Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](OCC)=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:30][NH2:31]>O>[CH3:30][NH:31][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CN
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)NC
Temperature: 70 °C

Procedure:
A mixture of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (2.0 g, 6.1 mmol), THF (10 mL), and methylamine (available as a 40% solution in water, 4 mL, 52 mmol) was sealed in a high-pressure vessel and heated at 70° C. overnight. An analysis by TLC indicated the presence of starting material, and the reaction was sealed and heated at 80° C. for nine hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The resulting solution was washed with 5% aqueous sodium hydroxide (2×25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 1.83 g of N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH2:23]O)[CH:20]=[CH:21][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[N:8]2[CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: OCc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc2ccc(F)cc2[nH]1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: COC(=O)c1cc2ccc(F)cc2n1Cc1cccc(C(F)(F)F)c1
Yield: 81.7 %

Procedure:
This compound was prepared according to a process similar to that described in step 16.1, by reacting 475 mg (2.459 mmol) of methyl 6-fluoro-1H-indole-2-carboxylate with 0.67 mL (4.918 mmol) of 3-trifluoromethylphenylmethanol in the presence of 1.18 g (4.918 mmol) of cyanomethylenetributylphosphorane (CMBP). The crude reaction product is then purified by chromatography on a column of silica in a mixture of heptane and ethyl acetate, to give 706 mg of the expected product in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]1)[CH3:2].[C:25]([O:29][C:30](=[O:44])[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([N:40]=[C:41]=S)[C:34]=1[Cl:43])([CH3:28])([CH3:27])[CH3:26].CC(C)N=C=NC(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([F:22])([F:21])[F:23])[CH2:16][CH2:15]2)=[CH:7][C:8]2[N:12]([CH3:13])[C:41]([NH:40][C:35]3[C:36]([Cl:39])=[CH:37][CH:38]=[C:33]([CH2:32][NH:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:44])[C:34]=3[Cl:43])=[N:11][C:9]=2[CH:10]=1)=[O:24])[CH3:2]
Reactant: CCOC(=O)c1cc(N)c(NC)cc1N1CCC(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)OC(C)(C)C)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1

Procedure:
The title compound is prepared in analogy to 1e from ethyl-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoate (compound 52b, 4.31 g, 12.5 mmol), (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (compound B; 4.16 g, 12.5 mmol), DIC (2.17 mL, 15.4 mmol) and DMF (50 mL). Yield: 6.9 g. HPLC Rt=1.49 min (method A). MS m/z: 644 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:6](=[O:21])[N:5]([CH2:22][CH3:23])[C:4]=2[N:3]=1.O.[OH-].[Li+]>CO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:6](=[O:21])[N:5]([CH2:22][CH3:23])[C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCCn1c(=O)c2[nH]c(Cl)nc2n(CC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Temperature: 40 °C
Reaction time: 17 h
Yield: 94.4 %

Procedure:
A solution of ethyl 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (2.3 g, 6.7 mmol) in methanol (75 ml) was treated with water (3 ml) and lithium hydroxide (0.481 g, 20.1 mmol) and the mixture stirred at 40° C. for 17 h. The mixture was evaporated to dryness and the residue treated with 50 ml of ethyl acetate and 50 ml of water. The 2 phases were separated and the aqueous phase adjusted to pH5 using 2M aqueous hydrochloric acid. The precipitated product was filtered off and dried to yield 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid as a white solid (1.99 g, 95%).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Reactant: C1CCNC1
Agent: Cl
Product: O=C(c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1)N1CCCC1
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 1 from 5-(3-piperidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride and pyrrolidine to give the desired product as a colorless solid (70%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH3:16].CO>>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:16])=[N:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cccc(Br)n2)COCC(=S)N1
Reactant: N
Solvent: CO
Product: CC1(c2cccc(Br)n2)COCC(N)=N1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 5-(6-bromo-pyridin-2-yl)-5-methyl-morpholine-3-thione (1.4 g, 4.88 mmol) in 7N NH3/MeOH (20.89 ml, 146 mmol) was stirred at 50° C. for 3 d in an autoclave. The reaction mixture was evaporated to dryness and purified by FC (gradient cyclohexane:EtOAc 75:25 to 50:50, then +10% Et3N, finally MeOH+10% Et3N) to obtain the crude title compound that was further purified by washing with DCM. HPLC RtH4=0.54 min; ESIMS: 270, 272 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.51 (br s, 2H), 7.83-7.79 (m, 1H), 7.63-7.61 (m, 2H), 4.45 (s, 2H), 4.11 (d, 1H), 3.84 (d, 1H), 1.51 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]1[CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:37])[CH3:36])[CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])=[O:26]>CO.ClCCl>[O:1]=[C:2]1[C:7]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:3]1[CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:37])[CH3:36])[C:29](=[O:34])[C:30]([F:32])([F:31])[F:33])=[O:26]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Cc2ccccc2)c1=O)C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Cc2ccccc2)c1=O)C(=O)C(F)(F)F

