Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21]>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:22]([CH2:23][CH:24]=[CH2:25])[CH2:19][CH:20]=[CH2:21])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCNCC=C
Reactant: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Product: C=CCN(CC=C)Cc1ccc([C@H]2CC[C@H](OC(C)=O)CC2)cc1

Procedure:
from trans-O-acetyl-4-(4-chloromethylphenyl)-cyclohexanol and diallylamine. Colourless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([C:13]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]3)=[CH:27][CH:26]=2)[C:16]2=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]2[N:14]=1)[CH3:12].[OH-].[Na+]>C1COCC1>[CH2:11]([C:13]1[N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][CH2:32][C@H:33]3[CH2:34][CH2:35][C@H:36]([OH:39])[CH2:37][CH2:38]3)=[CH:29][CH:30]=2)[C:16]2=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]2[N:14]=1)[CH3:12]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCC(=O)CC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC[C@H]2CC[C@H](O)CC2)cc1
Reaction time: 0.08 h

Procedure:
Lithium aluminum hydride (23.3 mg, 0.616 mmol) was suspended in THF (0.6 mL), and a solution of aluminum chloride (41.1 mg, 0.308 mmol) in THF (0.6 mL) was added to the suspension at 0° C., followed by stirring for 5 minutes. Then the mixture was added with a solution of Compound 148 (60.0 mg, 0.154 mmol) in THF (1.4 mL) followed by stirring at 0° C. for 0.5 hours. The reaction mixture was added with 2 mol/L aqueous sodium hydroxide solution and extracted with ethyl acetate twice. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=1:49). The obtained compound was crystallized from diethyl ether to obtain Compound 152 (cis:trans=15:85, 38.1 mg, 0.0971 mmol, 63.2%).
Reaction SMILES: CN(C)C=[CH:4][C:5](=[O:13])[C:6](=[CH:9][N:10](C)[CH3:11])[C:7]#[N:8].C([O-])(=O)C.[NH4+]>CCO>[OH:13][C:5]1[C:6]([C:7]#[N:8])=[CH:9][N:10]=[CH:11][CH:4]=1
Reactant: CN(C)C=CC(=O)C(C#N)=CN(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: N#Cc1cnccc1O
Yield: 52.3 %

Procedure:
A mixture of 5-(dimethylamino)-2-[(dimethylamino)methylene]-3-oxopent-4-enenitrile (64.3 g, 333 mmol) and ammonium acetate (126 g, 1.66 mol) in EtOH (1.8 L) was heated at reflux for 60 h and concentrated to remove solvent. The resultant semi-solid residue was diluted with EtOAc, filtered and washed with EtOAc followed by CH2Cl2. The filtrate was evaporated to a reduced volume. The precipitated solids were collected by filtration, washed with EtOAc and a minimum amount of EtOH. The process of evaporation and crystallization was repeated to obtain more solid product from the mother liquor. The combined off-white solids provided 20.9 g of 4-hydroxynicotinonitrile (53%); melting range: 234-236° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[CH3:25][N:26]([CH3:36])[C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:29]=[N:28][C:27]([N:26]([CH3:36])[CH3:25])=[N:32][CH:31]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: CN(C)c1ncc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3cnc(N(C)C)nc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 105 °C
Yield: 32 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 2-dimethylaminopyrimidine-5-boronic acid (52 mg, 0.31 mmol), K3PO4 (87 mg, 0.41 mmol), H2O (7.4 mg, 0.41 mmol), SPhos (4.2 mg, 0.010 mmol) and Pd(OAc)2 (4.2 mg, 0.0062 mmol) in toluene (5 mL) was heated at 105° C. under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (20 mL) were added. 1 M HCl was added with stirring until pH was about 3-4, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+2% AcOH) to give 29 mg of the title compound as a bright yellow solid. MS: (+) m/z 432.29 (M+1).
Reaction SMILES: [CH2:1](C1CCCCC1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1Cc1ccccc1
Reactant: NC1CCCCC1Cc1ccccc1
Product: c1ccc(CNC2CCCCC2Cc2ccccc2)cc1

