Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C@H:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[NH2:14])[CH2:8][CH2:7]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=2)[CH:32]=[CH:31]1>>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([NH:14][C@@H:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[CH2:21][CH2:22]3)=[O:16])[CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]3)=[O:40])[CH:37]=2)[CH:32]=[CH:31]1
Reactant: CN1CCC(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(C[C@@H](NC(=O)c2ccc3cc[nH]c3c2)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-[β-(1-methylpiperidin-4-yl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and indole-6-carboxylic acid (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][CH:23]=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Nc1cc[nH]n1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1Cl
Yield: 98.4 %

Procedure:
A mixture of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (3.95 g, 14.9 mmol) and commercially available 3-aminopyrazole (1.24 g, 14.9 mmol) in acetic acid (40 mL) was refluxed for 5.5 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (4.57 g, 98%) as ayellow solid. MS (EI) 311.2 [(M)+]; mp 114° C.
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6]([CH3:8])=O)C.[CH2:10]([CH:13]([NH:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH3:12]>C(O)C>[CH3:8][C:6]1[NH:21][N:20]([CH:13]([CH2:10][CH2:11][CH3:12])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:4](=[O:9])[CH:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCC(NN)c1ccccc1
Solvent: CCO
Product: CCCC(c1ccccc1)n1[nH]c(C)cc1=O

Procedure:
13 g of acetoacetic acid ethyl ester were dissolved in 20 ml of absolute ethanol. 16.4 g of α-n-propylbenzylhydrazine in a little absolute ethanol were slowly added to this solution under nitrogen. After the exothermic reaction had subsided, the mixture was heated for 2 hours under reflux.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([S:23][CH3:24])=[N:19][CH:20]=2)[NH:15][C:14]1=[O:25].[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([N:15]2[C:16]3=[N:17][C:18]([S:23][CH3:24])=[N:19][CH:20]=[C:21]3[CH2:22][N:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])[C:14]2=[O:25])[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(SC)nc3NC2=O)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(SC)nc32)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a 250-mL dry, round-bottomed flask was added 3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-methylsulfanyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine (1.5 g, 4.08 mmol), ethyl-4-hydroxycyclohexanecarboxylate (2.11 g, 12.23 mmol), triphenylphosphine (3.21 g, 12.23 mmol), and tetrahydrofuran (50 mL), and the solution was blanketed with a nitrogen atmosphere. The solution was then cooled to 0° C., and diisopropylazodicarboxylate (2.41 mL, 12.23 mmol) was added dropwise. The solution was then warmed to room temperature and stirred overnight. The crude mixture was then concentrated in vacuo and taken up in dichloromethane, washed with water, dried over sodium sulfate, and concentrated. The crude was purified by flash silica chromatography eluting with 3:2 hexane/ethyl acetate to yield the title compound (1.17 g, 55% yield): LRMS: 523.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1
Reaction time: 3 h
Yield: 97.7 %

Procedure:
Morpholine (190 μl, 2.17 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (209 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=3/1). Thus, 4-[2-nitro-4-(trifluoromethyl)phenyl]morpholine (270 mg, 97.7%) was yielded as an orange-colored oily material.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25].C(OCC)(=O)C>O>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCC(F)(F)F)cc2c1=O
Temperature: 140 °C
Yield: 25.3 %

