Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[O:14][CH3:15])#[N:2].[C:16]1([CH3:34])[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=[C:24]([C:30]([F:33])([F:32])[F:31])[N:23]=2)[CH:17]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([NH:29][CH2:28][C:27]2[C:22]([C:18]3[CH:17]=[C:16]([CH3:34])[CH:21]=[CH:20][CH:19]=3)=[N:23][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:25][CH:26]=2)=[O:12])=[CH:5][C:4]=1[O:14][CH3:15])#[N:2]
Reactant: COc1cc(C(C)C(=O)O)ccc1C#N
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
To a stirred solution of 2-(4-cyano-3-methoxyphenyl)propanoic acid (112 mg, 0.545 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (145 mg, 0.546 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (157 mg, 0.819 mmol), N-hydroxybenzotriazole (111 mg, 0.819 mmol) and triethylamine (0.19 mL, 1.36 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-Cyano-3-methoxyphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (222 mg) was obtained as 90% yield.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[CH3:13]I>O1CCCC1>[CH3:13][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: CI
Reactant: O=c1[nH]c2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)oc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
NaH (280 mg, 7.00 mmol) was added to a chilled (0° C.) solution of benzo[d]oxazol-2(3H)-one (650 mg, 4.81 mmol) in tetrahydrofuran (20 mL). After 0.5 hours, methyl iodide (1.03 g, 7.25 mmol) was added dropwise with stirring, maintaining a temperature of 0° C. The resulting solution was then stirred for 6 hours at room temperature. The reaction mixture was then quenched by the addition of ethanol (10 mL), and the mixture was concentrated. Water (50 mL) was then added and the resulting solution was extracted with dichloromethane (3×20 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated to afford 0.62 g (82%) of 3-methylbenzo[d]oxazol-2(3H)-one as a light red solid.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)([OH:17])[CH2:13][CH2:12]1)(OCC1C=CC=CC=1)=O.C1CCCCC=1>C(O)C.[Pd]>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]2([OH:17])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[CH:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: OC1(c2cccnc2)CCNCC1
Yield: 93.5 %

Procedure:
To a solution of 1-carbobenzyloxy-4-(3-pyridyl)piperidin-4-ol (described in example 87d) (3.17 g, 10.2 mmol) in ethanol (100 mL) was added 10% palladium on carbon (2.0 g). This was followed by cyclohexene (50 mL) in large excess. The reaction was heated to reflux under nitrogen for 2 h. The suspension was cooled, filtered and the catalyst rinsed with fresh ethanol. The filtrate was reduced in vacuo to yield 1.70 g (94%) of an off-white solid which did not require any additional purification. 1H NMR (D6 -DMSO, 300 MHz) 8.68 (d, J=2.0 Hz, 1H), 8.42 (dd, J=1.5, 4.6 Hz, 1H), 7.83 (ddd, J=1.9, 2.1, 4.0 Hz, 1H), 7.35 (dd, J=4.8, 8.0 Hz, 1H), 2.97 (ddd, J=2.3, 12.2 Hz, 2H), 2.78 (m, 2H), 1.86 (ddd, J=4.5, 12.9 Hz, 2H), 1.56 (m, 2H), 2.50 (m, 1H) MS (CI, CH4) m/z 179 (M+1,100), 207 (M+29,16), 161 (39)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[S:53]CC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][S:53][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: C1CSCCN1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCSCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and thiomorpholine and isolated as light-yellow gum (10.2 mg, 54%). MS(m/e): 403.4 (MH+).
Reaction SMILES: [CH3:1][C@:2]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:3]2=[O:4].C(OCC)(OCC)OCC.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35](S(O)(=O)=O)=[CH:34][CH:33]=1.C(O)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:42]([O:14][C:13]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:2]2([CH3:1])[C@H:7]3[CH2:6][CH2:5][C:3]2=[O:4])[CH:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCc1ccccc1
Solvent: CCOC(OCC)OCC
Product: C[C@]12CCC(OCc3ccccc3)=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 12348.1 %