Procedure:
In a series of procedures similar to preparations A and B, 2-benzyl cyclohexanone was converted into 1-amino-2-benzylcyclohexane in 65% via the intermediate oxime. This material (3.05 g, 16.1 mmol) was then converted to the title compounds in a procedure similar to preparation C, isolated as an oil:
Reaction SMILES: CN(C)/C=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].I([O-])(=O)(=O)=[O:20].[Na+]>O.O1CCCC1>[CH3:14][O:13][C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:20])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1)=[O:12]
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 119.5 g (0.478 mol) of (E)-1-(dimethylamino)-2-[4-(methoxycarbonyl)-2-nitrophenyl]-ethene and 1.3 l of water/tetrahydrofuran mixture (1/1 v/v) were added, in batches, 308.0 g (1.44 mol) of sodium metaperiodate, whilst the reaction temperature was regulated at under +30° C. by external cooling with ice water. The mixture was stirred for a further 2.5 hours at room temperature and then filtered. The precipitate was thoroughly washed with ethyl acetate. The organic phase was separated off, the aqueous phase was thoroughly extracted with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulphate and evaporated down in vacuo. The oil which crystallised after one day was further processed without any more purification. Yield: 87 g (87% of theory).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4](=[O:30])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][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][CH3:29])[CH:6]=1.[OH-].[Na+]>CO>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([C:4](=[O:30])[C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=1)[CH2:13][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][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)C(=O)O)c1
Yield: 86.6 %

Procedure:
To 2.98 g (6.9 mmol) of 3-(octadecyloxy)-alpha-oxobenzeneacetic acid methyl ester in 200 ml of hot methanol was added 7.6 ml (7.6 mmol) of 1N NaOH. The solution was stirred at reflux for 5 minutes and the solvent was then removed under reduced pressure. The residue was treated with water and 15 ml of 1N HCl and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized form acetone-hexane to give 2.5 g (88% yield, mp 77°-79°) of 3-(octadecyloxy)-alpha-oxobenzeneacetic acid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([N:22]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=O)[C:23](=[O:41])[NH:24][C:25]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:26]=2[O:27][CH2:28][O:29][CH3:30])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[N:49]1[C:53](=O)[CH2:52][CH2:51][C:50]1=O.C(NCC)C>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C.O1CCCC1>[C:16]1([N:22]([CH2:42][CH2:43][CH2:44][C:45]([N:49]([CH2:53][CH3:52])[CH2:50][CH3:51])=[O:47])[C:23](=[O:41])[NH:24][C:25]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([C:37]([CH3:39])([CH3:40])[CH3:38])[C:26]=2[O:27][CH2:28][O:29][CH3:30])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1O
Reactant: COCOc1c(NC(=O)N(CCCC(=O)O)c2ccccc2)cc(OC)cc1C(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)CCCN(C(=O)Nc1cc(OC)cc(C(C)(C)C)c1OCOC)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
Under ice-cooling, 2.5 g of 1,3-dicyclohexylcarbodiimide (DCC) was added to a mixture of 5.0 g of {2-[3-phenyl-3-(3-carboxypropyl)ureido]-4-methoxy-6-tert-butyl-phenoxy}methoxymethane, 1.4 g of N-hydroxysuccinimide (HOSu) and 50 ml of tetrahydrofuran (THF). The mixture was stirred at room temperature for 5 hours. Insoluble materials were filtered off and the filtrate was condensed. Under ice-cooling, a mixed solution of 1.2 ml of diethylamine and 10 ml of dimethylformamide (DMF) was added dropwise to a mixture of the obtained residue, 1.9 ml of tri-ethylamine and 10 ml of DMF. The resulting mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture and the mixture was washed and dried, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=1:2) to give 3.95 g of {2-[3-phenyl-3-(3-diethylaminocarbonylpropyl)ureido]-4-methoxy-6-tert-butylphenoxy}methoxymethane (yield: 70%, state: pale yellow oily product, IR: 3340, 1676, 1635, 1590, 1519 cm-1).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[OH:9].[CH3:12]C([O-])(C)C.[Na+].COS(OC)(=O)=O>C1COCC1>[CH3:12][O:9][C@H:4]1[C:3](=[O:2])[CH2:8][CH2:7][O:6][CH2:5]1
Reactant: CC(C)(C)[O-]
Reactant: COC1(OC)CCOCC1O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CO[C@@H]1COCCC1=O