Procedure:
A mixture of 200 mg (0.628 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 1.08 ml (13.68 mmol) of 2,2,2-trifluoro-ethylamine in a closed vial is heated in a microwave reactor at 140° C. for 20 hours. After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic phase dried and concentrated to yield a precipitate which is filtered off and submitted to purification by medium pressure chromatography on a RP-C18 column (20 μM material) with tetrahydrofuran/water 4:3 as eluent, containing 0.1% TFA. During concentration of the fractions the product precipitates and is collected by filtration, giving 63 mg of a red powder, m.p. 250° C. (decomp.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:8][C:7]([C@H:9]([N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:13]([C:16]2[CH:24]=[CH:23][C:19]3[N:20]=[CH:21][S:22][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[CH2:10][OH:11])=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]([NH:33][C@H:34]([C:48](O)=[O:49])[CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[S:22]1[C:18]2[CH:17]=[C:16]([S:13]([N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:9]([C:7]3[S:8][C:4]([CH2:3][NH:2][C:48](=[O:49])[C@H:34]([CH:35]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:33][C:31]([O:30][CH3:29])=[O:32])=[CH:5][CH:6]=3)[CH2:10][OH:11])(=[O:15])=[O:14])[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21]1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN([C@H](CO)c1ccc(CN)s1)S(=O)(=O)c1ccc2ncsc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO)N(CC(C)C)S(=O)(=O)c2ccc3ncsc3c2)s1)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of N-{(1R)-1-[5-(aminomethyl)thiophen-2-yl]-2-hydroxyethyl}-N-(2-methylpropyl)-1,3-benzothiazole-6-sulfonamide hydrochloride (30 mg, 0.065 mmol), N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (21 mg, 0.071 mmol) and DIPEA (45 μL, 0.26 mmol) in DMF (300 μL) at 0° C. was added BOP (32 mg, 0.071 mmol). The reaction mixture was stirred at 0° C. for 4 hours before being quenched with a saturated solution of sodium bicarbonate (3 mL). The quenched mixture was extracted with ether/ethyl acetate (1/1 3×3 mL). The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate. MS: m/z=729.1 (MNa+).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][CH:10]([OH:12])[CH3:11])[CH3:8].[H][H]>[Pd].C(O)C>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:9][CH:10]([OH:12])[CH3:11])[CH3:8]
Reactant: CC(=CC(C)O)c1ccccc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(O)CC(C)c1ccccc1-c1ccccc1

Procedure:
To a pressure vessel, mixture of 0.675 g. of 2-(p-biphenylyl)-2-penten-4-ol (obtainable by Example 1) and 0.5 g. 10% palladium on carbon in 175 ml. of ethanol, is added hydrogen at about 2 at. pressure via below pressure hydrogenation. The catalyst is then removed, and the solution is evaporated to give a colorless oil which solidifies on standing to give solid 2-(p-biphenylyl)-pentan-4-ol, m.p. 53° C., which may also be designated 4-(p-biphenylyl)-pentan-2-ol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])[C:13]3[NH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Cl:37])C(=O)C1>C(Cl)Cl>[Cl:37][C:16]1[C:14]2[N:15]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:11]=[C:12]([O:19][C:20]3[C:21]([CH3:29])=[CH:22][C:23]([C:24]#[N:25])=[CH:26][C:27]=3[CH3:28])[C:13]=2[NH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2cc[nH]c12
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c(Cl)c[nH]c12
Yield: 68.9 %

Procedure:
To a solution of 4-(2-(4-cyanophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (28.1 mg, 0.07 mmol) in CH2Cl2 (4 mL) was added NCS (9.9 mg, 0.07 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC eluting with hexanes:ethyl acetate (2:1), to give the product as a pink solid (20 mg, 65%).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.N1C=C[CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:24]([O:5][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH2:9][CH:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:23]#[CH:22]
Reactant: CCCCCC(C)CC=CC(C)=CC(=O)O
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: C#CCOC(=O)C=C(C)C=CCC(C)CCCCC
Temperature: 22 °C
Reaction time: 1 h

Procedure:
1.6 g of 3,7-dimethyl-2,4-dodecadienoic acid is dissolved in 20 ml of absolute diethyl ether and 0.55 ml of pyridine. The resulting mixture is added dropwise over a period of about 10 minutes to 0.57 ml of thionyl chloride at a temperature between 0°C. and +10°C. Subsequently the mixture is stirred for 1 hour at room temperature (22°C.), then decanted off, and the residue is washed with absolute diethyl ether. The solution is evaporated to dryness under anhydrous conditions. The residue is dissolved in 10 ml of absolute diethyl ether. The ethereal solution is added dropwise at a temperature between 0°C. and +10°C., over a period of about 20 minutes, to a solution consisting of 0.56 ml of propargyl alcohol and 0.55 ml of pyridine in 10 ml of absolute ether. After stirring overnight (16 hours) at room temperature (22°C.) the mixture is diluted with diethyl ether, washed with 1-N hydrochloric acid, saturated aqueous sodium bicarbonate solution and finally with aqueous sodium chloride solution. After drying, the ethereal phase is evaporated. The crude product is chromatographed on a 30-fold amount of Kieselgel, using hexane/diethyl ether (19:1 parts by volume) as the eluant. There is obtained 3,7-dimethyl-2,4-dodecadienoic acid propargyl ester as a colorless oil; boiling point 105°C/0.05 mmHg (bulb tube); n25 25= 1.4951.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:39][C@H:40]([C:53]([O:55]CC1C=CC=CC=1)=[O:54])[CH2:41][CH2:42][C:43]([O:45]CC1C=CC=CC=1)=[O:44]>>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:39][C@H:40]([C:53]([OH:55])=[O:54])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)=C(C)C1=O
Yield: 25.6 %

