Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:41](=[O:63])[C:42]([C:45]([N:47]3[CH2:52][CH2:51][N:50]([C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:54])[CH2:49][CH2:48]3)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:64])=[C:28]([CH:65]([CH3:67])[CH3:66])[NH:27][N:26]=1)(=O)C.C[O-].[Na+]>CO>[CH2:56]([O:55][C:53]([N:50]1[CH2:51][CH2:52][N:47]([C:45]([C:42]([CH3:44])([CH3:43])[C:41]([NH:40][CH2:39][CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:30][C:29]3[C:25]([O:24][C@@H:6]4[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]4[OH:4])=[N:26][NH:27][C:28]=3[CH:65]([CH3:67])[CH3:66])=[C:32]([CH3:64])[CH:33]=2)=[O:63])=[O:46])[CH2:48][CH2:49]1)=[O:54])[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCNC(=O)C(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.14 g) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 0.015 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give 4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole (70 mg). This material was dissolved in methanol (4 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (54 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Br)cc32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].[Br:9][C:10]1[N:11]=[N:12][C:13](Br)=[CH:14][CH:15]=1.[H-].[Na+]>C1COCC1>[Br:9][C:10]1[N:11]=[N:12][C:13]([O:6][C:4]([CH3:7])([CH3:5])[CH2:3][N:2]([CH3:8])[CH3:1])=[CH:14][CH:15]=1
Reactant: CN(C)CC(C)(C)O
Reactant: Brc1ccc(Br)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CC(C)(C)Oc1ccc(Br)nn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
In a 100 mL round bottom flask was added 1-(dimethylamino)-2-methylpropan-2-ol (1.48 g, 12.6 mmol, Eq: 1.5), THF and 3,6-dibromopyridazine (2 g, 8.41 mmol, Eq: 1.00). The flask was cooled to 0° C. followed by addition of NaH (572 mg, 14.3 mmol, Eq: 1.7) in one portion. The turbid reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. The resultant black reaction mixture was absorbed onto silica gel and purified by LC chromatography eluting with 0-5% MeOH in 1/1 EtOAc/Hex to afford 1.5 g (65%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:42][C:43]1[C:51]2[C:50]([N:52]3[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]3)=[N:49][CH:48]=[N:47][C:46]=2[NH:45][CH:44]=1>CN(C)C=O>[CH3:42][C:43]1[C:51]2[C:50]([N:52]3[CH2:57][CH2:56][CH:55]([NH:58][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:9])[CH2:54][CH2:53]3)=[N:49][CH:48]=[N:47][C:46]=2[NH:45][CH:44]=1
Reactant: O=C(O)c1ccncc1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4ccncc4)CC3)c12
Reaction time: 18 h

Procedure:
To a solution of 4-pyridinecarboxylic acid (59.8 mg, 0.486 mmol), EDC.HCl (115 mg, 0.598 mmol), HOBt (92 mg, 0.598 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.934 mmol) in N,N-dimethylformamide (1 mL), stirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride (100 mg), DU, and the reaction stirred for 18 h. The solvent was removed in vacuo and the mixture purified by high pH MDAP to give the title compound E27 (45 mg). 1H NMR (d6-DMSO) δ 11.53 (1H, s), 8.72 (2H, d), 8.66 (1H, d), 8.22 (1H, s), 7.78 (2H, d), 7.07 (1H, s), 4.09 (1H, m), 4.02 (2H, d), 3.06 (2H, t), 2.37 (3H, s), 1.95 (2H, d), 1.74 (2H, ddd), MS(ES+) 337 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[CH:12]1>C(Cl)(Cl)Cl>[C:5]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]2[NH:25][CH:24]=[CH:23][N:22]=2)=[CH:12]1)(=[O:7])[CH3:6]
Reactant: NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Reaction time: 0.17 h
Yield: 47 %

