Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]([C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[CH:28]=1)=[O:23]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:33][C:30]3[CH:31]=[CH:32][C:26]4[O:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:28][C:27]=4[CH:29]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine, N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine and 2-methoxycarbonyl-5-aminobenzofuran were reacted to give N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine. LCMS: retn, time: 26.76 min.; purity: 97%; MS (m/e): 435 (MH+); 1H NMR (DMSO-d6): δ 9.41 (2H, sl), 8.27 (1H, s), 8.21 (1H, d, J=3.9 Hz), 7.98 (1H, m), 7.77-7.60 (3H, m), 7.37 (1H, t, J=8.1 Hz), 7.22 (1H, d, J=8.1 Hz), 3.98 (3H, s), 1.34 (9H, s).
Reaction SMILES: C1(C[O:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][CH2:16][CH:17]3[CH2:19][CH2:18]3)=[O:14])=[CH:11][CH:10]=2)C=CC=CC=1.[H][H]>[Pd].CC(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[O:14])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: O=C(OCC1CC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(OCC1CC1)c1ccc(O)cc1
Yield: 100 %

Procedure:
A mixture of 14 parts of (cyclopropylmethyl) 4-(phenylmethoxy)benzoate and 200 parts of 2-propanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 8.1 parts (100%) of (cyclopropylmethyl) 4-hydroxybenzoate as a residue (int. 4).
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.CC(C)=O.[CH3:15][O:16][CH:17]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]([N:24]=[C:25]=[O:26])[CH2:18]1>[OH-].[Na+].O>[CH3:15][O:16][CH:17]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]([NH:24][C:25](=[O:26])[NH2:10])[CH2:18]1
Reactant: COC1CC(N=C=O)CCC1C
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC1CC(NC(N)=O)CCC1C
Reaction time: 2 h

Procedure:
5 g of 4-(β-<3-methoxy-methoxy-thiophen-2-carbonamido>-ethyl)-benzenesulfonamide (melting point 160° - 162°C) were dissolved in 7 ml of 2N sodium hydroxide solution and 50 ml of acetone and 2.4 g of 3-methoxy-4-methylcyclohexyl-isocyanate (boiling at 90°C under a pressure of 10 mm of mercury) were added dropwise at 0° - 5° C. Then stirring was continued for 2 hours, then the whole was diluted with water, and any undissolved matter was filtered off, and the filtrate was acidified with dilute hydrochloric acid. The N-[4-(β-<3-methoxy-methoxy-thiophen-2-carbonamido> -ethyl)-benzenesulfonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea precipitating in crystalline form melted at 125° - 127° C after recrystallization from methanol.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:29])[CH2:26][C:27]#[N:28])[CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[Si](C)(C)C.[I-].[Na+]>C(#N)C>[O:29]=[C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]3[N:13]([C:9]([C:8]4[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][N:11]=3)[N:14]=2)[CH2:20]1)[CH2:26][C:27]#[N:28]
Reactant: COc1ncccc1-c1cnc2ccc(N[C@@H]3CCCN(C(=O)CC#N)C3)nn12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCC(=O)N1CCC[C@@H](Nc2ccc3ncc(-c4ccc[nH]c4=O)n3n2)C1
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 35.3 %

