Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[CH:21]/[C:22](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[CH:21]/[C:22]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: O=C(Cl)/C=C/c1ccco1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccco1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-(2-furyl)acryloyl chloride (New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlemmer, R. F.; VanderMaelen, C. P.; Cipollina, J. A. J. Med. Chem., 1989, 32, 1147) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 287.32; mp: 164.0-165.0° C.; 1H-NMR (CDCl3) δ: 8.80-8.75 (1H, m), 8.00 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.83-7.78 (1H, m), 7.78 (1H, d, J=15.4 Hz), 7.54-7.39 (4H, m), 7.37-7.16 (2H, m), 7.01 (1H, d, J=15.4 Hz), 6.51 (1H, d, J=3.3 Hz), 6.44 (1H, dd, J=3.3, 1.8 Hz).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:13]([NH:31][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCCCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
In the first process step, glucose (a) is reacted with octadecylamine (b) to give N-octadecyl-β-D-glucopyranosylamine (c) which, in the second process step is acylated with oleyl chloride to give N-octadecyl-N-oleyl-β-D-glucopyranosylamine (I).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([O:9][CH2:10][C:11]1[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])=[N:13][O:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[CH2:2]2.CC(N(C)C)=O.[F:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1F)[C:40]([O:42][CH3:43])=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[CH:16]1([C:15]2[O:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:28])([F:27])[F:29])[C:11]=2[CH2:10][O:9][CH:3]2[CH2:2][CH:1]3[N:8]([C:46]4[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][C:37]=4[F:36])[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH2:17][CH2:18]1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Reactant: COC(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)(F)F)noc2C2CC2)C3)c(F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The amine, 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (41.5 mg, 0.102 mmol), dimethylacetamide (0.6 mL), methyl 3,4 difluorobenzoate (510 mg, 3.0 mmol), and cesium carbonate (108 mg, 0.33 mmol) were combined sequentially and heated to 100° C. for about 20 minutes and then 120° C. for approximately 1 hour. The mixture was diluted with ethyl acetate 20 mL and water washed (2×3 mL). The organics were dried under vacuum to a residue, the resulting residue was diluted with 3 mL of MeOH, and the liquid was directly purified using mass directed reverse phase HPLC under a gradient of 30 to 90% acetonitrile/water that was TFA modified (0.05%). The resulting product was cold vacuum concentrated and free based using an SPE polymer support cartridge and MeOH (5 mL) mobilizing solvent (product SPE PLHCO3 MP part no PL3540-C603). All resulting methanol effluent was concentrated to give the free based intermediate ester as a dense oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:26][CH:27]([C:30]#[N:31])[C:28]#[N:29].C([O-])(=O)C.[Na+]>C(OCC)(OCC)OCC.O>[NH2:29][C:28]1[N:1]([C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=2[CH3:14])[C:5]([NH:7][CH:8]2[CH2:9][CH2:10]2)=[O:6])[CH:15]=[N:26][C:27]=1[C:30]#[N:31]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: N#CC(N)C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C#N)c1N
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
A mixture of 3-amino-N-cyclopropyl-4-methyl-benzamide (380 mg, 2.0 mmol) in 2.0 mL of triethyl orthoformate was stirred at 120° C. in microwave for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in 5 mL of acetic acid and then was added aminomalononitrile p-toluenesulfonate (506 mg, 2.0 mmol) and sodium acetate (164 mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with 20 mL of water and the resulting precipitate was filtered to give 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide 3A as a colorless solid (170 mg, 30%). HPLC tR=1.39 min; MS m/z 282 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C@H:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][C@@H:33]([CH3:32])[CH:34]([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)[C@H](C)N
Product: CC(C)[C@H](C)NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 18 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (S)-1,2-dimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1, 2) gave 40 mg (18%) of the title compound as white crystals. 1H NMR (300 MHz, CDCl3): d=0.85 (dd, 6H), 1.05 (d, 3H), 1.7 (m,1H) 3.10 (m, 1H), 7.43 (s, 2H), 7.48 (d, 2H), 7.70 (s, 1H), 7.80 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C-:11]#[N:12].[K+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: [C-]#N
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [K+]
Solvent: O