Procedure:
Using p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and dibenzyl L-glutamate p-toluenesulfonate (250 mg, 0.5 mmol) and following the procedure of Example 4, there was obtained 3-(2,3-dimethoxy-5-methylbenzoquinon-6-yl)propionyl-L-glutamic acid (49 mg).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@@H:43]1[C:50](=[O:51])[N:49]2[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]2[CH:47]=[CH:46][CH2:45][CH2:44]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:42][C@@H:43]1[C:50](=[O:51])[N:49]2[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]2[CH:47]=[CH:46][CH2:45][CH2:44]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCC=C[C@H]2CCCCN2C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC/C=C\[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21
Agent: Cl
Agent: N[C@H]1CC/C=C\[C@H]2CCCCN2C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCC=C[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((7S,11aR,Z)-6-oxo-2,3,4,6,7,8,9,11a-octahydro-1H-pyrido[1,2-a]azocin-7-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 55 (4.9 mg, 0.021 mmol) to give a white solid (10 mg, 74% yield). Anal. Calcd. for C42H54N4O6S m/z 742.4. found: 743.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.08 (12H, m), 5.94 (1H, t, J=9.3 Hz), 5.81-5.71 (1H, m), 5.33 (1H, t, J=4.7 Hz), 5.15-5.10 (1H, m), 5.04-4.95 (1H, m), 4.92-4.84 (1H, m), 4.73-4.65 (1H, m), 4.21 (1H, d, J=13.2 Hz), 3.68 (3H, s), 3.16 (1H, ddd, J=14.2, 11.1, 2.7 Hz), 2.87-2.65 (6H, m), 2.48-2.30 (4H, m), 2.18-2.07 (1H, m), 2.07-2.00 (2H, m), 1.91-1.42 (16H, m), 1.11-0.98 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[S:24])=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCCCC2=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Nc1ccc(N2CCCCC2=S)cc1
Reaction time: 0.75 h

Procedure:
15 g (78.8 mmol) of 1-(4-aminophenyl)piperidin-2-one are heated to the boil together with 16.0 g (39.5 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) in 100 ml of anhydrous toluene. After 45 minutes, the solvent is evaporated, and the residue is taken up in dichloromethane and 2 N HCl. The aqueous phase is extracted three times with dichloromethane and adjusted to a pH of 12 using conc. NaOH. Extraction with dichloromethane, drying over sodium sulfate and evaporation of the solvent give 1-(4-aminophenyl)piperidine-2-thione as a colourless solid, ESI 207.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:18]C(=O)C)[CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[NH2:18][CH:14]([CH:15]([CH3:17])[CH3:16])[C:12]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1)=[O:13]
Reactant: CC(=O)NC(C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 88.6 %