Procedure:
A mixture of 3-((3R)-3-{[3-(2-methoxypyridin-3-yl)imidazo[1,2-b]pyridazin-6-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (Preparation 3c, 58 mg, 0.15 mmol), chloro(trimethyl)silane (0.06 mL, 0.44 mmol) and sodium iodide (67 mg, 0.45 mmol) in acetonitrile (1.5 mL) was stirred at 80° C. for 50 minutes. The solvent was removed under reduced pressure and the residue was treated with water. The precipitate obtained was filtered, washed with more water and diethyl ether and dried in vacuo to give a solid that was purified by reverse phase chromatography (100% water to 1:1 water/(acetonitrile/methanol 1:1)) to yield the title compound (20 mg, 35%) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.[C:15](O)(=O)[CH3:16]>>[CH:3]([C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[OH:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:2][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:15][CH3:16]
Reactant: CC(=O)O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: Cl
Product: CCCCCCCCCCC=CC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
2.5 g (14.4 mmol) of 2-hydroxy-1,4-naphthoquinone was added to 50 ml of acetic acid, and 5.4 g (2.03 mol times relative to 2-hydroxy-1,4-naphthoquinone) of n-dodecylaldehyde and 7.5 g (1.4 mol times relative to 2-hydroxy-1,4-naphthoquinone) of concentrated hydrochloric acid were added as catalyst, and the reaction was conducted at 85° C. for two hours. The reaction solution thus obtained was cooled to about 5° C., whereby no crystal precipitated. Therefore, the reaction solution was poured into 300 ml of water and extracted with 200 ml of benzene. This organic layer was washed twice with 150 ml of a 1% sodium carbonate aqueous solution and once with 150 ml of water and dried over anhydrous sodium sulfate. Benzene was distilled off, and the obtained oil layer was purified by silica gel column chromatography to obtain 1.97 g of 2-(1-dodecenyl)-3-hydroxy-1,4-naphthoquinone. The yield was 40.2 mol %.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:25])=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=2)[C:14](=[O:26])[CH2:13][CH:12]1[CH3:27])=O)C1C=CC=CC=1>C(O)C.[Pd]>[F:25][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][C:18]=1[C:21]([F:22])([F:24])[F:23])[NH:11][CH:12]([CH3:27])[CH2:13][C:14]2=[O:26]
Reactant: CC1CC(=O)c2cc(F)c(C(F)(F)F)cc2N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1CC(=O)c2cc(F)c(C(F)(F)F)cc2N1
Reaction time: 1 h

Procedure:
6-Fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (3.0 g, 7.9 mmol) was combined with 250 mg of 10% Pd/C in 50 mL of ethanol and agitated under a hydrogen atmosphere (40 psi) for 1 hour before being filtered through Celite®, rinsing with ethyl acetate, and evaporating the volatiles under reduced pressure to afford 1.34 (69%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 1.4 (d, 3H), 2.5 (dd, 1H), 2.7 (dd, 1H), 3.7-3.9 (m, 1H), 4.4 (bs, 1H), 6.9 (d, 1H), 7.6 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[C:14]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[C:13]([CH3:31])=[CH:12][CH:11]=1)[CH3:7]>CN(C=O)C>[CH2:1]([NH:3][C:4]([N:28]1[CH2:29][CH2:30][CH:25]([C:20]2[C:19]3[C:23](=[CH:24][C:16]([C:14]4[CH:15]=[C:10]([C:9]([NH:8][CH2:6][CH3:7])=[O:32])[CH:11]=[CH:12][C:13]=4[CH3:31])=[CH:17][CH:18]=3)[NH:22][N:21]=2)[CH2:26][CH2:27]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4CCNCC4)n[nH]c3c2)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4CCN(C(=O)NCC)CC4)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl isocyanate (4 μL) was added to N-ethyl-4-methyl-5-[3-(4-piperidinyl)-1H-indazol-6-yl]benzamide (Intermediate 16, 20 mg) in DMF (3 mL) at room temperature under nitrogen and the reaction mixture was stirred at room temperature for 30 min. The product was concentrated under vacuum and the residue was purified by preparative HPLC to give the title compound as a white solid (13 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[C:28]([N:2]2[CH2:3][CH:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]=3)[CH2:5]2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Reactant: Clc1nccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccnc1N1CC(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 56.8 %

Procedure:
To a solution of 2-azetidin-3-yl-quinoline hydrochloride (1.70 g, 7.75 mmol) in DMF (30 mL) at room temperature was added Cs2CO3 (5.2 g, 16 mmol) and 2,3-dichloro-pyrazine (1.3 g, 9.0 mmol). The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (60 mL) and brine (60 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.30 g, 4.4 mmol, 58% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:8]=2[O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([S:17]([N:20](COC)[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)(=[O:19])=[O:18])=[C:12]([F:30])[CH:11]=2)=[CH:5][N:4](C2CCCCO2)[N:3]=1.CO.O>Cl>[NH2:1][C:2]1[C:6]([C:7]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:8]=2[O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([S:17]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)(=[O:19])=[O:18])=[C:12]([F:30])[CH:11]=2)=[CH:5][NH:4][N:3]=1
Reactant: COCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2cn(C3CCCCO3)nc2N)cc1F
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1n[nH]cc1-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 108.5 %

