Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21][C:22]#N)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].SC[C@@H]([C@@H](CS)O)O.IC>>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]([C@H:24]2[CH2:25][CH2:26][C@H:27]([CH3:30])[CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21][CH3:22])=[CH:19][N:20]=2)=[O:14])[CH2:10][CH2:11]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Solvent: CI
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and iodomethane.
Reaction SMILES: C1(S([N:10]2[CH2:15][CH:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:19])[CH:12]([CH2:20][O:21][CH3:22])[CH2:11]2)(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1.[ClH:30]>C1(C)C(C)=CC=CC=1>[ClH:30].[CH3:22][O:21][CH2:20][CH:12]1[CH2:11][NH:10][CH2:15][CH:14]([CH2:16][O:17][CH3:18])[N:13]1[CH3:19]
Reactant: COCC1CN(S(=O)(=O)c2ccccc2)CC(COC)N1C
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: COCC1CNCC(COC)N1C
Temperature: 140 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a mixture of the above described (2SR,6SR)-4-benzenesulfonyl-2,6-bis-methoxymethyl-1-methyl-piperazine (910 mg, 2.771 mmol) in xylene (20 ml) was added sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (2.154 ml, 7.065 mmol) and the mixture was stirred at 140° C. for 18 h. Cooled to 23° C., poured into 2 M HCl, extracted twice with tert-butyl methyl ether, the aqueous layer was made alkaline with 10 M NaOH-sol., extracted twice with tert-butyl methyl ether, the combined organic layer was dried over sodium sulfate, filtered, to the filtrate was added ethanol (5 ml) and chlorotrimethylsilane (ca. 0.5 ml) and all volatiles were removed in vacuum to give the title compound as a colorless oil (350 mg, 56%), MS (ISP) m/e=189.3 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH3:13])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[O:21])=[CH:18][C:17]=1I.C(NCC)C>[Cu](I)I>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[CH:33]=[CH:34][C:16]=1[NH2:15])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCN(C)C(=O)OC(C)(C)C
Reactant: COc1ccc(NC(=O)c2ccc(N)c(I)c2)cc1OC
Agent: I[Cu]I
Solvent: CCNCC
Product: COc1ccc(NC(=O)c2ccc(N)c(C#CCCCN(C)C(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500 mL round bottom flask was charged with methyl-pent-4-ynyl-carbamic acid tert-butyl ester (1.70 g, 8.62 mmol), 4-amino-N-(3,4-dimethoxyphenyl)-3-iodobenzamide (3.0 g, 7.53 mmol), copper iodide (0.225 g, 1.18 mmol), palladium tetrakistriphenylphosphine (0.93 g, 0.805 mmol), and diethylamine (258 mL) and the resulting mixture stirred at room temperature for 24 h. The resulting mixture was then concentrated in vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF40-400 g column, gradient 90:10-10:90 Heptane:EtOAc) to yield {5-[2-amino-5-(3,4-dimethoxy-phenylcarbamoyl)-phenyl]-pent-4-ynyl}-methyl-carbamic acid tert-butyl ester. MS (ES+) 468 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=1
Reactant: Nc1ccccn1
Reactant: Cc1ccnc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccnc(Nc2ccccn2)c1
Reaction time: 17 h
Yield: 77.3 %