Procedure:
Androstenedione (5 g) was dissolved in dry benzene (100 ml). Triethyl orthoformate (3.25 ml) was added, followed by p-toluenesulphonic acid (20 mg) and the solution heated at 50° for 45 minutes. Benzyl alcohol (7.5 ml) and benzene (150 ml) were then added and the solution distilled until 150 ml of distillate had been collected. A few drops of pyridine were added and the solution evaporated under reduced pressure to give a yellow solid. This solid was recrystallised from ethanol to give 3-benzyloxy-androsta-3,5-dien-17-one (5.4 g) as white needles, M.p. 172°-178°.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.C(Cl)(=O)C(Cl)=O.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:9][O:8][C:1](=[O:7])/[CH:2]=[CH:3]/[C:4]([N:26]1[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]1)=[O:6]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
Mono methyl fumarate (650 mg, 5.0 mmol) was taken up in 10 mL of CH2Cl2 and oxalyl chloride (420 μL, 5.0 mmol) was added. After a few drops of DMF was added, the reaction mixture was stirred at room temperature until all gas evolution had ceased (1 h). This freshly prepared solution of acid chloride was then added dropwise at 0° C. to a solution containing Boc-piperazine (930 mg) and triethylamine (1.0 mL, 7.5 mmol) in 20 mL of CH2Cl2. The resulting reaction mixture was stirred at room temperature for 1 h and washed with brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 310 mg of (E)-tert-butyl 4-(4-methoxy-4-oxobut-2-enoyl)piperazine-1-carboxylate (21% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:7]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccccc2)cc1C#N
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture was prepared by adding 104 grams (1.1 moles) of phenol, 173 grams (1 mole) of 4-nitrophthalonitrile, and 207 grams of potassium carbonate in 1667 ml of dimethylformamide. The mixture was heated to 70° C. and mechanically stirred. Samples were taken of this reaction mixture periodically and analyzed by GLC. After five hours, the reaction was complete. The 4-phenoxyphthalonitrile was isolated by quenching the crude reaction mixture in ice water. The product was further purified by washing the crude precipitate with dilute sodium carbonate and then water. Finally the 4-phenoxyphthalonitrile was vacuum dried at 60° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-aminopentanoate hydrochloride (prepared from (S)-2-aminopentanoic acid (Novabiochem) using General Procedure H), the title compound was prepared as a solid (mp=154-155° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:35])[N:11]([CH2:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([S:38]P([O-])(OCC)=S)C.O>C1COCC1>[C:29]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][N:11]([CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10](=[O:35])[NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]([NH2:2])=[S:38])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N#Cc1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Reactant: CCOP([O-])(=S)SCC
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Temperature: 40 °C
Reaction time: 27 h

Procedure:
70 mg (0.15 mmol, 1 eq.) of 3-(3-cyanophenyl)-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea (obtained in Example 19) are dissolved in 0.5 mL of THF under argon. 142 μL (0.90 mmol, 6 eq.) of diethyldithiophosphate and 50 μL (0.01 mmol, 0.1 eq.) of water are added. The mixture is stirred for 27 hours at 40° C. Water is added to the medium and the aqueous phase is extracted with dichloromethane, washed twice with water then brine, dried over MgSO4, filtered and concentrated. The oil obtained is subjected to chromatography over silica gel (eluent: 97/3 dichloromethane/methanol) in order to obtain the expected product in the form of a yellow powder (55 mg, yield=73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:20]C)=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc2c(-c3cccc(F)c3)n[nH]c2cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
A total of 96.2 mg of 3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid obtained in Production Example II-1-e was dissolved in 3.36 ml of dichloromethane, 4.0 ml of a 1.0 M solution of boron tribromide in dichloromethane was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed brine, dried over magnesium sulfate and the solvent was evaporated, to give 84.1 mg of the crude product of the title compound.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]([NH2:19])=[O:18].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.Cl>CCO>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:19][C:17](=[O:18])[NH:16]2)=[CH:24][CH:23]=1
Reactant: NC(N)=O
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc1
Temperature: 85 °C
Yield: 102 %

