Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=1)[NH2:2].[C:18](/[N:20]=[C:21](\OC1C=CC=CC=1)/[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)#[N:19]>C(O)(C)C>[N:7]1[C:6]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=[C:3]([N:1]2[C:18]([NH2:19])=[N:20][C:21]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:27][CH:28]=3)=[N:2]2)[N:8]=1
Reactant: NNc1cc2c(nn1)-c1ccccc1CCC2
Reactant: N#C/N=C(/Nc1ccc(OCCN2CCCC2)cc1)Oc1ccccc1
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)nn1-c1cc2c(nn1)-c1ccccc1CCC2
Temperature: 25 °C

Procedure:
Diphenylcyanocarbonimidate (1.1 equiv) and 4-(2-(pyrrolidin-1-yl)ethoxy)aniline (1 equiv) were stirred in iso-propyl alcohol at ambient temperature overnight. The resulting white precipitate was filtered and washed with iso-propyl alcohol and dried to yield (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate. 3-Hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (82 mg, 0.36 mMol) and (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate (128 mg, 0.36 mMol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). The precipitate which formed in the microwave vial was re-dissolved in hot isopropanol. The mixture was cooled to ambient temperature and then filtered to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #1, as a yellow solid, 23 mg. 1H NMR (CDCl3, 300 MHz) 7.90 (s, 1H), 7.83 (t, 1H), 7.43 (m, 3H), 7.29 (t, 1H), 6.93 (d, 1H), 6.83 (br s, 2H), 6.39 (s, 1H), 4.17 (m, 2H), 2.98 (m, 2H), 2.60-2.80 (m, 8H), 2.32 (m, 2H), 1.87 (m, 4H) ppm; MS (ES) 483.16 (M+H).
Reaction SMILES: [Br:1][CH2:2][Si:3](Cl)([CH3:5])[CH3:4].[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[Br:1][CH2:2][Si:3]([CH3:5])([CH3:4])[NH:11][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C[Si](C)(Cl)CBr
Reactant: CC(C)(C)N
Solvent: CCOCC
Product: CC(C)(C)N[Si](C)(C)CBr
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a stirred solution of 10.00 g (53.32 mmol) of (bromomethyl)chlorodimethylsilane in 200 ml, of diethylether a solution of 7.80 g (106.64 mmol) of t-butyl amine in 10 mL of ether was added. A white solid deposited instantaneously. The reaction mixture was stirred overnight, filtered through a medium frit and the solvent was removed under reduced pressure to give 11.06 g of colorless liquid. Yield 93 percent.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[N:30]([CH3:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.7 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (600 mg), 2-chloromethyl-1-methyl-1H-benzimidazole (360 mg), potassium carbonate (550 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (730 mg, yield: 84%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=Cc1cccc(Cl)c1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 30.44 g of 5-aminopyridine-2-carboxylic acid methyl ester, 30.9 g of m-chlorobenzaldehyde and 400 ml of benzene is refluxed on a water-trap for 3 days. It is evaporated and the residue recrystallized from benzene/ethylacetate/diethyl ether, to yield the 5-(m-chlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 139°-142°.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=O)[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:22])=[N:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: O=P(Cl)(Cl)Cl
Product: C=CCn1cnc2c1c(Cl)nc(=O)n2CCCCC
Yield: 71.2 %

Procedure:
A mixture of 7-allyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (0.80 g, 3.0 mmol) and phosphoryl chloride (10.0 mL, 100 mmol) was refluxed for 2 h. The excess phosphoryl chloride was removed by vacuum distillation. The residue was diluted with ice-water, neutralized with solid K2CO3, and then extracted with DCM three times. The combined organic layers were dried, filtered and concentrated to provide the crude product (0.60 g), which was used for next step without further purification. LCMS calculated for C13H18ClN4O (M+H): 281.1. found: 281.1.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([I:36])=[CH:32][CH:31]=1)=[O:28]>>[I:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(I)cc2)c1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(I)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-iodo-phenyl)-benzamide. mp 205-210° C. Calculated for C26H22IN3O4 : C 55.04; H 3.91; N 7.41; found C 55.13; H 4.04; N 7.12.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8]OS(C)(=O)=O)[CH:6]=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.CN(C=O)C>CC(=O)OCC>[N:27]1([CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([Br:1])[N:3]=[C:4]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCN2CCC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A reaction mixture of tert-butyl 4-(4-bromo-1-(2-((methylsulfonyl)oxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (28.0 g) and azetidine (11 ml) in to DMF (200 ml) was stirred at 50° C. overnight. The reaction was diluted with EA, washed with water followed by saturated aqueous sodium chloride, dried and concentrated. The residue was purified by column chromatography to give tert-butyl 4-(1-(2-(azetidin-1-yl)ethyl)-4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate as off-white solid. (17.2 g).
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([Cl:24])[C:18]([CH2:22]Br)=[C:19]([Cl:21])[CH:20]=1.Cl>CN(C=O)C.C(OCC)C>[Br:14][C:15]1[CH:16]=[C:17]([Cl:24])[C:18]([CH2:22][N:2]2[CH2:3][CH2:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:1]2=[O:11])=[C:19]([Cl:21])[CH:20]=1
Reactant: O=C1NCCC12CCCCC2
Reactant: Clc1cc(Br)cc(Cl)c1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
Treat a solution of 2-aza-spiro[4.5]decan-1-one (0.138 g, 0.901 mmol) in DMF (5 mL) with 60% sodium hydride (0.054 g, 1.35 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0° C., treat with 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (0.316 g, 0.991 mmol), and stir for 15 minutes at 0° C. Warm to room temperature and stir for 2 hours under N2. Acidify the reaction with 1 N HCl. Dilute with diethyl ether and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.258 g (73%) of the titled product. Rf=0.24 (3/1 ethyl acetate/hexanes). MS (m/z): 392 (M+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11](=O)[N:10]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(C(F)(F)F)nc2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1