Procedure:
Acetic anhydride (0.20 g) was added dropwise to a stirred solution of 1-(2-aminoethyl)-3-(1-imidazolylmethyl)indole (0.48 g) in dry chloroform (10 ml) at room temperature. The solution was stirred for 10 minutes and then evaporated. The residue was stirred with aqueous sodium bicarbonate solution and the solid product was filtered off, washed with water, dried and crystallised from ethyl acetate/petrol (b.p. 60°-80° C.) to give 1-(2-acetylaminoethyl)-3-(1-imidazolylmethyl)indole (0.26 g), m.p. 126°-128° C. Found: C, 68.08; H, 6.43; N, 20.17. C16H18N4O requires: C, 68.06; H, 6.43; N, 19.85%.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26](Cl)=O.O=P(Cl)(Cl)Cl>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COc1ccc(CCC(=O)Cl)c(OC)c1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)c(OC)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), 2,4-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.013 mg (3.7%); MS m/z: 351.3[M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 2.97-3.00 (m, 2H); 3.11-3.13 (m, 2H); 3.71 (s, 6H); 6.41-6.43 (m, 1H); 6.51 (br s, 1H); 7.06-7.08 (m, 1H); 7.75-7.77 (m, 1H); 7.81-7.83 (m, 1H); 8.15 (br s, 1H); 8.43 (s, 1H); HPLC (METHOD [A]): rt 12.06 min (100%)
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCCOCOCCCCCCCCCCCC(O)=O.[CH:47]1([N:53]=[C:54]=[N:55][CH:56]2[CH2:61][CH2:60][CH2:59]CC2)CCCCC1>O1CCCC1>[CH3:1][N:53]([C:54]1[CH:59]=[CH:60][CH:61]=[CH:56][N:55]=1)[CH3:47]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COCCOCOCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 856 mg of 12-(methoxyethoxymethoxy)dodecanoic acid, 6 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 893 mg of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].CNNC.[CH3:29][N:30](C=O)[CH3:31]>O>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:30]([CH3:31])[CH3:29])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Reactant: CN(C)C=O
Agent: CNNC
Solvent: O
Product: CN(C)c1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1
Yield: 25 %

Procedure:
A solution of 3-cyano-1-[4-fluoro-benzoyl]-pyrrolo[1,2-a]quinoline (56 mg, 0.18 mmol) and dimethylhydrazine (118 mg, 1.96 mmol) in DMF (5 mL) was refluxed for 24 h. It was diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried, concentrated and the residue was purified by column chromatography (EtOAc/Hexane 6:1) to give 15 mg (25%) of the title compound. 1H NMR (CDCl3): 8.11–8.05–7.95 (m, 3H), 7.82–7.78 (m, 2H), 7.63–7.42 (m, 4H), 7.31 (s, 1H), 6.75 (d, J=9.30 Hz, 2H), 3.14 (s, 6H). MS, 340 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:23]=[C:22]2[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][C:22]4[C:21]5[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=5)[N:25]=[CH:24][CH:23]=4)=[CH:33][CH:34]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 22.5 °C
Reaction time: 10 h

Procedure:
The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30° C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25° C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25° C. and then at approximately 45° C. under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:31])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[C:21]([C:20]([OH:31])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C#Cc1ccc(Cl)c(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (262.5 g, 1.06 mol) in CH2Cl2 (0.6 l) was added dropwise over 60 min to a solution of (3,4-dichloro-phenyl)-propynoic acid ethyl ester (172.0 g, 0.71 mol) and trifluoroacetic acid (5.4 ml, 0.07 mol) in CH2Cl2 (0.7 l). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then evaporated to dryness, and the residue was dissolved in dioxane (1.6 l). An aqueous solution of NaOH (1.0 l, 1.9 mol, 2.8 eq.) was added. The resulting emulsion was stirred at r.t. for 20 h, and the low boiling organic solvent was removed under vacuum. Water (2.0 l) was added, and the aqueous layer was separated and washed with TBME (2 times 1.2 l). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was then stirred overnight, and the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 205.0 g (83%) of IIb as a white solid.
Reaction SMILES: C([N:4]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Br)=[CH:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=O)C.Cl[C:20]1[N:21]=[C:22]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[C:23]2[S:28][C:27]([CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]3)=[CH:26][C:24]=2[N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:5]([NH:4][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:20]2[N:21]=[C:22]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)[C:23]3[S:28][C:27]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]4)=[CH:26][C:24]=3[N:25]=2)=[CH:10][N:9]=1)(=[O:7])[CH3:6]
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC(=O)N(C(C)=O)c1ncc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)c2ccccc12
Temperature: 60 °C
Yield: 18.3 %

