaldehyde was added 16.2 g (105.0 mmol) of phosphorus oxychloride at 0° C., followed by 1 hour of stirring at room temperature. Furthermore, the whole was stirred at 100° C. for 1 hour. After the completion of the reaction was confirmed, the reaction solution was poured into water and the pH was made 10 or more with a 25% sodium hydroxide solution and then the aqueous layer was washed with ethyl acetate. The pH of the resulting aqueous layer was made about 4 with a saturated citric acid solution and then extracted with diethyl ether. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.5 g (yield: 23.2%) of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:32][CH2:33][CH3:34])/[CH:13]=[C:14](/[CH2:16][CH2:17][CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][C@@H:24]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:25])[CH3:20])\[CH3:15]>C(Cl)Cl>[CH2:12]([S:32]([CH2:33][CH3:34])=[O:9])/[CH:13]=[C:14](/[CH2:16][CH2:17][CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][C@@H:24]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:25])[CH3:20])\[CH3:15]
Reactant: CCSC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)C/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
5.1 g of m-chloroperbenzoic acid was added to a solution of 10.0 g of ethyl phytyl thioether dissolved in 30 ml of methylene chloride. The resulting mixture was stirred for 2 hours at room temperature. After the completion of the reaction, the reaction mixture was washed with 2% aqueous sodium hdyrogensulfite solution, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane:ethyl acetate =9:1) to obtain 9.4 g (yield: 90%) of oily ethyl phytyl sulfoxide.