Procedure:
reacting said 4,4-dimethoxytetrahydro-2H-pyran-3-ol in the presence of THF, NaOt-Bu, Me2SO4, and an acid to form (3R)-3-methoxytetrahydro-4H-pyran-4-one.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[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][CH3:16].C(N(CC)CC)C.ClC(OCC)=O.[NH2:52][C@H:53]([C:57]([NH:59][C@H:60]([C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:74])[CH2:61][CH2:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])=[O:58])[C@@H:54]([CH3:56])[OH:55]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:52][C@H:53]([C:57]([NH:59][C@H:60]([C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:74])[CH2:61][CH2:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])=[O:58])[C@@H:54]([CH3:56])[OH:55])=[O:23])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: -20 °C
Yield: 81.5 %

Procedure:
To a solution of 3-hexadecanoyloxyoctadecanoic acid (55 g) and triethylamine (16 ml) in tetrahydrofuran (500 ml) was added ethyl chloroformate (11 ml) dropwise with stirring at -20° C., and the mixture was stirred for 1 hour at the same temperature. To the mixture was added triethylamine (32 ml) and then, a solution of dibenzyl N-(L-threonyl)-L-glutamate (77 g) in tetrahydrofuran (100 ml) dropwise and the mixture was stirred for 3 hours at room temperature. Tetrahydrofuran was removed under reduced pressure to give the residue which was taken up in ethyl acetate. The ethyl acetate solution was washed with diluted hydrochloric acid and diluted sodium bicarbonate and dried. Evaporation of the solvent gave the residue which was recrystallized from ethanol to leave dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-glutamate (79 g).
Reaction SMILES: [CH3:1][N:2]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:21])[NH:3][C:4](=[O:19])[CH2:5][C:6]([NH:8][N:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:11])=[O:7].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([N:8]([C:6](=[O:7])[CH2:5][C:4]([NH:3][N:2]([CH3:1])[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[S:21])=[O:19])[N:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:11])(=[O:30])[CH3:29]
Reactant: CN(NC(=O)CC(=O)NN(C)C(=S)c1ccccc1)C(=S)c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N(C(=O)CC(=O)NN(C)C(=S)c1ccccc1)N(C)C(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N′1,N′3-dimethyl-N′1,N′3-di(phenylcarbonothioyl)malonohydrazide (a, 2.0 mmol) in TEA (5 mL) and DCM (10 mL) was added dropwise acetyl chloride (4.0 mmol) and the mixture was stirred at rt for 12 h before quenching with aqueous 1N NaHCO3 (10 mL). The organic layer was separated and evaporated. The residue was purified by flash chromatography to give b as yellow solids (7 mg).
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:33]([Cl:34])=[CH:32][C:10]3[N:11](COCC[Si](C)(C)C)[C:12]([O:14][CH:15]4[CH2:18][CH:17]([C:19]([O:21]CC)=[O:20])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.S(=O)(=O)(O)[O-].[K+]>C(O)=O>[C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:33]([Cl:34])=[CH:32][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=CO
Product: O=C(O)C1CC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)C1
Temperature: 80 °C

