Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].C([Sn](CCCC)=O)CCC.[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[NH:27][C:28]1[N:29]=[CH:30][C:31]2[CH2:36][N:35]([C:37]([O:39][CH2:40][CH2:41][CH2:42][C:43]#[N:44])=[O:38])[CH2:34][C:32]=2[N:33]=1>C1(C)C=CC=CC=1>[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[NH:27][C:28]1[N:29]=[CH:30][C:31]2[CH2:36][N:35]([C:37]([O:39][CH2:40][CH2:41][CH2:42][C:43]3[NH:44][N:3]=[N:2][N:1]=3)=[O:38])[CH2:34][C:32]=2[N:33]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCOC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(OCCCc1nnn[nH]1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 100 °C
Yield: 8.8 %

Procedure:
Add azidotrimethylsilane (3.5 mL; 9.7 equiv; 26.27 mmoles) and dibutyloxostannane (0.163 g; 0.25 equiv; 0.66 mmoles) to a solution of 3-cyanopropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (0.98 g; 1.0 equiv; 2.70 mmoles) in toluene (20.4 mL). Heat the reaction mixture to 100° C. for 18 hours. Concentrate the solution and purify by reverse phase chromatography followed by silica gel chromatography (0 to 15% methanol in chloroform) to afford the desired 3-(1H-tetrazol-5-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (0.097 g; 9%) as a brown solid: MS (m/z): 407(M+1).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)=[CH:3][C:4]([C:25]([F:28])([F:26])[F:27])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1ccc(F)cc1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(F)cc3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 4-fluoro-phenylboronic acid (35 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 490 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=2)([CH3:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[OH-].[K+].Cl>>[CH:21]([C:16]1[CH:15]=[C:14]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:5]=2)([CH3:12])[CH3:13])[CH:19]=[CH:18][C:17]=1[OH:20])=[CH:22][CH3:23]
Reactant: C=CCc1cc(C(C)(C)c2ccc(O)c(CC=C)c2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC=Cc1cc(C(C)(C)c2ccc(O)c(C=CC)c2)ccc1O

Procedure:
2,2-Bis(3-allyl-4-hydroxyphenyl)propane (1 mole) was mixed with potassium hydroxide pellets (2.2 moles) and the mixture was stirred and heated at 110° for 30 minutes. The mixture was cooled, neutralised with dilute hydrochloric acid, and the product was extracted to give methylene chloride. The solution was dried and evaporated to give substantially pure 2,2-bis(3-(1-propenyl)-4-hydroxyphenyl)propane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=2[CH3:23])=[CH:9][C:8]=1[CH3:24])[CH3:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:32][C:31]3[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=3)=[CH:17][C:16]=2[CH3:23])=[CH:9][C:8]=1[CH3:24])[CH3:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2C)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a stirred solution of compound 21.4 (13.5 g, 37.7 mmol) in CHCl3 (135 mL) was successively added 4-(trifluoromethyl)aniline (6.07 g, 37.7 mmol) and AcOH (3.24 mL). After stirring at room temperature for 30 min, the reaction was cooled to 0° C., sodium triacetoxyborohydride (12.0 g, 56.6 mmol) was added, and the reaction was stirred at room temperature for 3 h. The reaction mixture was poured into 150 mL of ice-water and the product was extracted with 2×50 mL CHCl3. The organics were sequentially washed with 150 mL aqueous NaHCO3 and 150 mL brine, dried over MgSO4, and concentrated to a yellow oil, which was purified with flash chromatography (SiO2 gel 60 N, eluted with 10% EtOAc/hexanes—20% EtOAc/hexanes). The fractions containing the desired product were combined and concentrated to yield a colorless solid (18.7 g). 1H NMR (400 MHz) (CDCl3) δ 7.38 (2H, d, J=8.5 Hz); 7.20 (1H, s); 7.14 (1H, s); 6.97 (1H, d, J=8.1 Hz); 6.70-6.50 (4H, m); 4.66 (2H, s); 4.40-4.20 (5H, m); 2.38 (3H, s); 2.30 (3H, s); 2.22 (3H, s); 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[OH:13])[CH3:3].Cl[C:15]1[N:16]=[N:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=1>>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]([CH:11]=1)[CH2:5][N:4]([C:15]1[N:16]=[N:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=1)[CH2:2][CH3:3]
Reactant: N#Cc1ccc(Cl)nn1
Reactant: CCNCc1cc(Br)ccc1O
Agent: Cl
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C#N)nn1
Yield: 50 %