Product: N#CC(O)c1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A solution of 80.2 g of Na2S2O5 in 250 ml of water is heated to 50° C., 50 g of 3,4-difluorobenzaldehyde are added and the reaction mixture is stirred for 1 hour at 50° C. and left to stand overnight at RT. It is cooled to 0° C., a solution of 77.7 g of KCN in 100 ml of water is added dropwise, the mixture is stirred while the temperature is allowed to rise to RT, and stirring is then continued for 1 hour at RT. The reaction mixture is extracted with ether, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 48 g of the expected product, which is used as such.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C@@H:29]([NH2:36])[C@H:28]1[OH:37]>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:36][C@@H:29]2[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:27][C@@H:28]2[OH:37])=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=S(=O)(Nc1cccc2nc(N[C@@H]3c4ccccc4C[C@@H]3O)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=468.5 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonyl chloride and (1R,2S)-(+)-cis-1-amino-2-indanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[CH2:11]=[C:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:15][C:14](=[O:22])[N:13]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:11]=[C:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH2:18][CH2:17]2)[O:15][C:14](=[O:22])[N:13]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: C=C1N(c2ccccc2)C(=O)OC12CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C1N(c2ccccc2)C(=O)OC12CCN(C(=O)N1CCN(C)CC1)CC2
Yield: 83 %

Procedure:
The solution of 3.9 g of 4-methylpiperazin-1-yl-carbonyl chloride in 5 ml of chloroform is dropwise added at a temperature between 0° and 5° C. to a solution containing 4.9 g of 4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane and 7.4 ml of triethylamine in 74 ml of chloroform under stirring. Thereafter, the reaction mixture is stirred at room temperature for an additional 30 minutes. After termination of the reaction the chloroform phase is washed to chloride-free with water, dried over anhydrous sodium sulfate, then the solvent is evaporated under reduced pressure. After recrystallization of the crude product obtained from ethanol under clarifying by activated carbon the title compound is obtained in 83% yield, m.p.: 198°-199° C.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[Cl:19][C:20]1[C:25]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][C:23]([C:34]#[N:35])=[CH:22][C:21]=1[N:36]1[CH2:41][CH2:40][C@@H:39]([NH:42][C:43](=[O:45])[O-:44])[C@H:38](O)[CH2:37]1.[CH2:47](N(CC)CC)C>ClCCl>[Cl:19][C:20]1[C:25]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[CH:24][C:23]([C:34]#[N:35])=[CH:22][C:21]=1[N:36]1[CH2:37][CH2:38][C@@H:39]([NH:42][C:43](=[O:45])[O:44][CH3:47])[C@H:40]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH2:41]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CC[C@@H](NC(=O)[O-])[C@H](O)C2)c1Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 118 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (0.288 mL, 1.060 mmol) was added to a solution of ((3R,4R)-1-(2-chloro-5-cyano-3-(N-Boc-amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (150 mg, 0.353 mmol) and triethylamine (0.196 mL, 1.412 mmol) in dichloromethane (5 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between saturated sodium bicarbonate and dichloromethane. The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-10% ethyl acetate/dichloromethane). methyl ((3R,4R)-1-(2-chloro-5-cyano-3-(N-Boc-amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (242 mg) was obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][C:28]=1[O:35][CH3:36].C(N(CC)CC)C>C(O)CC>[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[CH:29][C:28]=1[O:35][CH3:36]
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Reactant: COc1cc(CN)ccc1O
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCCO
Product: COc1cc(CNc2ncnc3c2ncn3C2CCCO2)ccc1O
Yield: 80 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)-purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1838 mg) of 4-hydroxy-3-methoxybenzylamine and 5 mL of triethylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane) (1:1) (v:v): single spot; HPLC: purity>98%. 1H NMR (400 MHZ, DMSO): 0.90d (3H, J=6.6 Hz); 1.32m (1H); 1.57m (1H); 1.84m (1H); 1.95m (1H); 2.12m (2H); 2.29m (1H); 3.26m (1H); 3.51 bs (2H); 3.73m (1H); 3.89m (1H); 4.40t (1H, J=5.1 Hz); 6.12d (1H, J=5.2 Hz); 7.74bs (1H); 8.18s (1H); 8.28s (1H. MS (ES): [M+H]+=342 (100).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17]C)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].Cl>CO.O>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCOc1cccc(C(=O)O)c1

Procedure:
A solution of methyl 3-decyloxybenzoate (9.64 g, 0.033 mol) and sodium hydroxide (6.60 g, 0.165 mol) in methanol (150 ml) and water (15 ml) was heated under reflux for 2 h. The reaction mixture was then allowed to cool, followed by addition of dilute HCl (100 ml). The crude product was filtered off, washed with water and then dried in vacuo. The material was recrystallised to yield colourless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]12[CH2:78][CH2:77][CH:74]([CH2:75][CH2:76]1)[CH:73]([NH2:79])[CH2:72]2>CN1C(=O)CCC1>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:79][CH:73]5[CH:74]6[CH2:77][CH2:78][N:71]([CH2:76][CH2:75]6)[CH2:72]5)=[O:34])=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:18][CH2:17]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)NC2CN3CCC2CC3)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 40 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to according to example 68 with quinuclidin-3-amine (79 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (24.3 mg, 40% yield); MS (ESI) m/z=614.7
