Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:13]([C@@H:14]([OH:29])[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:30][CH2:31][CH3:32])[CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C@H:15]([NH:25][C:26](=[O:28])[CH3:27])[C@@H:14]([C@H:13]1[CH2:12][O:11][C@H:10]([O:30][CH2:31][CH3:32])[CH2:9][NH:8]1)[OH:29]
Reactant: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCO[C@@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Dissolve (R)-5-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.060 g, 0.131 mmol) in dichloromethane (5 mL) and add trifluoroacetic acid (0.74 g, 6.5 mmol). Stir at room temperature for 1.5 hours and concentrate to give the title compound (60 mg, 97%).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[F:1][C:2]1[C:7]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccccc2)cc1CO
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (4,5-difluoro-2-nitrophenyl)methanol (950 mg, 5 mmol) in DMF (15 mL) were added potassium carbonate (1.23 g, 10 mmol) and phenol (520 mg, 5.5 mmol). The resulting mixture was stirred at 50° C. overnight, cooled to room temperature, filtered, washed with ethyl acetate (2×20 mL), and concentrated. The resulting crude mixture was purified by chromatography (silica gel, 30-70% ethyl acetate in heptane) to yield a slightly yellow solid.
Reaction SMILES: C[O:2][C:3]1[C:6](=[O:7])[C:5](=O)[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:17](=[O:26])[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH:13]=[CH:14][CH:15]=1.[NH3:35]>C(O)C>[NH2:35][C:5]1[C:6](=[O:7])[C:3](=[O:2])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([N:16]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:17](=[O:26])[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(N(C(=O)C(C)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(N(C(=O)C(C)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), a solution of N-[3-(2-methoxy-3,4-dioxo-1-cyclobutenylamino)phenyl]-N-(4-methoxyphenyl)-2-phenylpropionamide (600 mg) [prepared as described in step (b) above] in ethanol (4 ml) and a solution of ammonia in ethanol (2N, 6 ml) were reacted, to afford the title compound (521 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][CH2:43][C:44](=[O:46])[N:45]=2)[CH2:37][CH:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][C:43](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:3]=3[C:2]([F:26])([F:1])[F:27])[N:7]=[C:8]4[I:17])[C:44](=[O:46])[N:45]=2)[CH2:37][CH:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)CC1CO
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(I)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)CC1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and 2-Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following General Procedure D.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][C:64]=1[Cl:65])[CH2:60]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:60][C:59]5[CH:62]=[CH:63][C:64]([Cl:65])=[C:57]([Cl:56])[CH:58]=5)=[CH:43][CH:44]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@H:46]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
(S)-2-{[(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (64 mg, 0.087 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (0.43 mmol) and potassium carbonate (0.43 mmol) were added. The mixture was stirred at room temperature for 8 hours and was poured onto ethyl acetate and 10% sodium carbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (24 mg, LC/MS: m/z 899).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:29][S:30][CH2:31][CH2:32]Cl.C>CN(C=O)C.C(#N)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH2:32][CH2:31][S:30][CH3:29])[CH:4]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CSCCCl
Agent: C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCSC
Yield: 31.8 %

Procedure:
A stirred mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (10.0 g, 31.06 mmoles) (from Preparation No. 1A), anhydrous potassium carbonate (12.84 g, 93.16 mmoles), sodium iodide (4.66 g, 31.06 mmoles) and 2-chloroethyl methyl sulfide (3.70 ml, 4.10 g, 37.26 mmoles) in 60 ml of dry DMF was refluxed for 10 hours. The solvent was evaporated under reduced pressure and the dark semi-solid was partitioned between water and methylene chloride. Sodium hydroxide solution was added to bring the pH of the aqueous layer to 14. The mixture was shaken well and the layers were separated. The aqueous layer was extracted with 3 portions of methylene chloride. The combined organic solutions were dried over MgSO4 and evaporated. The solid obtained was dissolved in 100 ml of warm acetonitrile. The solution was treated with Darco G-60, filtered, evaporated to 30 ml, and stored at -15°. The solid was filtered to give 3.56 g (32%) of the title compound as off-white crystals, mp. 118°-120°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15](N)=[O:16]>>[N+:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[NH:14][C:15](=[O:16])[NH:1]2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: NC(N)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Product: O=c1[nH]c(=O)c2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 160 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 5 g (0.027 mol) of 2-amino-4-nitrobenzoic acid and 16.5 g (0.27 mol) of urea was heated to 160° C. for 2 hrs. and at 180° C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. 4.8 g (80%) of 7-nitro-1,2,3,4-tetrahydro-quinazoline-2,4-dione were obtained as a white solid;
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[C-:21]#[N:22].[K+]>CS(C)=O>[C:21]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:22]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(F)(F)F)c1F
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(C(F)(F)F)c1C#N
Temperature: 80 °C
Reaction time: 24 h