Procedure:
The title compound was prepared by reacting N-ethyl-5-bromo-2-hydroxybenzylamine hydrochloride and 3-chloro-6-cyanopyridazine using a similar method to that of reference example 18 except eluting with 2% diethyl ether/dichloromethane in the chromatography (yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23]O)[N:21]=1)=[CH:5]2.[CH3:25][O:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1([CH2:23][CH2:22][C@@H:20]2[CH2:19][S:18][C:17]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:21]2)[CH2:33][CH2:32][CH2:31][NH:30]1)=[O:28]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: COC(=O)C1(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CCCN1

Procedure:
2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 5 and (S)-pyrrolidin-2-yl-carboxylic acid methyl ester were reacted according to the same procedure as Example 156 to give the title compound.
Reaction SMILES: Cl[C:2]1([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH:27]1([OH:33])[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:3]2[C:2]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([O:32][CH:29]3[CH2:30][CH2:31][CH:27]([OH:33])[CH2:28]3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:14][CH:15]=1
Reactant: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Reactant: OC1CCC(O)C1
Product: O=C1c2ccccc2C(OC2CCC(O)C2)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1

Procedure:
3-Chloro-2-(4-chlorobenzyl)-3-(4-chlorophenyl) isoindolin-1-one (157 mg, 0.390 mmol) was reacted with 1,3-cyclopentanediol (0.18 mL, 1.95 mmol.) as for general procedure C and the solvent evaporated under vacuum to leave a clear oil of crude 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-(3-hydroxycyclopentyloxy)isoindolin-1-one. This was purified by HPLC to give the pure product which was a clear glass (83 mg, 0.177 mmol., 45%). Rf 0.08 (40:60 EtOAc:petrol). λmax (CH3OH)/nm=220.5 (Abs=1.333). IR: 3426, 2935, 1696, 1695, 1597, 1489, 1467 cm−1. 1H NMR (300 Hz, DMSO); δ1.03-1.86 (m, 6H, cyclopentanediol C—H), 2.02 (m, 1H, N—CH2), 3.48-3.75 (M, 1H, N—CH2), 4.00-4.50 (m, 2H, cyclopentanediol O—C—H), 6.66-7.15 (m, 9H, Ar—H), 7.32-7.53 (m, 2H, Ar—H), 7.83 (m, 1H, Ar—H). 13C NMR (75 Hz, DMSO); δ 31.4 (N—CH2), 32.1, 33.8, 34.0, 42.9, 44.1 (cyclopentanediol), 95.0 (Ar2C(O)—N), 72.1, 73.0 (cyclopentanediol C—OH), 124.0, 124.3, 128.5, 128.6, 130.2, 130.8, 130.8, 132.7 (Ar). LC/MS-ES+ m/z 470.3, 468.3, 245.1, 243.1. Anal. Calcd. for C26H23Cl2NO3.0.4H2O: C, 65.66; H, 5.04; N, 2.95%. Found C, 65.49; H, 4.94; N, 3.02%. HRMS (EI) m/z: 467.1055. Found 467.1055.
Reaction SMILES: [Cl:1][CH:2]([C:7]1([C:16]([F:19])([F:18])[F:17])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([CH:2]([Cl:1])[C:3]([F:6])([F:5])[F:4])([C:16]([F:19])([F:18])[F:17])[O:11][C:10]=2[CH:12]=1
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccc(Br)cc2O1