Procedure:
A mixture of 1,2-diphenylethanone (1 g, 5.1 mmol), urea (1.22 g, 20.38 mmol), 4-methoxybenzaldehyde (0.76 g, 1.1 mmol) and conc. HCl (0.4 mL) in EtOH (100 mL) was heated at 85° C. for 108 h. The volatiles were removed under reduced pressure and the residue was purified by column chromatography to afford 4-(4-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one as a yellow solid (400 mg, 22%)
Reaction SMILES: [C-]#N.[Na+].[CH:4]1([NH:10]CCCS(O)(=O)=O)CCCCC1.[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].[O:30]([C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O.CCCCCCC>[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:41][CH:40]([C:4]#[N:10])[C:39]2[CH:42]=[CH:43][CH:44]=[C:37]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:38]=2)=[O:25])[C:22]1([CH3:28])[CH3:27]
Reactant: O=S(=O)(O)CCCNC1CCCCC1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
A stirred mixture of sodium cyanide (18.0 g, 0.36 mole) and 3-(cyclohexylamino)propanesulfonic acid (1.34 g, 0.006 mole) in 300 ml of water was warmed to 40°. During a one hour period, maintaining a reaction temperature of about 40°, a solution of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (71.7 g, 0.315 mole) and 3-phenoxybenzaldehyde (61.9 g, 0.3 mole) in 262.2 g of n-heptane was added. The mixture was then stirred at 40° for one additional hour, after which it was washed with an aqueous solution containing 20% sodium carbonate and then with water. The organic phase was separated from the mixture and the solvent removed by distillation under reduced pressure to give α-cyano-3-phenoxybenzyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][CH:7]([O:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)[CH3:8]>CO>[CH3:6][CH:7]([O:9][C:10]1[N:11]=[N:12][C:13]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:14][CH:15]=1)[CH3:8]
Reactant: CC(C)Oc1ccc(Cl)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OC(C)C)nn1

Procedure:
2.30 g(0.1 mol) of metallic sodium was dissolved in 150 ml of absolute methanol and then mixed with 9.28 ml(0.1 mol) of allylmercaptan. To this mixture was added 17.26 g(0.1 mol) of 3-(2-propoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:18])=[CH:9][C:10]=1[NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)=O.[NH3:19]>CO>[Cl:18][C:8]1[N:7]=[N:6][C:5]([C:3]([NH2:19])=[O:2])=[C:10]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:9]=1
Reactant: N
Reactant: COC(=O)c1nnc(Cl)cc1Nc1ccn(C)n1
Solvent: CO
Product: Cn1ccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reaction time: 16 h
Yield: 100 %

Procedure:
6-Chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid methyl ester (75 mg, 0.28 mmol) was suspended in 7M ammonia in methanol (3 mL). After 16 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide (70 mg, 100%) as an off-white solid which was used directly in the next step without purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.39 (s, 1H) 8.77 (br. s., 1H) 8.24 (s, 1H) 8.13 (br. s., 1H) 7.72 (d, J=2.3 Hz, 1H) 6.18 (d, J=2.3 Hz, 1H) 3.84 (s, 3H); LCMS (EI/CI) m/z: 253 [M+H].
Reaction SMILES: [C:1]([C:3]1[C:4]([S:13](=[O:16])(=[O:15])[NH2:14])=[C:5]([C:9](OC)=[O:10])[S:6][C:7]=1[CH3:8])#[N:2].NC1C(C#N)=C(C)SC=1C(OC)=O.O.[NH2:31][NH2:32]>C(O)C>[C:1]([C:3]1[C:4]([S:13]([NH2:14])(=[O:16])=[O:15])=[C:5]([C:9]([NH:31][NH2:32])=[O:10])[S:6][C:7]=1[CH3:8])#[N:2]
Reactant: NN
Reactant: COC(=O)c1sc(C)c(C#N)c1S(N)(=O)=O
Agent: COC(=O)c1sc(C)c(C#N)c1N
Solvent: O
Solvent: CCO
Product: Cc1sc(C(=O)NN)c(S(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-cyano-5-methyl-3-sulfamoyl-thiophene-2-carboxylate (2.9 g), prepared from methyl 3-amino-4-cyano-5-methyl-thiophene-2-carboxylate in analogy with known procedures, e.g. F. Junquera et al., Eur.J.Med.Chem. 23, 329 (1988), was suspended in 10 ml of ethanol. Hydrazine monohydrate (2 ml) was added and the mixture was stirred for 1 h at room temperature and then evaporated. The oily residue (3.3 g) was triturated with 10 ml of water and the precipitating crystals were collected by filtration, washed with water and dried to give the title compoundas yellow crystals (yield 1.62 g); m.p. 186-91° C.; 1H-NMR (DMSO-d6), δ(ppm): 7.25 (br, 5H, NH/NH2), 2.51 (s, 3H, CH3).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]3[NH:40][C:39]([C@@H:41]5[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]5C(OC(C)(C)C)=O)=[N:38][CH:37]=3)[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:46][C@@H:44]1[CH2:43][NH:42][C@H:41]([C:39]2[NH:40][C:36]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[CH:34][CH:35]=[C:26]([C:23]5[CH:22]=[CH:21][C:20]([C:17]6[NH:16][C:15]([C@@H:10]7[CH2:11][C@H:12]([CH3:14])[CH2:13][NH:9]7)=[N:19][CH:18]=6)=[CH:25][CH:24]=5)[CH:27]=4)[N:32]=3)=[CH:37][N:38]=2)[CH2:45]1
Reactant: C[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc5nc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)OC(C)(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CN[C@H](c2ncc(-c3ccc(-c4ccc5nc(-c6cnc([C@@H]7C[C@H](C)CN7)[nH]6)ccc5c4)cc3)[nH]2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 158 %