Procedure:
4-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamide (Preparation 887, 58 mg, 0.093 mmol) in methanol (1 mL, 20 mmol) and 2 M of hydrogen chloride in water (1 mL, 2 mmol) was heated at 60° C. for 2 hours then concentrated. The residue was liophilized from acetonitrile-water to give 50 mg of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C(OC([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)/[C:26](=[CH:34]/[C:35]2[CH:40]=[C:39]([Br:41])[CH:38]=[CH:37][C:36]=2[O:42][CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)/[C:25]1=[O:56])=O)(C)(C)C>C1(C)C=CC=CC=1>[Br:41][C:39]1[CH:38]=[CH:37][C:36]([O:42][CH:43]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]2)=[C:35]([CH:34]2[CH2:12][C:10](=[O:11])[NH:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:26]32[C:27]2[C:32](=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[NH:24][C:25]3=[O:56])[CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Reactant: C=C(N=Cc1cccc(F)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(F)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in example 36a (24 mmol) in toluene (100 mL) was added E/Z-3-[5-bromo-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.85 g, 6 mmol). The reaction mixture was stirred under argon at 140° C. for 5 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography (20%-30% EtOAc:DCM) to give the title compound as a off white solid (Yield: 0.38 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:18])([F:17])[F:19])=[N:14][N:15]=4)[CH:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Cl)cc4)CC3)cn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-chlorobenzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:35])([F:36])[F:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-trifluoromethyl-phenyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H25F3NO5 [M+H]+: 467.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[CH3:21][O:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]1[N:34]=[C:33]([NH2:35])[CH:32]=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][O:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]1[N:34]=[C:33]([NH:35][C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[N:5]=[C:6]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COCC1CCCN1c1cccc(N)n1
Reactant: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COCC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)OC)c3)nn3ccnc23)n1
Temperature: 100 °C
Yield: 36.3 %

Procedure:
A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (0.10 g, 0.3 mmol), 6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-amine (0.083 g, 0.4 mmol), Pd2(dba)3 (0.019 g, 0.033 mmol), BINAP (0.083 g, 0.134 mmol) and Cs2CO3 (0.326 g, 1.0 mmol) in dioxane (20 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:15) to afford methyl 3-(8-(6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (0.050 g) as a yellow solid. LC-MS: [M+1]+=459, tR=1.985 min. This contained some unidentified impurities and was used directly without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].ClS([N:25]=[C:26]=O)(=O)=O.CN(C)C=O.O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:17]=[CH:18][CH:19]=[C:20]2[C:26]#[N:25])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(COC(C)=O)cc(-n2cccc2)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(COC(C)=O)cc(-n2cccc2C#N)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-acetoxymethyl-5-(pyrrol-1-yl)benzoate (4.68 g) in dichloromethane (94 ml) was added chlorosulfonyl isocyanate (2.1 ml) at -20° C. under nitrogen. After being stirred for 1 hour at -20° C., to the reaction mixture was added N,N-dimethylformamide (14.0 ml) at -20° C. After being stirred for 1 hour at -20° C. to -10° C., the reaction mixture was poured into water and the product was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to afford methyl 3-acetoxymethyl-5-(2-cyanopyrrol-1-yl)benzoate (4.26 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:19]2[CH2:20][CH2:21][O:16][CH2:17][CH:18]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCOCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C2=CCOCC2)c(O)c(C(C)(C)C)c1
Reaction time: 60 h
Yield: 47.1 %

Procedure:
A mixture consisting of 21.9 g (0.106 mol) of 2,4-di-tert-butylphenol, 5.3 g (0.053 mol) of tetrahydro-4H-pyran-4-one and 5 ml of acetic acid is melted melted together and is then saturated, with stirring, with hydrochloric acid gas at 40-45° C. After standing for 60 hours at room temperature, the reaction mixture is diluted with toluene and washed with water, sodium chloride solution and sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is crystallised from methanol, giving 7.2 g (47%) of 2,4-di-tert-butyl-6-(3,6-dihydro-2H-pyran-4-yl)phenol, m.p. 135-139° C. (compound (103), Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:22])[C:20]=1[OH:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=[O:6].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:22])[C:20]=1[O:21][CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(O)c(Cl)c2)cc1
Reactant: BrCC1CC1
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OCC3CC3)c(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 103.5 %