Procedure:
51 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 2 or 17 were dissolved in 300 ml of carbon tetrachloride, and 0.5 g of anhydrous FeCl3 was added. 32 g of bromine were then added and the mixture was stirred under reflux for 3 hours. After cooling, the mixture was washed with 10% strength NaHSO3 solution, dried with MgSO4 and distilled. The yield was 49 g (63% of theory), and the boiling point was 94°-98° C. under 8 mbar.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:32]=[CH:31][C:19]([CH2:20][NH:21][C@@H:22]4[CH2:25][C@H:24]([C:26]([O:28]CC)=[O:27])[CH2:23]4)=[CH:18][CH:17]=3)=[N:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].[ClH:35]>CO>[ClH:35].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:32]=[CH:31][C:19]([CH2:20][NH:21][C@@H:22]4[CH2:25][C@H:24]([C:26]([OH:28])=[O:27])[CH2:23]4)=[CH:18][CH:17]=3)=[N:13][N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)[C@H]1C[C@@H](NCc2ccc(-c3nnc(-c4ccc(CC(C)C)cc4)o3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1ccc(-c2nnc(-c3ccc(CN[C@H]4C[C@@H](C(=O)O)C4)cc3)o2)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl cis-3-({4-[5-(4-isobutylphenyl)-1,3,4-oxadiazol-2-yl]benzyl}amino)cyclobutane carboxylate (0.300 g, 0.692 mmol), 1N NaOH (6.0 mL), and methanol (5 mL) was heated in a microwave oven at 100° C. for 3 minutes. The reaction mixture was cooled to room temperature and pH was adjusted to 7 with 1N HCl, causing a white solid to precipitate. The reaction mixture was filtered and the solid was washed with water, then treated with 1N HC in ether to give the title compound (0.170 g, 61% yield).
Reaction SMILES: CN(CCN([CH2:8][CH2:9][N:10](C)C)C)C.O=[C:14]1O[C@H:19]([C@H:21]([CH2:23]O)O)[C:17]([O-])=[C:15]1O.[Na+]>O>[CH:14]1[CH:23]=[CH:21][C:19]([CH2:8][CH2:9][NH2:10])=[CH:17][CH:15]=1
Reactant: CN(C)CCN(C)CCN(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Product: NCCc1ccccc1

Procedure:
A solution of Cu(I) catalyst at 1 mM and PHEA-MA at 1 mM (30 mg/mL) was prepared by dissolution of Cu(II)Br (2.35 mg, 10 μmol), PMDETA (6 μL, 30 μmol), sodium ascorbate (39.6 mg, 200 μmol) and PHEA-MA (300 mg, 10 μmol) in 10 mL of milli-Q water solution. The solution was then filtered with a 0.45 μm filter (Acrodisc Syringe Filter). Si wafers coated with the initiator layers were immersed vertically into the Cu(I) catalyst/PHEA-MA solution and allowed to polymerize for a predetermined time. To quench the reaction, the slides were washed 3 times with milli-Q water, soaked overnight in milli-Q water and then dried under air flow before ellipsometry or AFM analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][CH2:16][C:17]([OH:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:42][N:43]([CH:60]([C:68](=[O:71])[NH:69][CH3:70])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:44](=[O:59])[CH:45]([NH:57][CH3:58])[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][CH2:16][C:17](=[O:19])[N:57]([CH3:58])[C@@H:45]([C:44](=[O:59])[N:43]([CH3:42])[C@@H:60]([C:68](=[O:71])[NH:69][CH3:70])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1COCC(=O)O
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC1CCCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 2-(carboxymethoxymethyl)piperidine-1-carboxylic acid tert-butylester (225 mg, 0.82 mmol) in 5 ml of dichloromethane was added 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (173 mg, 0.90 mmol) and the mixture was to stirred for 30 min. N-Methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(2-naphthyl)propionamide (332 mg, 0.82 mmol) in dichloromethane (5mL) was added followed by diisopropylethylamine (0.14 ml, 0.82 mmol) and the mixture was stirred overnight at room temperature. The mixture was washed with water (5 ml) aqueous sodium bicarbonate (5 ml), water (2×5 ml), brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (20 g) with ethyl acetate to give 416 mg of 2-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)piperidin-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[CH:10]([CH2:11][C:12](=[O:16])[NH:13][N:14]=3)[CH2:9][CH2:8][C:7]=2[CH:17]=1.O1[CH:23]=[CH:22][C:21](=[O:24])[CH:20]=[CH:19]1>O>[O:24]=[C:21]1[CH:22]=[CH:23][N:2]([C:3]2[CH:4]=[CH:5][C:6]3[C:15]4[CH:10]([CH2:11][C:12](=[O:16])[NH:13][N:14]=4)[CH2:9][CH2:8][C:7]=3[CH:17]=2)[CH:19]=[CH:20]1
Reactant: Nc1ccc2c(c1)CCC1CC(=O)NN=C21
Reactant: O=c1ccocc1
Agent: Cl
Solvent: O
Product: O=C1CC2CCc3cc(-n4ccc(=O)cc4)ccc3C2=NN1
Yield: 10.3 %