Procedure:
2-Bromo-4-methylpyridine (0.195 mL, 1.74 mmol), 2-aminopyridine (180 mg, 1.91 mmol), potassium tert-butoxide (293 mg, 2.61 mmol), (±)-BINAP (4.3 mg, 6.96 mmol) and Pd2(dba)3 (4 mg, 4.35 mmol) were stirred in toluene (2.5 mL) at 90° C. under Ar(g). After 17 h stirring, the reaction mixture was diluted with CH2Cl2 (2.5 mL) and silica was added. The solvent was removed under reduced pressure and the resulting dry loaded material purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:1 to 100:2) to furnish I as a yellow solid (249 mg, 77%).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:26][C:27]1[S:31][C:30]([NH:32][C:33]2[C:38]([Cl:39])=[CH:37][C:36]([Cl:40])=[CH:35][C:34]=2[Cl:41])=[N:29][C:28]=1[C:42]([F:45])([F:44])[F:43].CCOCC>C(Cl)Cl>[CH2:2]([N:9]([CH2:26][C:27]1[S:31][C:30]([NH:32][C:33]2[C:34]([Cl:41])=[CH:35][C:36]([Cl:40])=[CH:37][C:38]=2[Cl:39])=[N:29][C:28]=1[C:42]([F:44])([F:43])[F:45])[CH2:10][CH2:11][C:12]([F:14])([F:13])[F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)CCNCc1ccccc1
Reactant: FC(F)(F)c1nc(Nc2c(Cl)cc(Cl)cc2Cl)sc1CCl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: FC(F)(F)CCN(Cc1ccccc1)Cc1sc(Nc2c(Cl)cc(Cl)cc2Cl)nc1C(F)(F)F
Reaction time: 12 h
Yield: 94 %

Procedure:
A stirred suspension of benzyl-3,3,3-trifluoropropyl-amine hydrochloride (152.8 mg, 3 equiv.) in methylene chloride (10 mL) at room temperature was treated with diisopropylethylamine (0.132 mL, 3 equiv.). Within a few minutes the mixture became homogeneous and then a 12.5 mg/mL solution of (5-chloromethyl-4-trifluoromethyl-thiazol-2-yl)-(2,4,6-trichloro-phenyl)-amine in ether (8 mL, 0.2525 mmoles) was added all at once. After 12 hours at room temperature, the mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 12% ethyl acetate/hexane, to give the product as a colorless glass (133.6 mg, 94%). 1H-NMR δ (CDCl3) 2.27 (m, 2H), 2.75 (ABq, 2H), 3.62 (s, 2H), 3.74 (s, 2H), 7.28 (m, 5H), 7.48 (s, 2H), 8.75 (br, 1H). Mass spec.: 563.98 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:16]1)[C:5]([O:7]CC(C)=C)=[O:6].O.[OH-].[Li+].ClCCl.Cl>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:16]1)[C:5]([OH:7])=[O:6]
Reactant: C=C(C)COC(=O)c1ccc(C2CCCC(OCC(=C)C)C2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C=C(C)COC1CCCC(c2ccc(C(=O)O)cc2Cl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-methylallyl 3-chloro-4-(3-((2-methylallyl)oxy)cyclohexyl)- benzoate (0.153 g, 0.42 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL) was added a solution of lithium hydroxide monohydrate (0.088 g, 2.10 mmol) in water (2 mL). The reaction mixture was stirred for 16 hours at ambient temperature. After dilution with dichloromethane (50 mL), 1N hydrochloric acid (5 mL) was added. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was obtained as a colorless solid (0.130 g, quant.) and used without further purification: MS (ES−) m/z 307.2, 309.2 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:4]/[C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[F:1])/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Product: COc1ccc(/C(C#N)=C/c2cc([N+](=O)[O-])ccc2F)cc1OC
Yield: 14.6 %

Procedure:
2-Fluoro-5-nitrobenzaldehyde (85 mg) and 3,4-dimethoxybenzyl cyanide (89 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (24 mg, yield: 15%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)C[C@H](CC(C)C)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@H](CC(=O)O)CC(C)C)cc3)ccc2C(C)(C)C)c1
Reaction time: 19 h
Yield: 72.2 %