Procedure:
To a solution of ethyl 3-{[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-benzimidazol-2-yl]oxy}cyclobutanecarboxylate (100 mg, 0.173 mmol) in formic acid (1.7 ml) was added a saturated aqueous solution of potassium bisulfate (0.3 ml, 0.173 mmol). The reaction mixture was heated at 80° C. for 1 h. Then the volatiles were removed in vacuo and the resulting residue was acidified with 1N aqueous HCl and extracted with EtOAc. The organic phase was separated, washed with water, and concentrated in vacuo. Purification of the resulting residue by reverse phase HPLC eluting with 30-100% MeCN:H2O afforded the title compound as a white solid. LC-MS: calculated for C24H19ClN2O3 418.11, observed m/e: 418.93 (M+H)+ (Rt 2.16/4 min). 1H NMR (500 MHz, CD3OD): δ 7.75-7.35 (m, 11H), 5.25-5.20 (m, 1H), 2.90 (m, 31-1) 2.50 (m, 2H).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:23](=[O:24])/[CH:22]=[CH:21]/[C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(/C=C/c1ccc([N+](=O)[O-])cc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-nitrophenyl)propenoic acid; MS (ES+) 302 (MH+).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]=[CH2:27])=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([F:28])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]=[CH2:27])=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:28])[CH:14]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoate (2.4 g, 6.2 mmol) in dichloromethane (10 mL), was added trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 16 h and then concentrated in vacuo. The residue was triturated in hexanes (50 mL), the solid was filtered and dried to give the title compound as a light yellow solid (1.5 g, 73% in 2 steps): 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br s, 1H), 7.92 (d, J=8.6 Hz, 1H), 6.96-6.81 (m, 2H), 5.84-5.78 (m, 1H), 5.32-5.28 (m, 1H), 3.62 (s, 2H), 3.34 (s, 3H), 1.95 (s, 3H), 1.70-1.60 (m, 12H); MS (ES+) m/z 331.2 (M+1); MS (ES−) m/z 329.4 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([OH:31])[C:29]#[CH:30].C(N(C(C)C)CC)(C)C>[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:30]#[C:29][CH2:28][OH:31])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(I)c1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C#CCO)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3-methyliodobenzene (25.1 g), copper(I) iodide (440 mg), triphenylphosphine (1.50 g), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (2.39 g), propargyl alcohol (7.50 ml), diisopropylethylamine (80.0 ml) and tetrahydrofuran (230 ml) was stirred at room temperature for 10 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (8.6 g) as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[F:24])[CH2:10]1)=[O:8]
Reactant: Fc1ccccc1CBr
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C2CN(Cc3ccccc3F)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
In 3 mL of anhydrous dimethylformamide was suspended 16 mg (0.4 mmol) of sodium hydride (60%), 86 mg (0.31 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a was added and the mixture was stirred at rt. After 30 minutes, 75.6 mg (0.40 mmol) of 2-fluorobenzylbromide was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched by the addition of 10 mL of water. The crude product precipitated out were isolated by filtration and purified by flash chromatography to yield 25 mg of colorless solid 41: LC-MSD, m/z for C25H20FNO2 [M+H]+=386.4, [M+2H]+=387.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.526 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.2-2.3 (d, 6H), 5.7 (s, 2H), 7.1-7.3 (m, 4H), 7.3-7.4 (m, 1H), 7.4-7.5 (m, 2H),7.54 (s, 1H), 7.6-7.66 (d, 1H), 7.67-7.74 (t, 1H), 8.2 (d, 1H), 8.58 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2)#[N:4].[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(O)(=O)C>O1CCCC1.ClCCl>[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][CH2:5][C:3]#[N:4])[CH:12]=[CH:13]1
Reactant: N#CCOc1cccc2cc[nH]c12
Reactant: BrCc1cccc(C2OCCO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CCOc1cccc2ccn(Cc3cccc(C4OCCO4)c3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60% Sodium hydride dispersion in mineral oil (90 mg, 2.25 mmol) was added to a stirred, cooled solution of 7-cyanomethoxyindole (Example 1a) (0.32 g., 1.86 mmol) in tetrahydrofuran (8 ml). The dark mixture was stirred for 15 minutes at room temperature then cooled again whilst a solution of 3-(1,3-dioxolan-2-yl)benzyl bromide (0.50 g., 2.06 mmol) in tetrahydrofuran (2 ml) was added. The mixture was stirred at room temperature for 20 hours then treated with glacial acetic acid (130 μl), diluted with dichloromethane, washed with water, dried and evaporated. The residue was chromatographed on silica in ethyl acetate-hexane (1:3).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][NH:7][S:8]([C:11]1[S:15][C:14]([NH:16][C:17]([N:19]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:18])=[N:13][CH:12]=1)(=[O:10])=[O:9])C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)CCNS(C1SC(N)=NC=1)(=O)=O)C.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:31]1([CH2:30][N:19]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=2)[C:17](=[O:18])[NH:16][C:14]2[S:15][C:11]([S:8]([NH:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])(=[O:10])=[O:9])=[CH:12][N:13]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)CCNS(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)CCNS(=O)(=O)c1cnc(N)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(S(=O)(=O)NCCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via 3-{2-[3-cyclopentylmethyl-3-(4-methanesulfonylphenyl)-ureido]-thiazole-5-sulfonylamino}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and 3-(2-amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester the latter prepared in a similar manner as (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.