Procedure:
A stirred mixture of 8-amino-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one hydrochloride (1.5 g) and 4H-pyran-4-one (0.84 g) in water (40 ml) was heated under reflux for 2 hours in a nitrogen atmosphere. The resultant solid was washed with dilute hydrochloric acid to give a crude product, 0.5 g. Purification by column chromatography (silica gel, 9:1 chloroform:methanol) gave the title compound 0.18 g, m.p. >300° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=[O:9])=[C:6]([NH2:10])[N:5]=[C:4](SC)[N:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>O>[NH2:1][C:2]1[C:7]([N:8]=[O:9])=[C:6]([NH2:10])[N:5]=[C:4]([NH:21][CH2:20][CH2:19][C:18]2[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:3]=1
Reactant: CSc1nc(N)c(N=O)c(N)n1
Reactant: COc1ccc(CCN)cc1
Solvent: O
Product: COc1ccc(CCNc2nc(N)c(N=O)c(N)n2)cc1
Yield: 84 %

Procedure:
The starting material was prepared as follows:-1) A mixture of 4,6-diamino-2-methylthio-5-nitrosopyrimidine (10 g, 5.4 mM), 4-methoxyphenethylamine (7.92 ml, 5.4 mM) and water (180 ml) was heated to reflux for one hour. After cooling the red solid was separated by filtration, washed with water, and dried. There was thus obtained 4,6-diamino-2-[2-(4-methoxyphenyl)-ethyl]amino-5-nitrosopyrimidine (13.4 g, 84% yield). NMR: DMSO-d6 ; 2.7-2.85(m,2H, CH2 --CH2), 3.4-3.6(m, 2H, CH2 --NH), 3.7 (s, 3H, OCH3), 6.75-6.8(m,2H, aromatic-H), 7.05-7.25 (m, 2H, aromatic-H), 7.4-10.5 (m,5H, NH2 ×2, NH), m/e [M+H[+ 289.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].CCOCC.[N+:17]([O-])([OH:19])=[O:18]>O>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc2c(c1)CCCC2
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1c(O)ccc2c1CCCC2
Reaction time: 1 h
Yield: 32.6 %

Procedure:
5,6,7,8-Tetrahydro-2-naphthol (50 g, 0.337 mol) was mixed with ether (400 ml), and the mixture was added dropwise with 60% nitric acid (28 ml, 0.368 mol) while the reaction temperature was kept below 15° C. , and then stirring was continued at 15° to 20° C. for 1 hour. The reaction mixture was added with water (500 ml) and extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 900 g, eluent: hexane/ethyl acetate=50/1 to 60/1) to give 2-hydroxy-5,6,7,8-tetrahydro-1-nitronaphthalene (21.2 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26]([NH2:28])=O)[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26]#[N:28])[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Reaction time: 0.83 h
Yield: 72.5 %

Procedure:
To a solution of 6-(6-cyclopropyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamide (137 mg) in N,N-dimethylformamide (1.5 mL) was added dropwise phosphoryl chloride (0.051 mL) under ice-cooling. This mixture was stirred for 50 minutes under ice-cooling. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (94.4 mg). 1H-NMR (CDCl3) δ ppm: 0.69-0.77 (2H, m), 0.92-1.03 (2H, m), 1.97-2.07 (1H, m), 4.46 (2H, s), 6.86 (1H, dd, J=1.5, 8.3 Hz), 7.11-7.17 (1H, m), 7.21-7.32 (2H, m), 7.33-7.64 (7H, m), 8.09 (1H, br s).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH-].[Na+].Cl.[C:10]([NH2:13])(=[NH:12])[CH3:11].C(Cl)Cl>O>[CH2:5]([O:4][C:2]([NH:13][C:10](=[NH:12])[CH3:11])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NC(C)=N
Yield: 72 %

