Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:5]=2[S:4][CH:3]=1.C(C1C=C2C(=CC=1)C([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]1)=CC=C2)#N>>[C:11]([C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:25]3[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]3)=[CH:3][S:4][C:5]=2[CH:10]=1)#[N:12]
Reactant: C[C@@H]1CN(c2cccc3cc(C#N)ccc23)CCN1
Reactant: N#Cc1ccc2c(Br)csc2c1
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1

Procedure:
3-Bromo-1-benzothiophene-6-carbonitrile was coupled with (2R)-methylpiperazine, as described above for (3R)-1-(6-cyano-1-naphthyl)-3-methylpiperazine, to yield (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C1C=CC=CC=1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1-c1ccccc1
Reaction time: 1 h

Procedure:
To a stirring solution of 1,1'-biphenylcarboxylic acid (1.0 g, 4.6 mmol) in 10 ml of dry benzene, under argon was added oxalyl chloride (0.40 ml, 2.0 eq.). To this solution was added DMF dropwise in 10 minute intervals, until no gas was evolved and the solution turned slightly cloudy (two drops). The mixture was stirred for 1 hour, then reduced on the rotovap without heating. The crude product, white solid, was carried directly on to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.Cl.C[OH:26]>[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CO
Reactant: CCCC/C(=C\c1ccc(OC2CCCCC2)c(Br)c1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Product: CCCCC(=O)Cc1ccc(OC2CCCCC2)c(Br)c1
Temperature: 25 °C

Procedure:
2-Bromo-1-cyclohexyloxy-4-((E)-2-nitro-hex-1-enyl)-benzene (8.3 mmol, 3.2 g), and iron powder (41.8 mmol, 2.3 g) were dispersed in methanol (20 mL), 3.0 N HCl (20 mL) and heated to reflux for 3.0 h. Cooled the reaction mixture to room temperature, filtered through celite washed with ether. Organic layer separated, dried (Na2SO4) filtered and concentrated under reduced pressure to provide 1-(3-Bromo-4-cyclohexyloxy-phenyl)-hexan-2-one (2.5 g).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH:7]([CH2:26][O:27]C(C)(C)C)[NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:33]([C:37]([OH:39])=[O:38])([F:36])([F:35])[F:34]>C1(C)C=CC=CC=1>[F:34][C:33]([F:36])([F:35])[C:37]([OH:39])=[O:38].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH:7]([C:6]([OH:32])=[O:5])[CH2:26][OH:27])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)(C)OCC(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(CO)C(=O)O)cc12

Procedure:
A solution of O-t-butyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-serine t-butyl ester in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was recystallised twice from MeOH-EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-serine trifluoroacetate (68 mg, 0.19 mmol) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42]>>[OH:42][CH2:41][CH:40]([NH:39][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1)[CH2:43][OH:44]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 74.5 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 45 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 604 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:5])[CH3:2]
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Temperature: -50 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a -50° C. solution of 12.1 g (25.1 mmol) of N-ethoxycarbonyl-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinone in 90 ml methanol and 90 ml of tetrahydrofuran is added 1.04 g (27.5 mmole) of sodium borohydride. The reaction is stirred 2 hours at -50° C. and then allowed to warm to 25° C. The reaction is quenched by addition to 300 ml saturated sodium chloride and the mixture extracted with ethyl ether (2 liters). The organic extract is washed with 300 ml saturated sodium chloride, dried over magnesium sulfate and the ether evaporated in vacuo. The crude product is purified via column chromatography on 2 kg silica gel eluting in 500 ml fractions with 2% methanol-5% ether-93% dichloromethane to yield (fractions 20-26) 6.04 g (50%) of the title compound as an oil and 3.75 g (31% of a mixture of the title compound and its trans-isomer. Further chromatography yields pure trans-isomer.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([O:20]C)=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[CH:3]=1.[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([OH:20])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[CH:3]=1
Reactant: COC(=O)Cc1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(CC(=O)O)c(C)nc3sc(C)cc23)cc1
Temperature: 60 °C
Yield: 48.3 %

Procedure:
To a solution of methyl 2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.080 g; 0.246 mmol) in dioxane (4 mL) and water (1.5 mL) was added a 1N lithium oxide solution (1.5 mL; 1.50 mmol). The reaction mixture was heated at 60° C. for 4 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.037 g (48%) of the title compound as a beige solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCc1ccc(OCc2ccccc2)cc1
Temperature: 56.5 °C
Yield: 77.5 %