Procedure:
Following General Procedure B of Suzuki coupling, N-acetyl-N-(4-bromoisoquinolin-1-yl)acetamide (57 mg) was reacted with 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (107 mg). After reaction completion, 1 M Na2CO3 (2 mL) and 1,4-dioxane (2 mL) were added to the mixture. The suspension was heated at 60° C. for 3 h. The reaction mixture was concentrated. Water (5 mL) was added. The contents were extracted with DCM (2×10 mL) The combined DCM solutions were dried (Na2SO4). The crude was purified with reverse-phase HPLC to give 144 (20 mg, 22%). LCMS: M+H+=589. 1H NMR (400 MHz, CDCl3) δ 8.86 (2H), 8.07 (, s, br, 2H), 7.75 (t, J=7.7, 1H), 7.64 (t, J=7.6, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 5.18 (s, 1H), 4.12-4.00 (m, 4H), 3.94-3.81 (m, 6H), 2.62 (s, 8H), 2.44 (s, 3H), 1.25 (s, 6H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:18]([CH3:19])[C:17]2[C:20]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=1.[C-:31]#[N:32].[K+]>CS(C)=O.O>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([NH:13][C:14]2[N:18]([CH3:19])[C:17]3[C:20]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)=[C:6]([CH:11]=1)[O:5][CH:4]([CH2:3][CH3:2])[C:31]#[N:32]
Reactant: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCCCBr)n(C)c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OC(C#N)CC)n(C)c12
Temperature: 25 °C
Yield: 106.5 %