Procedure:
123 parts of ethyl chloroformate and 170.4 parts of 50% strength sodium hydroxide solution are added via two inlets to a mixture of 94.6 parts of acetamidine hydrochloride in 750 parts of methylene chloride and 250 parts of water, at from 10° to 15° C., in the course of 30 minutes, while stirring. After the mixture has been stirred at 25° C. for 15 minutes, the phases are separated. The aqueous phase is extracted with twice 100 parts of methylene chloride, and the solvent is removed from the organic extract to give 93.4 parts (72% of theory) of N-ethoxycarbonylacetamidine of melting point 111°-114° C.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:20]=[CH:19][C:12]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl.O>CN(C)C=O>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O:1][CH:2]([C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(C(O)c2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
3.04 g (11.33 mmol) of methyl 4-(α-hydroxybenzyl)cinnamate was dissolved in 35 ml of N,N-dimethylformamide, thereafter 0.45 g (11.33 mmol) of 60% sodium hydride was added thereto, and the mixture was stirred overnight at room temperature. 2.44 g (22.66 mmol) of 2-dimethylaminoethyl chloride was then added thereto. The resulting mixture was heated at 80° C. and stirred for 5 hours. After cooling, the reaction mixture was poured into water, the obtained mixture was extracted twice with ethyl acetate, and the extract was washed with brine. The organic phase was dried (MgSO4) and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform:methanol =50:1 (v/v)) followed by alumina column chromatography (n-hexane:ethyl acetate=5:1 (v/v)) to obtain 0.19 g (0.560 mmol) of methyl 4-[α-(2-dimethylaminoethoxy)benzyl]cinnamate as a pale yellow oily substance. Its spectroscopic data are as follows:
Reaction SMILES: C([O:4][C:5](=[CH2:8])[C:6]#N)(=O)C.[CH:9]1[CH2:14][CH2:13]C=[CH:11][CH:10]=1>C(Cl)Cl>[CH:6]12[CH2:13][CH2:14][CH:9]([CH:10]=[CH:11]1)[CH2:4][C:5]2=[O:8]
Reactant: C=C(C#N)OC(C)=O
Reactant: C1=CCCC=C1
Solvent: ClCCl
Product: O=C1CC2C=CC1CC2
Temperature: 90 °C
Reaction time: 48 h
Yield: 20.5 %

Procedure:
A mixture of 7.0 g of α-acetoxyacrylonitrile and 3.2 g of 1,3-cyclohexadiene was heated in a closed microwave tube at 90° C. for 24 h. The obtained brown oil was taken up in DCM and evaporated. The crude mixture was washed over a pad of Celite (2 cm) using 300 mL of Hept-EtOAc (9:1) and then concentrated in vacuo. The yellow oil was redissolved in 10 mL DMSO and 3.2 g of KOH, dissolved in 5 mL water, was carefully added. The resulting black mixture was stirred for 2 d at rt, diluted with water and extracted 3 times with Hept. The combined organic phases were washed 3 times with brine, dried over Na2SO4 and concentrated in vacuo to obtain 1.0 g of rac-(1R*,4R*)-bicyclo[2.2.2]oct-5-en-2-one as beige solid.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])[C@H:12]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=CC=1)([O-])=O.Cl.[NH2:38][C@H:39]([C:41]([NH2:43])=[O:42])[CH3:40].C(N(CC)CC)C>CN(C)C=O>[C:14]([NH:13][C@H:12]([C:11]([NH:38][C@H:39]([C:41]([NH2:43])=[O:42])[CH3:40])=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: C[C@H](N)C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Yield: 95.4 %

Procedure:
Referring to Scheme 6, a solution of 5.0 g (0.010 mol) of Nα-BOC-Nε-CBZ-L-lysine p-nitrophenyl ester and 1.5 g (0.012 mol) of L-alanine amide hydrochloride and 1.67 ml (0.012 mol) of triethylamine in anhydrous N,N-dimethylformamide (50 ml) was stirred at room temperature for 16 hours before the solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate (200 ml) and washed with 3M NaOH (3×100 ml), water (3×100 ml), 1M HCl (2×100 ml) and finally with brine (100 ml). After drying over anhydrous sodium sulfate, the solution was filtered and concentrated in vacuo to give 4.3 g (96% yield) of Nα-BOC-Nε-CBZ-L-lysyl-L-alanine amide (6a) as a white solid. TLC: Rf 0.32 (chloroform-isopropanol 9:1); 1H NMR (d6 -DMSO) δ 1.20(d, 3H), 1.35(bm, 6H), 1.37(s, 9H), 2.97(m, 2H), 3.86(m, 1H), 4.21(m, 1H), 5.00(s, 2H), 6.95(d, 1H), 7.06(s, 1H), 7.24(t, 1H), 7.34(m, 6H), 7.78(d, 1H); 13C NMR (d6 -DMSO) δ 18.6, 22.8, 28.2, 29.2, 31.4, 40.1, 47.8, 54.5, 65.2, 78.2, 127.8, 128.4, 137.3, 155.5, 156.1, 171.7, 174.2.