Procedure:
Using a similar procedure to that described in Example 1, using methanol:dichloromethane (1:99) as the chromatography solvent, 2-(2-oxo-6-phenyl-3-phenylacetylamino-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was oxidized to afford the title product; HPLC: tR =6.92, FR=2.0, column A, water:acetonitrile (55.45); MS: m/z=514(M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([Br:10])=[C:7]([Br:9])[N:8]=1.I[CH2:12][CH3:13]>CN(C=O)C>[Br:3][C:4]1[N:5]([CH2:12][CH3:13])[C:6]([Br:10])=[C:7]([Br:9])[N:8]=1
Reactant: Brc1nc(Br)c(Br)[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(Br)nc(Br)c1Br
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (2.40 g, 60% mineral oil suspension, 60 mmol) in anhydrous DMF (50 ml) is added a solution of 2,4,5-tribromoimidazole (15.09 g, 50 mmol) in DMF (30 ml) at rt. The resulting mixture is stirred at 50° C. for 1 hr, and then cooled to 0° C., followed by the dropwise addition of iodoethane (8.19 g, 52.5 mmol, 1.05 eq.). The mixture is stirred at rt for 1 hr, and then heated to 50° C. for an additional 8 hr. The reaction mixture is cooled to rt, and poured into ice-water (200 ml). The mixture is extracted with EtOAc (100 ml×3). The combined organic layers are washed with water, brine, dried over anhydrous sodium sulfate, filtered, and solvent evaporated at reduced pressure. The crude product is purified by flash chromatography on silica gel to give the title product. LCMS 330 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH2:6]
Reactant: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CN)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[3-ethyl-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.24 g, 0.46 mmol) in DCM (5 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature 1 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:36](O)[CH:37]([CH3:39])[CH3:38].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:36][CH:37]([CH3:39])[CH3:38])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added isobutanol (0.03 mL, 0.33 mmol), and NaH (0.0132 g, 0.33 mmol). The resulting solution was stirred under nitrogen for 1 hour. The reaction was poured into H2O and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The crude solid was purified using flash chromatography (SiO2, 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.1088 g 76%). mp 166–169° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.84 (m, 1H), 3.29 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.51–7.63 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 433 (M+H)+, 450 (M+NH4)+. Anal. calc. for C21H21ClN2O4S: C, 57.07; H, 5.01; N, 6.33. Found: C, 57.06; H, 4.78; N, 6.13.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:31]5[CH:32]=[CH:33][C:28]([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)=[CH:29][CH:30]=5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound, white solid (117 mg, 92%), MS (ISP) m/z=511.6 [(M+H)+], mp 220.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and biphenyl-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:21](N1CCOCC1)(=[O:24])[CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(=O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
Under argon, 7.00 g (30.6 mmol) of tert-butyl(6-chloropyridin-2-yl)carbamate (Example 3A) were initially charged in 90 ml of THF and cooled to −50° C. 47.8 ml (76.5 mmol) of butyllithium (1.6 M in hexane) were added dropwise. After the dropwise addition had ended, the reaction was slowly warmed to 0° C. and kept at 0° C. for 1 h. The mixture was then cooled again to −40° C., and 9.85 g (61.2 mmol) of N-propionylmorpholine dissolved in 10 ml of THF were added. The reaction solution was stirred at −40° C. for another 1 h and then, at −40° C., poured into 1 l of ethyl acetate and 350 ml of ammonium chloride solution, and the organic phase was separated off and washed with water and saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The crude product was chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 1:1). This gave 2800 mg (32% of theory) of the product.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=O)C>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:27]4[CH2:31][CH2:30][NH:29][C:28]4=[O:32])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)nn3)CC2)c(C)c1
Yield: 12.2 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and 1-acetylimidazolidin-2-one (87 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (21 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:12])OC(C)=C.[Br:13][C:14]1[C:15]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[C:16]2[N:22]=[C:21]([C:23]3[CH:31]=[CH:30][C:26]([N:27]([CH3:29])[CH3:28])=[CH:25][CH:24]=3)[NH:20][C:17]2=[N:18][CH:19]=1.CN1CCCC1>C1COCC1>[Br:13][C:14]1[C:15]([N:32]2[CH2:33][CH2:34][N:35]([C:7]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:12])[CH2:36][CH2:37]2)=[C:16]2[N:22]=[C:21]([C:23]3[CH:31]=[CH:30][C:26]([N:27]([CH3:29])[CH3:28])=[CH:25][CH:24]=3)[NH:20][C:17]2=[N:18][CH:19]=1
Reactant: C=C(C)OC(=O)Nc1nccs1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCNCC4)c(Br)cnc3[nH]2)cc1
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A solution of prop-1-en-2-yl thiazol-2-ylcarbamate (prepared according to the procedure described in J. Org. Chem. 2005, 70, 6960-6963) (40 mg, 0.054 mmol) and 4-(6-bromo-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-N,N-dimethylaniline (1.0 eq, 0.054 mmol, 22 mg) in THF (0.5 mL) was heated to 55° C. Then N-methylpyrrolidine (0.1 eq, 0.005 mmol, 5 μL) was added and the mixture stirred at 55° C. for 2 h. Concentration in vacuo gave crude material as a solid. A small sample was purified by semi-preparative hplc to give the pure product as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 2.99 (s, 6H, N(CH3)2), 3.58-3.62 (m, 4H, piperazine N(CH2)2), 3.74-3.78 (m, 4H, piperazine N(CH2)2), 6.81 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 7.22 (d, J=3.6 Hz, 1H, thiazole H-4 or H-5), 7.35 (br s, 1H, NH), 7.48 (d, J=3.6 Hz, 1H, thiazole H-4 or H-5), 8.02 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:40]([CH2:42]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:41]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:42]=[N:40][CH:41]=2)[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3cnco3)c12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B, 200 mg, 0.441 mmol), potassium carbonate (63.9 mg, 0.463 mmol) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (90 mg, 0.463 mmol) were taken up in MeOH (1.8 ml) and were stirred at 65° C. overnight. The mixture was concentrated in vacuo while loading onto silica gel and purificied by MPLC 0-25% EtOAc/DCM to give 5-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)oxazole (54B). MS: [M+H]+ m/z 493.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:20]3)[C:14]([C:35](=[O:37])[NH2:36])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:53])[CH3:52])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1>O1CCOCC1>[C:51]([N:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:41]=[CH:40][C:39]([NH:38][C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:26])[CH2:20]4)[C:14]([C:35](=[O:37])[NH2:36])=[CH:13][N:12]=3)=[CH:44][CH:43]=2)[CH2:50][CH2:49]1)(=[O:53])[CH3:52]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCCN(C(=O)OCc5ccccc5)C4)n3)cc2)CC1
Reaction time: 3 h
Yield: 57.2 %