Procedure:
4M HCl (0.2 mL, 0.800 mmol) in dioxane was added to a solution of (2S,4S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinolin-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (16.6 mg, 0.024 mmol) in dioxane (1 mL) and the reaction mixture was stirred at rt for 3 d. The reaction mixture was concentrated to yield a crude HCl salt of 2-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline (19.1 mg) as yellow solid. LC-MS retention time 2.765 min; m/z 504.47 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[C:11][C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[C:19]3[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]3=[N:17][C:16]=4[NH2:27])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:30])C.[H][H]>[Pd].C(Cl)Cl>[O:30]1[C:9]2[CH:8]=[CH:7][C:6]([CH2:10][CH2:11][C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[C:19]3[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]3=[N:17][C:16]=4[NH2:27])=[CH:5][C:4]=2[CH2:3][CH2:2]1
Reactant: CCO
Reactant: [H][H]
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(C#Cc3ccc4[nH]ccc4c3)cc12
Agent: [Pd]
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc4c(c3)CCO4)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 2-((1H-indol-5-yl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1 eq.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 eq.). The content were vacuumed followed by hydrogen flush for three times. The reaction mixture was stirred vigorously under hydrogen balloon at room temperature overnight. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until the filtrate had no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product 2-(2-(2,3-Dihydrobenzofuran-5-yl)ethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (CDCl3): δ 8.54 (d, 1H), 8.34 (d, 1H), 8.28 (s, 1H), 7.99 (d, 1H), 7.64-7.56 (m, 1H), 7.50-7.35 (m, 1H), 7.24 (d, 1H), 7.12 (t, 1H), 7.08 (dd, 1H), 6.92 (dd, 1H), 6.41 (s, 1H), 6.01 (bs, 2H), 3.16-3.12 (m, 2H), 3.10-3.05 (m, 2H), 2.43 (s, 3H). LRMS [M+H]=353.2
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:23]=2[NH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21](=[O:20])[NH:22][C:23]=2[CH:29]=1)=[O:31]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2[nH]c(=O)[nH]c2c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid. MS: 420.3 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:27][CH2:26][NH:25][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCN1CCOCC1)c1n[nH]c2ccccc12
Yield: 24.3 %

Procedure:
Same procedure followed as described in Example 1. The following amounts were used: 1H-indazole-3-carboxylic acid (0.65 g, 4 mmol), 1,1 '-carbonyldiimidazole (0.65 g, 4 mmol) and 4-(2-aminoethyl)morpholine (0.52 mL, 4 mmol). The ethyl acetate extracts were evaporated to 0.468 g solid. Crystallization from ethyl acetate provided 0.267 g colorless crystals. Mass spectrum, m+ =274.