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.[CH3:21]I>N1C=CC=CC=1>[CH3:21][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2N)cc1
Reactant: CI
Solvent: c1ccncc1
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2NC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.01 moles of ethyl 2'-amino-4-biphenylylglycolate in 100 ml. of pyridine is added 0.1 moles of methyl iodide. The reaction mixture is stirred overnight at room temperature, filtered and concentrated. The residue is distilled to obtain ethyl 2'-methylamino-4-biphenylylglycolate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1(C)[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][NH:14]1.C([O-])([O-])=O.[K+].[K+].CCOCC>CCO>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: CC1=CNC(C)(N)C=C1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 93 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A mixture of 2-bromo-4′-methylacetophenone (90% pure, 10.21 g, 43.11 mmol), 2-amino-5-methyl picoline (4.66 g, 43.11 mmol) and K2CO3 (6.6 g, 47.75 mmol) in absolute EtOH (70 ml) was heated at 93° C. overnight. After cooled to 40° C., ether (100 mL) was added. The mixture was stirred for 30 minutes and cooled by ice-water bath. After removal of solvent through filtration, the solid was stirred with water (50 ml) for 30 minutes and filtered, rinsed with water and dried under vacuum at 80° C. for 2 hr to give 6.33 g of white solid (66.1% yield). m/e+ 223.4 for C15H15N2 (M+H)+; 1H-NMR (400 MHz, CDCl3, δ) 7.84 (m, 3H), 7.71 (d, J=9.531 Hz, 1), 7.51 (d, J=9.165 Hz, 1H), 7.24 (m, 2H), 7.00 (m, 1), 2.38 (s, 3H), 2.29 (d, J=6.23 Hz, 3H) ppm. 13C-NMR (100 MHz, CDCl3 δ) 145.065, 144.444, 137.991, 130.696, 130.635, 129.642, 129.483, 128.391, 128.262, 126.018, 123.652, 122.476, 116.486, 107.857, 21.520, 18.259 ppm.
Reaction SMILES: [NH:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>COCCOC>[CH2:23]([N:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCCCCS(=O)(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)CCCCCS(=O)(=O)N(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a cold solution (ice bath) of ethyl 6-(anilinosulfonyl)hexanoate (64b) (0.86 g, 2.88 mmol) in 1,2-dimethoxyethane (5 ml) a 60% suspension of sodium hydride in mineral oil (0.12 g, 3.0 mmol) and a solution of benzylbromide (0.49 g, 2.88 mmol) in 1,2-dimethoxyethane (3 ml) were added, and the resulting solution was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel with petroleum ether-tert-butylmethyl ether (3:2, v/v) as eluent to give the title compound (0.56 g, 50%) as an oil. 1H NMR (DMSO-d6, HMDSO), δ: 1.16 (3H, t, J=7.0 Hz); 1.21-1.87 (6H, m); 2.27 (2H, t, J=6.6 Hz); 3.21 (2H, t, partially overlapped with a signal of H2O, J=7.6 Hz); 4.05 (2H, q, J=7.0 Hz); 4.89 (2H, s); 7.14-7.58 (10H, m).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:46](/[CH:49]=[CH:50]/[C:51](=[O:64])[C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=2)=[CH:45][C:39]=1[O:40][CH2:41][C:42](O)=[O:43]>ClCCl.O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:42](=[O:43])[CH2:41][O:40][C:39]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51](=[O:64])[C:52]4[CH:53]=[C:54]([O:62][CH3:63])[C:55]([O:60][CH3:61])=[C:56]([O:58][CH3:59])[CH:57]=4)[CH:47]=[CH:48][C:38]=3[O:37][CH3:36])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(C(F)(F)F)cc2s1
Yield: 796.6 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9i) (480 mg, 80% yield)
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>O1CCCC1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: CSCC=COC(C)=O
Reactant: COC(=O)C(CCSC)OC(C)=O
Agent: [C]=O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 24.6 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z: E ratio 43:57), and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. A catalyst comprising [Pd(CH3CN)4 ]+2 [BF4 ]2- plus Pφ3 was added. Toluene LPd(CH3CN)4][BF4]2 was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 8.5 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 24.6 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Note that each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].CC(C)([O-])C.[K+].[N:38]1([C:44]2[N:49]=[CH:48][C:47]([CH:50]=O)=[CH:46][N:45]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C>[N:38]1([C:44]2[N:45]=[CH:46][C:47]([CH:50]=[CH:9][C:8]3[CH:7]=[C:6]([CH:31]=[CH:30][CH:29]=3)[C:4]([O:3][CH3:2])=[O:5])=[CH:48][N:49]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1cnc(N2CCOCC2)nc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C=Cc2cnc(N3CCOCC3)nc2)c1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
[3-(Methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (930 mg) was mixed with DMF (6 ml), and potassium tert-butoxide (300 mg) was added thereto at 0° C., followed by stirring for 30 minutes. 2-(Morpholin-4-yl)pyrimidine-5-carboaldehyde (300 mg) was added to the reaction mixture, followed by stirring at 0° C. for 1 hour, and stirring again at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain methyl 3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]vinyl}benzoate (377 mg).