Procedure:
1,1-Dimethylethyl {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}carbamate (1.17 g, 4 mmol) was dissolved in dimethylsulphoxide (5 ml) and treated with potassium cyanide (0.260 g, 4 mmol). The mixture was then heated at 80° C. under argon for 1.5 hrs and then at 120° C. overnight (16 hrs). Additional potassium cyanide (0.260 g, 4 mmol) was then added and heating continued at 120° C. for a further 24 hrs. The mixture was then cooled to room temperature, quenched with water, and diluted with ethyl acetate. The organic extracts were separated and washed three times with water and then with saturated aqueous sodium chloride solution. Drying and evaporation gave a brown gum which was purified by silica-gel column chromatography, eluting with a 1:10-1:5 gradient of ethyl acetate in hexanes, to give partially pure 1,1-dimethylethyl {[2-cyano-3-(trifluoromethyl)phenyl]methyl}carbamate as a dark solid/semi-solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: Cc1ccccc1NCc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccccc1N(Cc1cccnc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 10 g. portion of 3-(2-methylphenylaminomethyl)pyridine was dissolved in 100 ml. of dichloromethane, and 10 g. of potassium carbonate and 8 g. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature for 3 days, and was then diluted with 200 ml. of dichloromethane and extracted twice with 100 ml. portions of water. The organic phase was dried over magnesium sulfate and evaporated to an oil, which was chromatographed over silica gel with 1:4 acetone:toluene. The product-containing fractions were combined and evaporated, and the residue solidified upon standing and was recrystallized from hot diethyl ether to obtain 2.9 g. of the desired product, m.p. 97°-98°.
Reaction SMILES: [Cl-].C(CC[N+:7]1[CH:12]=[CH:11][C:10](C#N)=[CH:9][CH:8]=1)(=O)N.[OH:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>O>[OH:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:10]2[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=2)[CH2:21][CH2:20]1
Reactant: N#Cc1cc[n+](CCC(N)=O)cc1
Reactant: OCCCC1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCCC1CCN(c2ccncc2)CC1
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of N-(2-carbamoylethyl)-4-cyanopyridinium chloride (2.1 g) in water (5 ml) was added dropwise to a stirred mixture of 4-hydroxypropylpiperidine (2.4 g), water (10 ml) and 2.5M sodium hydroxide solution (4.6 ml) cooled in an ice-bath. The mixture was stirred at 0°-5° C. for 1 hour. 2.5M sodium hydroxide solution (7 ml) was added and the mixture heated at reflux for 3 hours. The mixture was cooled in an ice-bath and gummy solid separated out. The aqueous layer was decanted off and the gummy solid dissolved in dichloromethane (75 ml). The solution was washed with saturated sodium chloride solution (10 ml) and dried (MgSO4). The solvent was removed by evaporation to give a gummy solid (880 mg) which on trituration with ether gave a solid; NMR(d6DMSO): 1.0-1.35(m,4H), 1.35-1.6(m,3H), 1.7(dd,2H), 2.70-2.88(dt,2H), 3.38(t,2H), 3.89(brd,2H), 4.35(brs,1H), 6.78(d,2H), 8.1(d,2H); mass spectrum(CI+): 221(M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:45])[C@H:4]([OH:44])[CH2:5][NH:6][C:7](=[O:43])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[O:17])=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16](=[O:17])[N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C@@H:4]([OH:44])[C:3]([OH:45])=[O:2])=[O:43])=[CH:13][CH:12]=2)[C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[CH:20][C:21]=1[C:27]([F:28])([F:30])[F:29])#[N:26]
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(NC(=O)N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)c2ccc(C3CCCCC3)cc2)cc1C(F)(F)F
Reaction time: 1.5 h
Yield: 901.1 %

Procedure:
(R)-3-{4-[3-(4-Cyano-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl-amino}-2-hydroxypropionic acid methyl ester (0.07 g, 0.124 mmol) was suspended in ethanol (3 mL) and sodium hydroxide (4 N, 0.19 mL, 0.742 mmol) was added. The reaction mixture was stirred for 1.5 hour, and concentrated to remove the ethanol. The residue was diluted with water (10 mL) and acidified with hydrochloric acid (4 N, 0.21 mL). The mixture was extracted with ethyl acetate (2×10 mL) and the combined organic phases were washed with water (3×10 mL), dried with magnesium sulphate and concentrated in vacuo to afford the title compound (0.68 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1.C(O)(=O)C>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1
Reactant: O=C(/C=C/c1cccnc1)c1ccc2c(c1)CCCC2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CCc1cccnc1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.7 %