Procedure:
To a solution of 80 mg (0.16 mmol) of N2-[2-(3-bromopropoxy)-4-chlorophenyl]-1-methyl-N7,N7-dipropyl-1H-benzimidazole-2,7-diamine in 2 mL of dimethylsulfoxide was added 13 mg (0.19 mmol) of potassium cyanide. The reaction was stirred at room temperature for several hours, diluted with 10 mL water, and extracted twice with 10 mL ethyl acetate. The organics were washed with water, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography eluting with a solution of 20% acetone/hexanes to give 75 mg (100%) of the title compound.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]([C:21]1[C:22](O)=[N:23][C:24]2[C:29]([C:30]=1[CH3:31])=[CH:28][CH:27]=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)=[O:20])[CH3:17].CCN(CC)CC>C(Cl)Cl>[CH2:16]([O:18][C:19]([C:21]1[C:22]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[N:23][C:24]2[C:29]([C:30]=1[CH3:31])=[CH:28][CH:27]=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:25]=2)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
840 μl (5.0 mmol) trifluoromethanesulphonic acid anhydride was added in drops at 0° C. to a solution of 1.0 g (3.3 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester and 930 μl (6.7 mmol) NEt3 in DCM (30 ml). After 4 h of stirring at RT, the mixture was diluted with DCM (30 ml) and washed with water, a sat. aq. NaHCO3 sol. and brine. The organic phase was dried over Na2SO4 and concentrated in a vacuum. 1.32 g (3.1 mmol, 92%) 4-methyl-7-(trifluoromethyl)-2-(trifluoromethyl-sulfonyloxy)quinoline-3-carboxylic acid ethyl ester was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.C(N(CC)C(C)C)(C)C.[NH:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>C(#N)C>[CH3:29][C:12]1[S:11]/[C:10](=[N:9]\[C:8]([N:40]2[CH2:44][CH2:43][CH2:42][CH:41]2[C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[O:30])/[N:14]([C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:25])([F:26])[C:21]([F:23])([F:24])[O:22][C:17]=3[CH:16]=2)[CH:13]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: c1cncc(C2CCCN2)c1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CCCC2c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide core (Example 81A, 0.88 mL of 0.16 M in acetonitrile, 80 mg, 0.1 mmol) was added to a 20 mL vial, followed by N,N-diisopropylethylamine (0.88 mL of 0.2 M in acetonitrile, 24 mg, 0.13 mmol). 3-(Pyrrolidin-2-yl)pyridine (0.79 mL of 0.2 M in acetonitrile, 0.11 mmol) was added last. The resulting mixture was shaken at room temperature overnight. It was then concentrated in vacuo, and the residue was taken up in 1:1 MeOH/DMSO and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method) to give the titled compound. 1H NMR (300 MHz, DMSO-d6/D2O) δ ppm 1.74-1.93 (3H) 2.12-2.21 (3H) 2.33-2.44 (1H) 3.50-3.68 (2H) 4.95-5.07 (1H) 6.91-7.06 (1H) 7.21-7.59 (3H) 7.70-7.91 (1H) 8.33-8.42 (1H) 8.44-8.52 (1H); MS (ESI+) m/z 495 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.Cl[C:18]1[CH:23]=[CH:22][C:21]2=[N:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH3:40])=[C:31]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:32]=3)=[CH:26][N:20]2[N:19]=1>C(O)CCC>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([NH:33][C:31]1[CH:32]=[C:27]([C:25]2[N:24]=[C:21]3[N:20]([CH:26]=2)[N:19]=[C:18]([N:14]2[CH2:15][CH2:16][CH:12]([NH:11][CH3:10])[CH2:13]2)[CH:23]=[CH:22]3)[CH:28]=[CH:29][C:30]=1[CH3:40])=[O:39]
Reactant: CNC1CCNC1
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC1CCN(c2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)C1
Temperature: 180 °C
Yield: 14.8 %

Procedure:
An small microwave vial is charged butanol (0.183 mL), diisopropylethylamine (0.122 mL, 0.7 mmol), N-methylpyrrolidin-3-amine (0.050 g, 0.5 mmol), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.0397 g, 0.1 mmol). The vial is sealed and heated at 180° C. for 30 min in microwave. The mixture is concentrated, taken up in DMSO and purified on reverse phase preparative HPLC with gradient (15% B:85% A to 100% B, where solvent A=95% water, 5% acetonitrile and 0.1% TFA; solvent B=90% acetonitrile, 10% water and 0.1% TFA) to give the title compound (0.006 g, 15% yield). LCMS m/z=407.6 [M+H]+, tR=1.32 min. (compound same as Example 360)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:15])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OCC(C)(C)C(=O)O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCC(C)(C)C(=O)Cl

Procedure:
A benzene solution (25 ml) of crude 3-acetoxy-2,2-dimethyl propionic acid from Example 3(a) (7.4 g, 46.5 mmol), oxalyl chloride (6.45 g, 51 ml) and DMF (2 drops) was stirred at ambient temperature for 3 hours. The pale yellow solution was distilled to provide the title compound as a colorless liquid, b.p.15 85°-88° C. NMR (CDCl3) δ4.18 (2H, s), 2.08 (3H, s), 1.35 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:39](=[O:40])[C:38]2[CH:42]=[CH:43][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:36][CH:37]=2)=[CH:22][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl{2-[(4-aminophenyl)ethynyl]-4-chlorophenoxy}acetate (Intermediate 222; 72 mg; 0.20 mmol) and triethylamine (83 μl; 0.60 mmol) in DCM (2 ml) was treated with 4-(trifluoromethyl)-benzoyl chloride (30 μl; 0.20 mmol). After stirring at RT for 1 hour, the reaction was quenched with a saturated aqueous ammonia solution (1 mL). EtOAc and a saturated NH4Cl solution in water were added, the phases separated and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound.