Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:17]([CH2:18][N:19]([CH3:21])[CH3:20])=[N:16][C:15]([C:22]([NH2:24])=O)=[N:14]1)=[O:5].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CCOCC>N1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:17]([CH2:18][N:19]([CH3:21])[CH3:20])=[N:16][C:15]([C:22]#[N:24])=[N:14]1)=[O:5]
Reactant: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)Cc1nc(C#N)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4.18 g (0.01 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide and 2.86 g (0.015 mole) of p-toluenesulphonic acid chloride in 2.42 ml of pyridine and 24 ml of N,N-dimethylformamide is stirred for 2 hours at room temperature. The initially yellow colour of the reaction mixture changes during this time to green and then to red-brown. The reaction solution is poured into ice water, and extraction is performed twice with ether. The organic phase is washed three times with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to dryness. The residue is crystallised from isopropanol. After filtration with suction followed by drying, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carbonitrile, m.p. 117°-119°.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([F:23])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.C([Li])CCC.[O:30]1[CH:34]=[CH:33][C:32]([C:35]2[N:42]=[CH:41][CH:40]=[CH:39][C:36]=2[CH:37]=[O:38])=[CH:31]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:23][C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][C:19]=1[CH:37]([C:36]1[C:35]([C:32]2[CH:33]=[CH:34][O:30][CH:31]=2)=[N:42][CH:41]=[CH:40][CH:39]=1)[OH:38]
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=Cc1cccnc1-c1ccoc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc(C(O)c2cccnc2-c2ccoc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
100 mg (0.26 mmol) of tert-butyl((3,4-difluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 5 mL of tetrahydrofuran under nitrogen gas, and cooled to −78° C. After adding 0.25 mL (0.39 mmol) of n-butyllithium (1.6M in tetrahydrofuran) slowly, the mixture was stirred for 30 minutes as maintaining −78° C. 23 mg (0.13 mmol) of 2-(furan-3-yl)nicotinaldehyde was dissolved in 0.5 mL of tetrahydrofuran, and added to the above reacting solution. As warming from −78° C. to room temperature, the reacting solution was stirred for 24 hours. Ethyl acetate and water/1 N-hydrochloride were added to the reacting solution, and it was stirred. After separating layers, the organic layer only was collected and concentrated under reduced pressure. The obtained residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 7 mg (6.1% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)morpholine-4-carboxylate (Example 11, step 1) (1 g, 2.308 mmol) and sodium hydride (60% in oil) (0.111 g, 2.77 mmol) in DMF (20 mL) was stirred at 0° C. for 15 minutes. Iodomethane (0.216 mL, 3.46 mmol) was added and the mixture was left to stir at room temperature for 16 hours. The reaction was quenched with water (10 ml) to form a suspension. The suspension was diluted with H2O (100 ml) and extracted with EtOAc (200 ml). The organic portion was separated and washed with H2O (100 ml), dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4](N(CC)CC)=[O:5].C([Li])(CC)C.CN([CH:26]=[O:27])C.C1C[O:31]CC1>>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[CH:12]=[C:11]2[C:3]=1[C:4](=[O:5])[O:31][CH:26]2[OH:27]
Reactant: CN(C)C=O
Reactant: CCCc1ccc(C(=O)N(CC)CC)c(Cl)c1
Reactant: C1CCOC1
Agent: [Li]C(C)CC
Product: CCCc1cc(Cl)c2c(c1)C(O)OC2=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of 2-chloro-N,N-diethyl-4-propylbenzamide (1.82 g, 7.17 mmol) and N,N,N′N′-tetramethylethylenediamine (1.2 mL, 7.9 mmol) in 100 mL of anhydrous THF at −78° C. was added sec-butyllithium (7.9 mL of a 1.0 M solution in hexanes, 7.9 mmol). The reaction was stirred at −78° C. for 30 min and then there was added DMF (7.6 mL, 97.8 mmol). The reaction was stirred at −78° C. for 30 min and then was quenched with 1N HCl (10 mL). The reaction mixture was concentrated in vacuo. The residue was taken up in 6N HCl (40 mL) and stirred at 100° C. for 18 h. The reaction mixture was allowed to cool, was diluted with water and extracted with EtOAc. The organics were washed with brine, dried (MgSO4) and concentrated to afford a solid. This material was purified by acid-base extraction as follows. The solid was dissolved in 1:1 hexane/EtOAc and extracted twice with sat'd aq NaHCO3/sat'd aq Na2CO3. The organics were discarded. The combined aqueous extracts were acidified with 12 N HCl and extracted with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO4), and concentrated to afford 0.66 g (41%) of the title compound as a tan powder. 1H NMR (CDCl3): δ 7.25 (s, 1H), 6.55 (s, 1H), 4.85 (broad s, 1H), 2.68 (t, 2H, J=7.7 Hz), 1.72-1.63 (m, 2H), 0.95 (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25]>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:25][CH2:24][CH:23]([O:26][CH3:27])[O:22][CH3:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CNC(=O)c1ccc(OC(C)=O)cc1)OC
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of 4-(chlorocarbonyl)phenyl acetate (110 g, 553.87 mmol) in CH2Cl2 (500 mL) was cooled in an ice bath and treated with triethylamine (115 mL, 830 mmol, 1.5 equiv.) and 2,2-dimethoxyethanamine (63.36 mL, 581.56 mmol, 1.05 equiv.). The reaction mixture was allowed to warm to ambient temperature and the reaction was followed by TLC (CH2Cl2). The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and filtered. The filtrate was washed with water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water, dilute mono-potassium phosphate (pH=5.4, pH of solution about 7), water, and brine, dried, and concentrated to give 120 g (81% th.; 109% pract.) of 4-(2,2-dimethoxyethylcarbamoyl)phenyl acetate as a light brown waxy solid with no further purification; 1H NMR (CDCl3) δ 7.79 (d, 2H), 7.15 (d, 2H), 6.32 (br. t, 1H), 4.47 (t, 1H), 3.58 (d, 2H), 3.41 (s, 6H), 2.30 (s, 3H) ppm.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:47])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35]Br)=[C:19]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[OH:54][C:55]1[CH:64]=[C:63]([OH:65])[CH:62]=[CH:61][C:56]=1[C:57]([O:59][CH3:60])=[O:58]>CC(C)=O>[CH3:60][O:59][C:57](=[O:58])[C:56]1[CH:61]=[CH:62][C:63]([O:65][CH2:35][CH2:34][O:33][C:20]2[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[CH:22][C:17]([C:16](=[O:47])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:18][C:19]=2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=2)=[CH:64][C:55]=1[OH:54]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCOc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a solution of N-(8-phenyl octyl)-4-(2-bromo-ethoxy)-3,5-bis(m-trifluoromethylphenyl)benzamide (1.48 g, 2.05 mmol, 1 eq) in acetone (21 mL) was added K2CO3 (1.42 g, 10.25 mmol, 5 eq) and methyl 2,4-dihydroxybenzoate (0.340 g, 2.05 mmol, 1.0 eq). The reaction was heated at reflux for overnight, cooled to rt and concentrated in vacuo. The residue was partitioned between EtOAc and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford 2-hydroxy-4-{2-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-yloxy]-ethoxy}-benzoic acid methyl ester (0.98 g, 60%) as a colorless oil. 1H NMR (CDCl3) δ 10.90 (s, 1H); 7.92-7.78 (m, 7H); 7.66-7.50 (m, 4H); 7.27-7.12 (m, 5H); 6.18-6.10 (m, 3H); 3.92 (s, 3H); 3.66-3.40 (m, 6H); 2.58 (t, 2H); 1.60 (m, 4H); 1.28 (m, 8H).
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH:17]2[C:23](=[O:24])[N:22]([C:25]([CH:37]([CH3:39])[CH3:38])([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:26](=[O:28])[NH2:27])[C:21]3[CH:40]=[CH:41][CH:42]=[CH:43][C:20]=3[N:19]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[C:18]2=[O:50])=[O:15])[CH:8]=1)(C)(C)C.Cl.CCOCC>O1CCOCC1>[CH:37]([C:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)([C:26](=[O:28])[NH2:27])[N:22]1[C:23](=[O:24])[CH:17]([NH:16][C:14](=[O:15])[NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:51])=[O:5])[C:18](=[O:50])[N:19]([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[C:20]2[CH:43]=[CH:42][CH:41]=[CH:40][C:21]1=2)([CH3:39])[CH3:38]
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)Nc3cccc(C(=O)OC(C)(C)C)c3)C(=O)N(c3cccnc3)c3ccccc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)Nc3cccc(C(=O)O)c3)C(=O)N(c3cccnc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-{1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}-ureido)-benzoic acid tert butyl ester (115 mg, 0.224 mmol) and 4N HCl in dioxane (1 ml) was stirred at rt for 1.75 h after which time a further 1 ml of 4N HCl in dioxane was added and the reaction mixture stirred at rt overnight. Ether (20 ml) was added and the resultant precipitate was triturated with ether (3×30 ml) to afford the title compound as a white powder. 1H NMR (300 MHz, CDCl3).s 1H NMR (300 MHz, CDCl-3). s 8.61 (s, 1H), 8.56 (d, 1H, J=8.2), 7.91 (d, 1H, J=8.2), 6.91-7.83 (m, 16H), 6.41 (d, 1H, J=7.9), 5.43 (d, 1H, J=7.9), 4.91 (sept, 1H, J=6.8), 4.60 (d, 1H, J=11.8), 4.18 (d, 1H, J=11.8), 3.86 (s, 3H), 1.06 (m, 6H). Low resolution MS (FAB) m/e 637 (m+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:25][O:26][C:27](=[O:37])[C:28]1[C:33]([Cl:34])=[CH:32][C:31]([Cl:35])=[CH:30][C:29]=1[NH2:36].CCCCCC>CCOC(C)=O>[CH3:25][O:26][C:27](=[O:37])[C:28]1[C:33]([Cl:34])=[CH:32][C:31]([Cl:35])=[CH:30][C:29]=1[NH:36][C:16](=[O:18])[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([Br:20])[CH:11]=1)[CH3:19]
Reactant: CC(C(=O)O)c1ccc(OCc2ccccc2)c(Br)c1
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OCc2ccccc2)c(Br)c1
Yield: 70.6 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-benzyloxy-3-bromo-phenyl)-propionic acid (1.0 g, 3.00 mmol), SOCl2 (1.10 mL, 14.9 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (0.50 g, 2.40 mmol). After normal workup, the pure objective compound (0.91 g, 71%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.53 (s, 3H, CH3), 3.62 (q, J=7.1 Hz, 1H, CH), 3.79 (s, 3H, CO2CH3), 5.16 (s, 2H, CH2Ph), 6.94 (d, J=8.4 Hz, 1H, ArH), 7.15 (d, J=2.30 Hz, 1H, ArH), 7.20 (dd, J=8.6, 2.0 Hz, 1H, ArH), 7.31-7.48 (m, 5H, ArH), 7.54 (d, J=2.4 Hz, 1H, ArH), 8.41 (d, J=2.0 Hz, 1H, ArH), 9.15 (br s, 1H, NH).
Reaction SMILES: C([O:8][C:9](=[O:39])[C@@H:10]([NH:23][C:24](=[O:38])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])C1C=CC=CC=1.[NH2:40][CH2:41][C@@H:42]([C:44]1[CH:45]=[CH:46][C:47]([OH:55])=[C:48]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:49]=1)[OH:43]>>[OH:43][C@H:42]([C:44]1[CH:45]=[CH:46][C:47]([OH:55])=[C:48]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:49]=1)[CH2:41][NH:40][CH:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([NH:23][C@@H:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:39])=[O:8])=[O:38])=[CH:26][CH:27]=2)[CH2:36][CH2:35]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from (2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentanedioic acid dibenzyl ester (which was obtained in Example 156) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; mp>230° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.90–2.10 (m, 4 H), 2.31 (t, J=7.5 Hz, 2 H), 2.65–3.20 (m, 7 H), 3.00 (s, 3 H), 3.85–4.00 (m, 2 H), 4.25–4.35 (m, 1 H), 4.65–4.80 (m, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.08 (dd, J=8.4, 1.2 Hz, 1 H), 7.25 (d, J=1.8 Hz, 1 H), 7.74 (d, J=8.7 Hz, 2 H), 8.14 (d, J=7.2 Hz, 1 H); MS (ES) m/z: 579.1 (MH+); HRMS Calcd. for C26H35N4O9S (MH+): 579.1973. Found: 579.1955.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]Br.[C-:11]#[N:12].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][C:11]#[N:12]
Reactant: Fc1cccc(CCBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCc1cccc(F)c1
Temperature: 60 °C
Yield: 34.8 %

Procedure:
3-Fluorophenethyl bromide (23, 1.00 g, 12.3 mmol) was diluted in dry DMF (25 mL). Sodium cyanide (1.06 g, 61.6 mmol) was added in one portion, and the mixture was heated to 60° C. under argon for 16 h. The mixture was cooled and concentrated, and the residue was partitioned between EtOAc and H2O (50 mL each). The layers were separated, and the aqueous phase was extracted with EtOAc (2×20 mL). The organic layers were washed with H2O and sat. aq. NaCl (50 mL each), dried over anhydrous sodium sulfate, and concentrated. The resulting oil was purified by flash column chromatography (SiO2), eluting with a gradient of 5% EtOAc in hexanes to 30% EtOAc in hexanes to yield the desired product as a colorless oil (0.638 g, 87%). 1H-NMR (500 MHz; CDCl3): δ 7.31 (td, J=7.9, 6.0 Hz, 1 H), 7.03-6.93 (m, 3 H), 2.96 (t, J=7.4 Hz, 2 H), 2.63 (t, J=7.4 Hz, 2 H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[C:16]([Si:13]([CH3:15])([CH3:14])[C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)[C@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)[C@H]1CCNC1
Reaction time: 6 h

Procedure:
To a solution of Example 10 (24.78 g, 85 mmol) in ethanol (200 mL) was added palladium catalyst (10% on carbon) (6.0 g) and HCl (4 M in dioxane) (4.5 mL, 18 mmol). This was hydrogenated at 30° C. for 6 hours and then filtered through Celite. The solvent was removed in vacuo, and column chromatography (ethyl acetate:methanol:ammonia 40:9:1) gave the product as a yellow oil, 82 mmol, 96%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[S:12][CH2:13][CH2:14][N:15]=1.[H-].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([C:11]1[S:12][CH2:13][CH2:14][N:15]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: Cc1cccc(CNC2=NCCS2)c1C
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(Cc1cccc(C)c1C)C1=NCCS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
Under a dry nitrogen atmosphere, a solution of 0.25 gram (0.0011 mole) of ((2,3-dimethylphenyl)methyl)-1,3-thiazolin-2-ylamine dissolved in 10 mL of THF was added to a stirred suspension of 0.08 gram (0.0012 mole) of sodium hydride (60% suspension in oil). The mixture was stirred for 30 minutes, at which time a solution of 0.11 mL (0.0014 mole) of methyl chloroformate in 5 mL of THF was added slowly. The reaction mixture stirred at ambient temperature for about 18 hours. The reaction mixture was heated to 60° C. where it stirred for one hour. The reaction mixture was diluted with 25 mL of brine, then extracted with two 25 mL portions of ethyl acetate. The extracts were combined, washed with 25 mL of water, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to leave a solid residue. Analysis of the residue by TLC indicated that two compounds were present. The residue was purified by column chromatography on silica gel, eluting with hexanes:methylene chloride (1:1). The appropriate fractions were combined and concentrated under reduced pressure to yield 0.05 gram of methyl 2-(1-aza-2-(2,3-dimethylphenyl)ethylidene)-1,3-thiazolidine-3-carboxylate (Compound C53) and 0.14 gram of N-((2,3-dimethylphenyl)methyl)methoxy-N-(1,3-thiazolin-2-yl)carboxamide (Compound D5). The NMR spectra were consistent with the proposed structures.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.C(=O)([O-])O.[Na+]>C(O)CC>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[N:3]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: Cc1cc(Br)cn2cc(-c3ccc(Cl)cc3)nc12
Temperature: 80 °C
Yield: 58.2 %

Procedure:
1.70 g of 2-amino-5-bromo-3-methylpyridine and 2.13 g of 2-bromo-1-(4-chlorophenyl)ethanone in 75 ml of n-propanol are placed in a round-bottomed flask. 1.08 g of sodium hydrogen carbonate are added. The mixture is heated at 80° C. for 6 h. The reaction mixture is allowed to cool and the solvent is evaporated off under reduced pressure. The residue is taken up between dichloromethane and water, the organic phase is then separated and dried, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. The solid obtained is triturated from diethyl ether and recovered by filtration. 1.7 g of compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[N:4][C:5]([CH:14]=[CH:15][CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][CH:19]=2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[N:4][C:5]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[CH:22][CH:23]=2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCN(CC)c1ccc(C=CC=Cc2nc(N3CCOCC3)c(N)c(N3CCOCC3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)c1ccc(CCCCc2nc(N3CCOCC3)c(N)c(N3CCOCC3)n2)cc1
Reaction time: 18 h
Yield: 26 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 5-amino-2-[4-(4-diethylaminophenyl)butan-1,3-dienyl]-4,6-dimorpholinopyrimidine (500 mg, 1.08 mmol) (Compound 144) was dissolved in ethanol (30 ml), 300 mg of Pd/C was added, and catalytic reduction was carried out for 18 hours at room temperature. The Pd/C was filtered out of the reaction liquid using celite, the filtrate was taken and the solvent was distilled away under reduced pressure. The residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=1:1), and 131.4 mg of 5-amino-2-[4-(4-diethylaminophenyl)butyl]-4,6-dimorpholino pyrimidine (Compound 145) was obtained (yield 26%). The MS measurement result, and the NMR data for the obtained Compound 145 are shown below.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[C:11](N1C=CN=C1)(N1C=CN=C1)=[S:12].Cl.[C:24]12([CH2:34][CH2:35][NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:24]12([CH2:34][CH2:35][N:36]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:11]([NH:1][CH2:2][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)=[S:12])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: NCCCc1ccncc1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCCCCNCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=S)NCCCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.4 %

Procedure:
A solution of 4-(3-aminopropyl)pyridine (Intermediate No. 2-1) (0.24 g, 1.8 mmol) in anhydrous tetrahydrofuran (10 ml) was added to 1,1′-thiocarbonyldiimidazole (0.31 g, 1.8 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature. After one hour, a solution of 2-(1-adamantyl)-N-pentylethylamine hydrochloride (Intermediate No. 1-1) (0.50 g, 1.8 mmol) in anhydrous tetrahydrofuran (10 ml) was added to the mixture, and the whole was refluxed for 2.5 hours. The reaction mixture was allowed to stand, then ethyl acetate (50 ml) and a saturated aqueous sodium hydrogencarbonate solution (50 ml) were added to the reaction mixture, and layers were separated. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 0.18 g (24%) of the titled compound.