Procedure:
The product of step (i) (1.57 g) was dissolved in dichloromethane (14 ml) and trifluoroacetic acid (4 ml) added. After 2 hours at room temperature the solvent was removed, ethyl acetate and 2N aqueous NaOH solution were added to give pH 8.0. The organic phase was separated and concentrated to give the sub-titled product as an oil (1.24 g) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)C=Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)/C=C/c3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.106 g, 0.384 mmol) was reacted with N-(2-azidoethyl)cinnamamide (0.083 g, 0.384 mmol) following the general click procedure to give (E)-tert-butyl 2-amino-4-(5-(1-(2-cinnamamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), δ 7.51 (d, 1H), δ 7.28 (m, 6H), δ 6.45 (t, 2H), δ 6.08 (s, 2H), δ 4.47 (s, 2H), δ 3.79 (s, 2H), δ 2.57 (s, 2H), δ 2.23 (s, 2H), δ 1.50 (bs, 13H), δ 1.28 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.9, 150.4, 149.5, 148.3, 141.2, 138.9, 134.9, 129.9, 128.9, 128.0, 122.1, 120.8, 106.5, 84.8, 53.7, 49.5, 39.9, 31.1, 29.3, 28.9, 28.3, 28.2, 25.6 ppm; HRMS (ESI) calcd for C26H35N7O3(M+) 493.2801, found 493.2800, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)cinnamamide hydrochloride (0.097 g, 59% yield). 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), δ 7.49 (s, 3H), δ 7.32 (s, 3H), δ 6.30 d, 1H), δ 6.39 (s, 1H), δ 4.66 (s, 2H), δ 3.83 (s, 2H), δ 2.73 (s, 2H), δ 2.40 (s, 2H), δ 1.57 (s, 2H), δ 1.55 (s, 2H), δ 1.36 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 167.8, 160.5, 150.2, 147.3, 141.1, 134.8, 130.7, 129.9, 128.8, 127.8, 127.6, 124.9, 23 9, 120.2, 108.5, 108.3, 53.1, 39.3, 36.5, 30.6, 28.4, 28.1, 27.6, 26.5, 24.2, 24.1, 23.7 ppm; HRMS (ESI) calcd for C21H27N7O (M+) 393.2277, found 393.2273.
Reaction SMILES: [I-:1].Cl[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.CN1CCCC1=O>C(OCC)(=O)C>[I-:1].[N:24]1([C:3]2[CH:12]=[CH:11][C:10]3[N+:9]4[CH:13]=[C:14]5[CH:23]=[CH:22][C:21]6[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=6[N:15]5[C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: Clc1ccc2c(ccc3n4c(ccc5ccccc54)c[n+]23)c1
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)ccc1c[n+]3c4ccc(N5CCCC5)cc4ccc3n12

Procedure:
A mixture of 1.0 g. of 3-chloroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 1.0 ml. of pyrrolidine and 5 ml. of N-methyl-2-pyrrolidinone is stirred and heated at reflux for 17 hours, cooled and diluted with 100 ml. of ethyl acetate. The precipitate of 3-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, stirred with 50 ml. of 1% aqueous triethylamine hydroiodide and recollected; m.p. 312°-320° C. after crystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([OH:11])[N:5]=[C:4]([S:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[N:3]=1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(Cl)Cl>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][O:10][Si:24]([CH3:26])([CH3:25])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:6]([OH:11])[N:5]=[C:4]([S:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc(SCc2ccc3ccccc3c2)nc(O)c1CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCCc1c(N)nc(SCc2ccc3ccccc3c2)nc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(4-amino-6-hydroxy-2-[2-naphthylmethyl]thio-5-pyrimidinyl)-ethanol (Cpd #279; 106 mg, 0.32 mmol) is dissolved in pyridine (0.64 ml) and the solution is cooled to 0° C. then treated with t-butyl dimethylsilyl chloride (0.058 g, 0.39 mmol). The solution is stirred at 0° C. for 2 hours and two new spots developed in the mixture. The reaction mixture is poured into methylene chloride and washed 3× with 1 M HCl, 10% HCl, 3× H2O, 2× 6% NaHCO3, dried with MgSO4, then concentrated in vacuo. The crude product is then purified by chromatography (SiO2 1:1 hexane/ethyl acetate): 60 mg (0.18 mmol, 57%), mp 156-158° C.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:8]([CH2:9][NH:10][C:11](=[O:17])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7]
Reactant: CCCCOC(=O)NCCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOC(=O)NCC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of pyridine (1.8 mL) in 28 mL of CH2Cl2 was cooled in an ice bath and chromium trioxide (1.12 g) was added in one portion. The mixture was stirred at the same temperature for 20 min and at room temperature for 1 h. A solution of 67 (300 mg) in 2 mL of CH2Cl2 was added in one portion and the mixture was stirred for 1 h at room temperature. It was filtered through a pad of silica gel (5 g) and rinsed through with 50 mL of ethyl acetate. The filtrate was concentrated in vacuo to give the crude aldehyde which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=7.4 Hz, 3H), 1.38 (sextet, J=7.4 Hz, 2H), 1.61 (pentet, J=7.1 Hz, 2H), 4.09 (t, J=6.7 Hz, 2H), 4.14 (d, J=5.0 Hz, 2H), 5.30 (broad s, 1H), 9.66 (s, 1H).