Procedure:
To a stirred solution of 45.2 (0.048 g, 0.09 mmol) in THF (2.00 mL, 0.10 mmol) and EtOH (2.00 mL, 0.10 mmol) at 23° C. was added a 1 M solution of sodium hydroxide (1 mL, 1 mmol). The reaction was then stirred for 19 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 45 (32 mg, 71% yield) as a colorless oil. MS ESI (neg.) m/e: 983.5 (M−H)+, 491.2 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8](O)[CH3:9].S(Cl)([Cl:13])=O.C(=O)(O)[O-].[Na+]>O>[Cl:13][CH:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH3:9]
Reactant: CC(O)c1ccncc1F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(Cl)c1ccncc1F
Temperature: 80 °C
Yield: 39 %

Procedure:
1-(3-fluoropyridin-4-yl)ethanol (0.8 g, 5.7 mmol) was treated with thionyl chloride (5 mL) and the resulting mixture was heated to 80° C. for 2 h. Water (10 mL) and sat. sodium bicarbonate (aq., 10 mL) was added. The product was extracted with DCM (three times). The combined organic extracts were washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent heptane: ethyl acetate gradient) to yield 0.36 g (39% yield) of the title compound.
Reaction SMILES: C1OC1.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20]CCOC>>[CH2:19]([OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: CCCCCCCCCCCCCCCCOCCOC
Solvent: C1CO1
Product: CCCCCCCCCCCCCCCCO

Procedure:
Oxyethyleneated cetyl alcohol containing 10 moles of ethylene oxide, sold under the name BRIJ 56 by Messrs. ATLAS: 12 g
Reaction SMILES: CO[C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1S[N:10]=[CH:9][N:8]=1.S1C(N)=NC=N1.N1C=[CH:28][C:27](N)=NC=1>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][NH:6][C:7]2[CH:28]=[CH:27][N:10]=[CH:9][N:8]=2)=[CH:3][CH:15]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: Nc1ccncn1
Agent: Nc1ncns1
Product: COc1ccc(CNc2ccncn2)cc1

Procedure:
N-(4-methoxybenzyl)pyrimidin-4-amine (INTERMEDIATE AC) was prepared in a manner analogous to INTERMEDIATE A wherein 1,2,4-thiadiazol-5-amine was replaced with pyrimidin-4-amine
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:16][C:17]([N:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][C:24]#[CH:25])=[O:18])[CH:9]2[CH2:12][O:13]CC)=[CH:4][C:3]=1[O:32][CH3:33].[OH-].[K+].[O:36]1CCOCC1.Cl>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:16][C:17]([N:19]([C:28]([CH3:30])([CH3:31])[CH3:29])[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][C:24]#[CH:25])=[O:18])[CH:9]2[C:12]([OH:36])=[O:13])=[CH:4][C:3]=1[O:32][CH3:33]
Reactant: C#CCC(C)(C)CCN(C(=O)CN1CCc2cc(OC)c(Br)cc2C1COCC)C(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C#CCC(C)(C)CCN(C(=O)CN1CCc2cc(OC)c(Br)cc2C1C(=O)O)C(C)(C)C
Temperature: 60 °C