Procedure:
Acetone (500 ml) and potassium carbonate (154 g) were charged into RB flask followed by addition of p-hydroxy phenyl acetonitrile (100 g) under stirring. Benzyl bromide (154 g) was then added at ambient temperature, subsequently heating the reaction mass to 55-58° C. and maintaining for 2 hours. The reaction mass was then cooled to 25° C., filtered and washed with acetone (100 ml) to give 130 g (77.8%) of the p-benzyloxyphenyl acetonitrile.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:5]OS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)[CH2:4][O:3]1.[OH:19][C:20]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:21]=1[C:22]([NH:24][CH3:25])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][O:30][C:28]2[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[C:20]([O:19][CH2:1][C@:2]3([CH3:5])[CH2:4][O:3]3)[CH:29]=2)=[CH:37][CH:36]=1
Reactant: CNC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OCc2ccc(OC)cc2)cc1OC[C@]1(C)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (133 mg, 0.487 mmol), 2-hydroxy-4-[(4-methoxybenzyl)oxy]-N-methylbenzamide (140 mg, 0.487 mmol) and cesium carbonate, Cs2CO3, (198 mg, 0.608 mmol) in dimethylformamide (5 mL) was kept on stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-60% ethyl acetate in petroleum ether) to give the subtitled compound (130 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:15]([CH2:29][CH2:30][OH:31])[C:16](=[O:28])[C@@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:18][CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:20][C@@H:17]([CH2:18][CH3:19])[C:16]([N:15]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:29][CH2:30][OH:31])=[O:28]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)C(=O)N(CCO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
TFA(10 mL) was added to (S)-tert-butyl 1-(benzyl(2-hydroxyethyl)amino)-1-oxobutan-2-ylcarbamate (3 g, 8.92 mmol) in CH2Cl2 (50 mL) at 0° C. The mixture was stirred at 0° C. for 1.5 h, followed by solvent removal under reduced pressure. The residue was partitioned between CH2Cl2 (300 mL) and 25% aqueous sodium hydroxide (100 mL). The aqueous fraction was further extracted with CH2Cl2 (2×100 mL), and combined organic fraction was dried (Na2SO4), filtered and concentrated to afford (S)-2-amino-N-benzyl-N-(2-hydroxyethyl)butanamide as a yellow oil (1.84 g, 87%). 1H NMR consistent.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH2:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[S:23][CH:24]([CH3:29])[C:25](=[O:28])[NH:26][N:27]=3)=[C:18]([F:30])[CH:17]=2)[CH2:11]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:30][C:18]1[CH:17]=[C:16]([N:12]2[CH2:11][C@H:10]([CH2:9][NH:8][C:3](=[O:4])[CH3:2])[O:14][C:13]2=[O:15])[CH:21]=[CH:20][C:19]=1[C:22]1[S:23][C@@H:24]([CH3:29])[C:25](=[O:28])[NH:26][N:27]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1SC(c2ccc(N3CC(CN)OC3=O)cc2F)=NNC1=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)[C@H](C)S3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
2-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-6-methyl-4H-[1,3,4]thiadiazin-5-one, trifluoroacetate salt is dissolved in pyridine (2 ml) and acetic anhydride (0.0163 ml, 0.173 mmol) is added. The reaction is stirred at room temperature for 4 hours and then evaporated to dryness. The residue is purified by PTLC (10% MeOH/DCM) to give pure product as a white solid (0.046 g, 76%); 1HNMR (300 MHz, DMSO-d6) δ 1.34 (d, J=7.1 Hz, 3H), 1.82 (s, 3H), 3.41 (t, J=5.5, 2H), 3.71-3.82 (m, 2H), 4.14 (t, J=9.3 Hz, 1H), 4.71-4.79 (m, 1H), 7.41 (dd, J=1.9, 8.8 Hz, 1H), 7.58 (dd, J=1.7, 14, 1H), 7.68 (t, J=8.5, 1H), 8.25 (t, J=5.5 Hz, 1H), 11.7 (s, 1H); mp 200-2; MS (m/z): [M+H]+=381.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[CH:5][CH:4]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:7]1[N:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)[N:8]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1nccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 53.8 %