Procedure:
The title compound was prepared from 4-(6-trifluoromethyl-pyridin-3-yl)-6-trifluoromethyl-1H-pyrimidin-2-one (6.87 g, 0.022 mol) and phosphoroxychloride (35 ml) according to the general procedure I. Obtained as a light brown solid (7.18 g, 99%). MS (ISP) 329.2 [(M+H)+]; mp 87° C.
Reaction SMILES: [CH3:1][P:2](=[O:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[C:3]1([P:2]([CH2:1][CH:24]=[O:25])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: CP(=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=CCP(=O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of methyldiphenylphosphine oxide (2.0 g, 9.0 mmol) in THF (60 mL) at 0° C. was added BuLi (1.6 M in hexane, 6.94 mL, 11.0 mmol) and after 2 h at 0° C., the mixture was cooled to −78° C. and then DMF (0.85 mL, 11 mmol) was added. After 2 h at −78° C. the mixture was quenched with HCl (1 N, 25 mL) and the resulting mixture warmed up to room temperature. The mixture was extracted with ethyl acetate and the combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. The crude product (off-white oil, 2.41 g) was used directly in the next step. MS: m/e=245.2 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4](=[O:37])[CH2:5][C:6]([CH:27]=[C:28]([S:30][C:31]1[S:35][C:34]([CH3:36])=[N:33][N:32]=1)[CH3:29])=[C:7]2[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH3:38][O:39][N:40]=[C:41]([C:45]1[N:46]=[C:47]([NH:50][C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[S:48][CH:49]=1)[C:42](O)=[O:43].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH:14]([O:13][C:11]([C:7]1[N:8]2[CH:3]([S:4](=[O:37])[CH2:5][C:6]=1[CH:27]=[C:28]([S:30][C:31]1[S:35][C:34]([CH3:36])=[N:33][N:32]=1)[CH3:29])[CH:2]([NH:1][C:42](=[O:43])[C:41](=[N:40][O:39][CH3:38])[C:45]1[N:46]=[C:47]([NH:50][C:51]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[S:48][CH:49]=1)[C:9]2=[O:10])=[O:12])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2S(=O)C1)Sc1nnc(C)s1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(C)Sc3nnc(C)s3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 4 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of the Z form of 7-amino-2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (3.53 g) in methylene chloride (250 cc) is cooled to 4° C. 2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (3.28 g) and dicyclohexylcarbodiimide (1.54 g) are added successively. The mixture is stirred for 11/2 hours at 4° C. and then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is taken up in ethyl acetate (50 cc) and the insoluble material is filtered off. The solution is washed with a saturated aqueous solution of sodium bicarbonate (100 cc) and then with 0.1N hydrochloric acid (100 cc). It is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (80 g) (diameter of the column: 3 cm; height: 64 cm). Elution is carried out with a 35/65 (by volume) ethyl acetate/cyclohexane mixture (300 cc) and then with a 70/30 (by volume) ethyl acetate/cyclohexane mixture (1,200 cc), 60 cc fractions being collected. Fractions 12 to 20 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of the syn isomer of 2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (2 g) in the form of a hard white foam.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][N:9]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O)(C)(C)C.S(Cl)(Cl)=O.Cl>CO>[CH2:23]([O:22][C:20]([N:9]1[CH2:10][CH:11]([O:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:12][NH:8]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC(OC(=O)C(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(C)(C)C(=O)OC1CNN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
4-(2,2-Dimethylpropionyloxy)pyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 29, (1.76 g, 4.33 mmol) is dissolved in methanol (40 mL) and the solution cooled to 0° C. Thionyl chloride (3.16 mL, 43.3 mmol) is added dropwise and the reaction allowed to warm to room temperature and continue stirring 12 hours. The reaction solution is concentrated in vacuo to give afford 1.45 g (98% yield) of the desired product as the HCl salt as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[C:23]1([N:29]2[C:33]([N:34]3[CH2:37][C:36]4([CH2:40][NH:39][CH2:38]4)[CH2:35]3)=[N:32][N:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:39]3[CH2:40][C:36]4([CH2:37][N:34]([C:33]5[N:29]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[N:30]=[N:31][N:32]=5)[CH2:35]4)[CH2:38]3)=[O:21])[C:4]=12
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-n2nnnc2N2CC3(CNC3)C2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CC4(C3)CN(c3nnnn3-c3ccccc3)C4)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.050 g), 2-(1-phenyl-1H-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptane (0.044 g), BOP reagent (0.080 g) and Hunig's base (0.2 mL) were mixed in dry DMF (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with methanol (10 mL) and volatiles were removed under reduced pressure. The resulting oil was diluted with ethyl acetate (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by silica gel column chromatography using MeOH/CHCl3 (1:9) as an eluent to afford 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(6-(1-phenyl-1H-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1,2-dione (30 mg). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.47-2.49 (s, 3H), 3.93 (s, 4H), 4.08-4.13 (m, 2H), 4.20-4.36 (d, 2H), 7.54-7.62 (m, 5H), 7.84 (s, 1H), 8.30-8.32 (s, 1H), 9.22 (s, 1H), 12.26 (bs, 1H). LCMS MS (M+H)+ Calcd.: 526, Observ.: 526.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:13]([O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn(C)nc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)nc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (25.50 g), benzyl bromide (17.8 ml), potassium carbonate (31.10 g) and N,N-dimethylformamide (250 ml) was stirred overnight at 50° C. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-benzyloxy-1-methyl-1H-pyrazole-4-carboxylate (31.90 g, yield 82%) was obtained as a colorless crystal from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio) and recrystallized from ethyl acetate-hexane. melting point: 66–67° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:17]1C(=O)C3C(=CC=CC=3)C1=O)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.NN>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH2:17])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN
Yield: 71.7 %