Procedure:
A mixture of 430 mg of 24f, 300 mg of KOH, 10 ml of dioxane and 1.5 ml of water was warmed at 60° C. for 1 hr. Reaction was cooled and diluted with 30 ml of water and acidified to pH3 with 0.5 N HCl. The product was extracted into ethyl acetate. The organic extract was washed twice with water, dried and concentrated, to leave 390 mg of 24g, as a colorless oil. Rf (toluene/acetone 1/1) 0.55. NMR (CDCl3) δ 7.70 and 6.65 (2×s, 2, Ar—H), 5.79 (s, 1, CH), 3.90 (s, 3, OCH3), 1.97 (t, 1, acetylene), 0.90 (s, 6, 2×CH3), 1.55 (s, 9, tertC4H9).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[S:10][C:9](N)=[N:8][N:7]=1.[BrH:12].N([O-])=O.[Na+]>O>[Br:12][C:9]1[S:10][C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[N:7][N:8]=1
Reactant: Br
Reactant: Nc1nnc(C2CCCO2)s1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1nnc(C2CCCO2)s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 5-(Tetrahydro-furan-2-yl)-[1,3,4]thiadiazol-2-ylamine (0.5 g, 2.9 mmol) was added 48% HBr (7 ml) and H2O (7 ml). The reaction mixture was cooled to 0° C. using an icebath. Cu(I)Br (0.42 g, 2.9 mmol) was added, followed by a the dropwise addition of solution of NaNO2 (0.48 g, 10 mmol) in H2O (18 ml). The reaction mixture was stirred for a further 10 mins at 0° C. then allowed to warm up to room temperature over a 35 min period. A solution of saturated bicarbonated was added to the reaction mixture until the pH=6, then extracted with EtOAc, dried (MgSO4), filtered and the solvent removed in vacuo to afford the product (0.5 g, 2.1 mmol). MS: [M+H]+235, 237.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C=O)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: CC1CCN(c2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CC1CCN(c2nc(N3CCN(C)CC3)ncc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of 2-chloro-4-(4-methyl-piperidin-1-yl)-5-nitro-pyrimidine (as prepared in the previous step) (257 mg, 1.00 mmol) in DMF (10 mL) was added 1-methyl piperazine (110 μL, 1.00 mmol). The resulting mixture was heated at 80° C. for 48 h. The reaction mixture was allowed to cool to room temperature and partitioned between water/EtOAc. The EtOAc layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue obtained was purified on silica (0-10% MeOH:EtOAc) to obtain the title compound (192 mg, 63%). 1H-NMR (CDCl3; 400 MHz): δ 8.76 (s, 1H), 3.90 (br m, 6H), 2.96 (m, 2H), 2.40 (m, 4H), 2.32 (s, 3H), 1.82-1.6 (m, 3H), 1.2-1.3 (m, 2H), 1.02 (d, 3H, J=6.5 Hz).
Reaction SMILES: [CH2:1]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:23](=[O:25])[CH2:24][CH:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:22]
Reactant: NCCCCCCO
Reactant: CCCCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Product: CCCCCCCCCCCCCCCCCCC1CC(=O)N(CCCCCCO)C1=O
Yield: 69 %

Procedure:
A 300 mL reaction flask was charged with 63.2 g of octadecyl succinic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 21.0 g of 6-amino-1-hexanol (manufactured by Tokyo Chemical Industry Co., Ltd.), and the resulting mixture was reacted at 160° C. for 3.5 hours under continuous nitrogen purging and with vigorous stirring. The reaction product was purified by silica gel column chromatography, yielding 55.87 g of N-(6-hydroxyhexyl)octadecyl succinimide (yield: 69.0%).
Reaction SMILES: [ClH:1].Cl.C1(C=[N:10][N:11]2[CH2:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:12]2=[O:28])C=CC=CC=1.Cl.[H][H]>[Pd].O>[ClH:1].[NH2:10][N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[C:12]1=[O:28]
Reactant: [H][H]
Reactant: CN1CCN(CCCCN2C(=O)CN(N=Cc3ccccc3)C2=O)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CN1CCN(CCCCN2C(=O)CN(N)C2=O)CC1
Reaction time: 2 h