Procedure:
6-Cyano-2-methylthiopyrimidine (1.37 g, 9.06 mmol) and methyl thiosalicylate (3.05 g, 18.1 mmol) were dissolved in toluene (30 ml), and triethylamine (3.80 ml, 27.2 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (1.40 g, 54%) as pale yellow crystals.
Reaction SMILES: C(OC([O:8][C:9]1[C:18]2[NH:17][C:16](=[O:19])[CH2:15][O:14][C:13]=2[C:12]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][N:32]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[C:33](=[O:51])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH3:50])[CH:49]=3)[CH:40]=2)C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)=O)(C)(C)C.[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>C(Cl)Cl>[F:61][C:60]([F:63])([F:62])[C:58]([OH:64])=[O:59].[CH:52]1([N:32]([CH2:31][CH2:30][NH:22][CH2:21][CH2:20][C:12]2[C:13]3[O:14][CH2:15][C:16](=[O:19])[NH:17][C:18]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[C:33](=[O:51])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH3:50])[CH:49]=3)[CH:40]=2)[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)N(CCN(CCc3ccc(OC(=O)OC(C)(C)C)c4c3OCC(=O)N4)C(=O)OC(C)(C)C)C3CCCCC3)c2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cccc(CCOCCC(=O)N(CCNCCc3ccc(O)c4c3OCC(=O)N4)C3CCCCC3)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl(2-(N-cyclohexyl-3-(3-(1-methyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanamido)ethyl)carbamate [Example 5, Step iv)] (290 mg), DCM (5 mL) and TFA (2.5 mL) was stirred at 25° C. for 30 min. The reaction mixture was evaporated to afford crude product. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a 15-60% gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (94 mg). MS [M+H]+=591.3 (calc=591.3295) (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.69 (s, 1H), 7.57 (dt, J=1.6 and 8.0 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 4.60 (s, 2H), 4.12 (s, 3H), 3.75-3.64 (m, 5H), 3.52-3.44 (m, 2H), 3.12 (t, J=7.3 Hz, 2H), 3.02 (t, J=5.6 Hz, 2H), 2.88 (t, J=6.7 Hz, 2H), 2.86 (t, J=7.0 Hz, 2H), 2.63 (t, J=5.9 Hz, 2H), 1.80-1.72 (m, 2H), 1.69-1.58 (m, 2H), 1.46-1.24 (m, 5H), 1.15-1.03 (m, 1H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][OH:15])[CH:9]=[C:8]([NH2:16])[N:7]=1>O.C(O)(=O)C>[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]([N:1]=[O:3])=[C:8]([NH2:16])[N:7]=1
Reactant: O=N[O-]
Reactant: Nc1cc(OCCO)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(OCCO)n1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A solution of 4.55 g (0.066 mol) of sodium nitrite in 20 ml of water was added in drops to a solution of 8.50 g (0.050 mol) of 2-[(2,6-diaminopyrimidin-4-yl)oxy]ethan-1-ol in 100 ml of acetic acid (10% in water) over 1 h at 3-5° C. while stirring was performed. Then stirring was performed further for 2 h at room temperature. The resulting precipitate was sucked off, post-washed with water, and dried, whereby 2-[(2,6-diamino-5-nitrosopyrimidin-4-yl)oxy]ethan-1-ol (6.71 g, 67%) was obtained as a purple solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:29]=[C:27]([NH:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:30])[F:31])=[CH:25][CH:24]=4)[N:28]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Reactant: N=C(N)Nc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(C(F)(F)F)cc3)ncc1CC2
Yield: 8.1 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbaldehyde (200 mg, 1.02 mmol), N-(4-trifluoromethyl-phenyl)-guanidine nitrate (273 mg, 1.02 mmol), NaOH (41 mg, 1.02 mmol) and 2-methoxyethanol (1.25 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) followed by crystallisation from EtOAc gave the pure title compound as a white crystalline solid (30 mg, 8%): mp 212-213° C. Anal. RP-HPLC: tR 21.8 min (10-70% MeCN, purity 95%). 1H-NMR (CDCl3): δ 8.17 (s, 1H, Py-H), 7.71 (d, 2H, J 8.4, Ph-H), 7.52 (d, 2H, J 8.4, Ph-H), 7.16 (s, 1H, NH), 3.04 (t, 2H, J 6.6, CH2), 2.94 (t, 2H, J 6.6, CH2), 2.72 (s, 3H, CH3). MS (ESI−): m/z 360.95 (M−H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]3[O:13][C:14]4[C:20]([C:21]([NH2:23])=O)=[CH:19][CH:18]=[CH:17][C:15]=4[O:16][C@H:10]3[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[C:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]3[O:13][C:14]4[C:20]([C:21]#[N:23])=[CH:19][CH:18]=[CH:17][C:15]=4[O:16][C@H:10]3[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cccc2c1O[C@H]1CN(Cc3ccccc3)C[C@@H]1O2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#Cc1cccc2c1O[C@H]1CN(Cc3ccccc3)C[C@@H]1O2
Yield: 68.5 %