Procedure:
A mixture of [(E)-2-(3-pyridyl)ethenyl]-(5,6,7,8-tetrahydronaphthalen-2-yl)ketone (6.32 g), palladium black (150 mg) and acetic acid (3 ml) in MeOH (50 ml) was stirred under hydrogen atmosphere at room temperature for 6 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and brine, and dried. After removal of the solvent, the residue was recrystallized f rom hexane-ethyl acetate to give the titled compound (3.93 g).
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]([CH2:20][C:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[N+:7]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[OH-].[NH4+].[ClH:29]>>[ClH:29].[C:22]([C:21]1[N:2]=[C:3]2[N:4]([CH:20]=1)[C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[N:7]2[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cn1c(N)[n+](CCN2CCOCC2)c2ccccc21
Agent: Br
Agent: Cl
Agent: [NH4+]
Product: CC(C)(C)c1cn2c3ccccc3n(CCN3CCOCC3)c2n1

Procedure:
The hydrobromide obtained in Step A is heated at reflux in concentrated hydrochloric acid for 30 minutes. The solution is cooled and neutralised with an aqueous ammonium hydroxide solution. The reaction mixture is extracted with benzene and the extract is dried over sodium sulfate. Subsequently, pass through a stream of gaseous hydrochloric acid until acidity. The resulting precipitate is filtered and recrystallised from ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[CH3:10][CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:9][O:8][C:4]1[CH:3]=[C:2](/[CH:14]=[CH:13]/[CH2:12][CH:11]([OH:15])[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: C=CCC(C)O
Reactant: COc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COc1cncc(/C=C/CC(C)O)c1
Temperature: 140 °C
Yield: 83.6 %

Procedure:
A mixture of 5-bromo-3-methoxypyridine (4.11 g, 21.86 mmol), 4-penten-2-ol (2.25 g, 26.23 mmol), palladium(II) acetate (49 mg, 0.22 mmol), tri-o-tolylphosphine (266 mg, 0.87 mmol), triethylamine (13.71 mL, 98.37 mmol), and acetonitrile (15 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 3.53 g (70.3%) of a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:32].[Na+].CC(=O)CC>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][I:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: BrCC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: ICC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Yield: 91.2 %

Procedure:
First, 6 g of 2,2-bis(6-benzyloxyhexyl)ethyl bromide, 2.19 g of sodium iodide, and 150 ml of 2-butanone were placed in a 300 ml flask. The mixture was stirred under reflux for 16 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 6 g of 2,2-bis(6-benzyloxyhexyl)ethyl iodide (Y: 91.2%). The compound thus obtained had a purity of 95.3% by HPLC.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([OH:17])=O)=[CH:5][CH:4]=1)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[CH3:35])=[O:26])[CH2:19]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[N:34]4[C:30]([S:31][CH:32]=[CH:33]4)=[N:29][C:28]=3[CH3:35])=[O:26])[CH2:19]2)=[O:17])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)cc1

Procedure:
prepared by reaction of 5-(4-ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]3[CH:18]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[O:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:26](=[O:29])[CH:27]([OH:28])[C:18]1[N:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:32]
Reactant: CCOC(=O)C=O
Reactant: COc1ccc(-c2cn3cc(C)ccc3n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(O)c1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Temperature: 25 °C
Yield: 19.8 %

Procedure:
To a magnetically stirred solution of 2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine 13a (2.55 g, 10.71 mmol) and ethyl glyoxylate toluene solution (11.79 mL, 54.62 mmol) in toluene (130 mL) under Ar atmosphere was added p-toluenesulfonic acid monohydrate (60.9 mg, 0.32 mmol). The reaction mixture was equipped with a dean-stark trap and refluxed for 4 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.72 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 1.15 (t, J=7.0 Hz, 3H), 2.31 (s, 3H), 3.83 (s, 3H), 4.13 (m, 1H), 4.24 (m, 1H), 5.75 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.99 (s, 1H).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:31]([OH:33])=[O:32])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:31]([O:33][CH2:2][C:1]#[N:4])=[O:32])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
N,N-Diisopropylethylamine (46 μL, 0.263 mmol) and subsequently bromoacetonitrile (83 μL, 1.197 mmol) were added to a solution of (S)-6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk35) (100.9 mg, 0.239 mmol) in acetonitrile (0.4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 2.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk36) (108.5 mg, 98%).