Procedure:
A mixture of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride (8.04 g, 0.0187 mole), 2N HCl (125 ml) and 5% Pd/C:50% H2O (1.5 g, is subjected to hydrogen on a Parr apparatus at 40 psi at ambient temperature. After 2 hours, the catalyst is removed by filtration. The filtrate is divided into two equal portions. Each is concentrated under reduced pressure on a rotary evaporator to an oily residue of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione hydrochloride.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([F:31])=[C:6]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:29][CH3:30])=[C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10].C(=O)([O-])O.[Na+].O.[Cl-].[O:39]1C[CH2:42][CH2:41][CH2:40]1>CC(C)=O>[Cl:3][C:4]1[C:5]([F:31])=[C:6]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:29][CH3:30])=[C:19]([O:22][CH:23]4[CH2:24][CH2:25][N:26]([C:40](=[O:39])[CH:41]=[CH2:42])[CH2:27][CH2:28]4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COc1cc2ncnc(Nc3ccc(Cl)c(Cl)c3F)c2cc1OC1CCNCC1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: C=CC(=O)N1CCC(Oc2cc3c(Nc4ccc(Cl)c(Cl)c4F)ncnc3cc2OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (100 g) and sodium hydrogen carbonate (66 g) were added to a mixed solvent of tetrahydrofuran (630 ml) and water (1 L), and the temperature of the reaction mixture was cooled to 0° C. with iced water. Acryloyol chloride (24 ml) diluted with tetrahydrofuran (370 ml) was slowly added to the reaction mixture over 30 minutes, followed by stirring at 0° C. for 30 minutes. Upon completion of the reaction, aqueous acetone (2.0 L) was added to the resulting mixture, which was stirred for 12 hours and filtered to produce 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one (72 g, yield: 75%). The solid thus obtained was dissolved in a mixed solvent of dichloromethane (200 ml) and methanol (100 ml), added with ethyl acetate (1.2 L), and stirred for 12 hours. The resulting solid was filtered and washed with ethyl acetate (100 ml). The solid was dried at 40° C. in an oven to produce the compound of formula (II) (55 g, yield: 76%, total yield=57%).
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)=O>[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)c(Br)cnc32)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)ccnc32)cc1
Yield: 91.9 %

Procedure:
Toluene (30 ml) was mixed with 3.0 g (6.3 mmol) of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 10% Pd-C (100 mg) and 9.6 g (95 mmol) of triethylamine, followed by the dropwise addition of 2.9 g (63 mmol) of formic acid under stirring. The obtained mixture was heated under reflux for 10 hours. The reaction liquid was brought to room temperature, and filtered to remove the catalyst, and then the filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 2.3 g of the title compound (yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2=[O:20])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([CH2:14][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C)cn(-c2ccc(F)cc2)c1=O
Reactant: C1COCCN1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(CN2CCOCC2)cn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A mixture of ethyl 1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (0.275 g, 1 mmol), NBS (0.2 g, 1.1 mmol), AIBN (40 mg, 0.2 mmol) in CCl4 (20 mL) is heated at reflux for 3 hours. After the reaction is cooled down, morpholine (0.088 mL, 1 mmol) and K2CO3 (0.14 g, 1 mmol) are added. The reaction is stirred at RT for another 2 hours. The solvent is removed, and the residue is diluted with water (10 mL) and extracted with EtOAc (20 mL) twice. The combined organic phases are washed with saturated aqueous sodium chloride, dried, and concentrated. The residue is purified by silica gel column chromatography eluting with DCM:MeOH (from 100:1 to 50:1, containing 0.5% 2 N NH3 in MeOH), to afford the title compound (0.17 g, 47% yield). MS (m/z): 361.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][C:5]2[S:13][CH:14]=[CH:15][C:4]=2[S:3]1(=[O:17])=[O:16].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:1][N:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]2[S:13][CH:14]=[CH:15][C:4]=2[S:3]1(=[O:17])=[O:16]
Reactant: CCOC(=O)C1=Cc2sccc2S(=O)(=O)N1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CN1C(CO)=Cc2sccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step D (3.16 g, 11.6 mmol) in anhydrous THF (30 mL) at 0° C. was added DIBAL (1.0M, 29.0 mL, 29.0 mmol). This mixture was stirred for 30 min, warmed to ambient temperature, and stirred for an additional 30 min. The mixture was evaporated to dryness and the residue mixed with ethyl acetate (100 mL) and poured into 2N HCl (50 mL). The organic layer was seperated, washed with brine, dried (MgSO4) and evaporated to dryness. Column chromatography (silica, ethyl aectate/hexane) gave a viscous oil which solidified on standing: mp 78°-80° C.