Procedure:
An intimate mixture of Compound E (1.24 g) and phosphorus pentoxide (0.6 g) was heated to 165°. Two further aliquots of phosporus pentoxide (0.6 g each) were added at 10 minute intervals, mixing well in, while maintaining the temperature in the range 165° to 180°. Ten minutes after the final addition the solid mass was triturated with aqueous potassium hydroxide, ethyl acetate mixture and stirred well until free of solid. Evaporation of the organic layer gave a brown oil which was chromatographed on silica gel (50 g). Elution with ethyl acetate:petrol b.pt. 60°-80° (1:1) gave an oil (0.8 g) which solidified on trituration, with petrol, b.pt. 60°-80°. The product was collected, washed with petrol and dried to give the title compound as a buff coloured solid (0.57 g) m.pt. 101°-103°, NMR τ (CDCl3) 2.74 (5H, s, Ph), 2.5-3.4 (3H, m, aromatic), 5.4-6.1 (2H, m, 3a-H, 9a-H), 6.18 (2H, s, CH2Ph), 6.5-7.4 (4H, m, 1-H2, 3-H2).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:6][O:7][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CO)CCC1
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C)CCC2)cc1

Procedure:
To a solution of (1-methylcyclobutyl)methanol (32 mmol) in CH2Cl2 (100 mL) are added triethylamine (65 mmol), trimethylamine hydrochloride (6 mmol), and a solution of p-toluenesulfonyl chloride (49 mmol) in CH2Cl2 (50 mL) at 0° C., then the mixture is stirred at 0° C. for 0.5 h. The reaction is quenched by the addition of water, and the mixture is extracted with CH2Cl2. The combined organic extracts are washed with water and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo to give toluene-4-sulfonic acid 1-methylcyclobutylmethyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: C1([C:7]2C=CC=C[C:8]=2[CH2:9][OH:10])C=CC=CC=1.[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:9]([O:26][CH2:25][C:24]1[CH:23]=[CH:22][C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:28][CH:27]=1)(=[O:10])[CH:8]=[CH2:7]
Reactant: OCc1ccccc1-c1ccccc1
Reactant: OCc1ccc(-c2ccccc2)cc1
Product: C=CC(=O)OCc1ccc(-c2ccccc2)cc1

Procedure:
The same process as in Synthetic Example 1 was conducted except that the ortho-phenylbenzyl alcohol in Synthetic Example 1 was changed to para-phenylbenzyl alcohol Consequently, 22.4 g of para-phenylbenzyl acrylate was obtained. The obtained para-phenylbenzyl acrylate was solid at ordinary temperature and had a melting point of 32° C. and a refractive index of 1.5920 at 40° C. The measurement result of 1H-NMR is shown below.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[C:16]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(O)(C)C>[C:16]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:15]=[CH:14][C:9]4[NH:10][C:11](=[O:13])[O:12][C:8]=4[CH:7]=3)[CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2ccc(CCCCCl)cc2o1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=c1[nH]c2ccc(CCCCN3CCN(c4cccc5ccccc45)CC3)cc2o1
Yield: 543.1 %

Procedure:
To a 100 ml round-bottom flask equipped with condenser and nitrogen inlet were added 0.658 grams (3.10 mmol) of 6-(4-chlorobutyl)-benzoxazolone, 0.7 grams (3.10 mmol) of N-(1-naphthyl)piperazine, 0.328 grams sodium carbonate, 2 mg sodium iodide, and 50 ml isopropanol. The reaction was refluxed for 3 days, evaporated, taken up in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluent, and the product dissolved in acetone, precipitated with ethereal HCl, and the white solid filtered, washed with acetone, and dried to afford 6.76 grams (46.0%) of a white solid, m.p. 231°-233° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH3:12]>[Ni]>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: N
Agent: [Ni]
Product: CC(C)(C)C1CCC(N)CC1

Procedure:
312 g of 4-tert-butylcyclohexanone in 500 ml of ammonia-saturated methanol were hydrogenated at 100° C. and 100 bar in the presence of 10 g of Raney nickel. The catalyst was filtered off, the mixture was concentrated, and the crude product was purified on a thin-layer evaporator (105°/0.5 mm). 303 g of colorless liquid were obtained. The product is an isomer mixture in which the cis-cyclohexylamine derivative prevails. ##STR11##