Procedure:
A mixture of benzyl 3-((2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (0.404 g, 0.805 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.220 g, 1.00 mmol) and pTsOH monohydrate (0.167 g, 0.879 mmol) in dioxane (8 mL) was stirred at 100 C for 3 h. The mixture was then purified by HPLC to give benzyl 3-((2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate 45 (0.270 g).
Reaction SMILES: CO.[I:3][C:4]1[C:5](=[O:35])[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C:13]=1[CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>[Cl-].[Na+].O>[I:3][C:4]1[C@H:5]([OH:35])[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C:13]=1[CH2:14][O:15][C:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)O[C@@H]2C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)=C(I)C(=O)[C@@H]2O1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(I)[C@@H]2O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Into a 500 L reactor was charged 100 L of methanol, followed by addition of 6 (9.7 kg) and CeCl3-7H2O (7.2 kg) in 1 kg portions over 0.5 hour. Temperature of the reaction mixture rose ˜5° C. during the addition. The reaction mixture was cooled down to −10° C., and NaBH4 (0.77 kg) was added in portions (˜150 g) over 1 hour resulting in strong H2 evolution with elevation of the reaction temperature. The transparent reaction mixture was then stirred for 2 hours at 0° C. until HPLC indicated complete conversion. Then 150 L of brine were added to result in white precipitates. The suspension was concentrated under vacuum to remove most of methanol and ethyl acetate (100 L) was added to the resulting residue and the mixture was stirred for 30 minutes. Then the organic layer was separated washed with brine (20 L) and dried over sodium sulfate, filtered and concentrated to dryness, and the residue was used directly in the next step. Sample from the reaction mixture and standard samples for compounds 6 and 7 were applied to a commercial silica gel TLC plate, with petroleum ether/ethyl acetate=4:1 as the mobile phase. 6 and 7 can be detected under UV254 or visualized using iodine treatment. The Rf for 6 was ˜0.55 while the Rf for compound 7 was ˜0.57; 1H-NMR (300 MHz, CDCl3) δ 7.21-7.48 (m, 15H), 5.20 (d, J=5.7 Hz, 1H), 4.77 (t, J=5.7 Hz, 1H), 4.39 (dd, J=5.4, 11.2 Hz, 1H), 3.90 (d, J=12.0 Hz, 1H), 3.79 (d, J=12.0 Hz, 1H), 2.81 (d, J=11.2 Hz, 1H), 1.43 (s, 3H), 1.32 (s, 3H); 13C-NMR DEPT-135 (75 MHz, CDCl3) δ 128.79, 127.89, 127.11, 82.91, 78.14, 76.48, 62.58 (OCH2—), 27.54, 27.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].C([N:18](CC)CC)C.ClC(OCC)=O>C1COCC1.O>[C:5]([C:4]1[CH:3]=[C:2]([Cl:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=1)(=[O:6])[NH2:18]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(Cl)cc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a solution of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (72 g, 289 mmol) and triethylamine (40 mL) in THF (240 mL) at room temperature was added ethyl chloroformate (40 mL). The reaction mixture was stirred for 20 min at room temperature and filtered. To the filtrate was added (NH4)2CO3 (28 g, 292 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum-diethyl ether (5:1) to give methyl 4-carbamoyl-2,6-dichlorobenzoate (57 g, yield: 80%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 3H), 7.76 (s, 1H), 7.99 (s, 2H), 8.28 (s, 1H). LCMS (ESI) m/z: 248.0 [M+H+].