Procedure:
Methyl 4-(3,5-dichloro-4-(cyclopropylmethoxy)benzamido)benzoate (6) (120 mg, 100%) was prepared from methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate (5) (100 mg, 294 μmol) and (bromomethyl)cyclopropane (57 μL, 588 μmol) using a procedure essentially the same as in Step (i) for AAA-001 except the mixture was stirred at 50° C. for 18 h: m/z 392 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 7.99 (4H, d), 7.85 (2H, d), 3.99 (2H, d), 3.90 (3H, s), 1.49-1.29 (1H, m), 0.65-0.60 (2H, m), 0.37-0.34 (2H, m).
Reaction SMILES: OC1C=CC(C(C)C#N)=CC=1.[N+]([O-])(O)=O.[N+:16]([C:19]1[CH:20]=[C:21]([CH:26]([CH3:29])[C:27]#[N:28])[CH:22]=[CH:23][C:24]=1[OH:25])([O-])=O.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[NH2:16][C:19]1[CH:20]=[C:21]([CH:26]([CH3:29])[C:27]#[N:28])[CH:22]=[CH:23][C:24]=1[OH:25]
Reactant: [H][H]
Reactant: CC(C#N)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC(C#N)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(C#N)c1ccc(O)c(N)c1

Procedure:
4-Hydroxy-phenyl-propionitrile is nitrated in glacial acetic acid with 65% strength nitric acid at 10°-15° C, in the course of 2 hours, the 3-nitro-4-hydroxyphenyl-propionitrile (melting point = 104° C) is reduced with hydrogen, using 5% strength palladium charcoal as the catalyst, in ethanol at room temperature to give 3-amino-4-hydroxyphenyl-propionitrile (melting point = 125° C) and the amine compound is acetylated in toluene with molar equivalent amounts of acetic anhydride. The 3-acetamino-4-hydroxyphenyl-propionitrile (melting point = 191°-192°) is slowly warmed to 250°-260° and then rapidly heated up to 300°. The melt is cooled to room temperature, the oil is taken up in an alkaline aqueous solution, the pH of which is adjusted to 10, and the water/oil emulsion is extracted by shaking with chloroform. The chloroform solution is separated from the aqueous phase, dried with sodium sulphate and concentrated. The pink-beige needle crystals thus obtained melt at 69°-70° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[C:13](=[O:15])[N:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:30][C@@H:31]([CH2:44][NH2:45])[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[OH:30][C@@H:31]([CH2:44][NH:45][CH:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([CH:16]=[C:12]3[S:11][C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:14][C:13]3=[O:15])=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(NCCN4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1N=C(NCCN2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(2-morpholin-4-ylethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 20) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.43 (t, J=4.7 Hz, 2 H), 2.50-3.70 (m, 13H), 3.59 (t, J=4.7 Hz, 2 H), 3.75-4.15 (m, 5H), 4.86 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.62 (d, J=7.5 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.38 (d, J=9.0 Hz, 2 H), 7.47 (s, 1 H), 9.47 (s, 1 H), 10.57 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 311.5 ((M+2H)2+, 100%); 621.9 (MH+, 15%); HRMS Calcd. for C31H40N7O5S (MH+): 622.2812. Found: 622.2811.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[C:11]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl.C(N(CC)CC)C>[Si:15]([O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH:2]=[O:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(CO)c1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1cccc(C=O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxymethylbenzaldehyde (step 1) (3 g) in methylene chloride (15 mL) and triethylamine (4.1 mL) was slowly added t-butylchlorodiphenyl silane (8 mL). Finally, a few mgs of 4-pyrrolidinopyridine was added as a catalyst. The reaction mixture was stirred overnight at room temperature (R.T.). The solution was quenched with 25% ammonium acetate and extracted with ethyl acetate, which was washed with brine (2×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography, using 4% ethyl acetate in hexane afforded the title compound.