Procedure:
To a solution of 2-[(6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.7 g, 3.4 mmol) in ethanol (150 ml), being heated under reflux, was added hydrazine monohydrate (5 ml, 103 mmol), and the mixture was heated under reflux for 2 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (250 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (100 ml) and then saturated brine (100 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography, and crystallized from n-hexane-diisopropyl ether to give the title compound (0.90 g, yield 72%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.[I:18]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[I:18][C:9]1[N:8]2[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][C:7]2=[N:11][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(-c2ccccc2)cc2nccn12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2ccccc2)cc2ncc(I)n12

Procedure:
To a solution of 5-methoxy-7-phenylimidazo[1,2-a]pyridine (397 mg, 1.77 mmol) in acetonitrile (30 ml) was added N-iodosuccinimide (478 mg, 2.12 mmol). After 1 h the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give 3-iodo-5-methoxy-7-phenylimidazo[1,2-a]pyridine. 1H NMR (600 MHz, DMSO-d6) δ 7.86 (d, 1H); 7.83 (d, 1H); 7.52-7.53 (m, 1H); 7.48-7.45 (m, 2H); 7.38-7.40 (m, 1H); 7.33-7.35 (m, 1H); 6.61 (d, 1H); 4.10 (s, 3H). LRMS (ESI) calculated for C14H12IN2O [M+H]+, 351.0 found 350.9.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([CH3:34])[C:31]([CH3:33])=[CH:32][C:6]=2[N:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([CH3:34])[C:31]([CH3:33])=[CH:32][C:6]=2[N:5]=1
Reactant: Cc1cc2nc(CC(C)(C)C)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2nc(CC(C)(C)C)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1C

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2,2-dimethylpropyl)-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])=[N+:2]=[N-:3].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=NCCOCCOCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a solution in which the 2-(2-(2-azidoethoxy)ethoxy)ethanol (3.05 g, 17.40 mmol) compound of Chemical Formula 8 was dissolved in methylene chloride (15 mL), 4-dimethylaminopyridine (DMAP) (212.6 mg, 1.74 mmol), triethylamine (TEA) (7.28 mL, 52.20 mmol) and tosyl chloride (3.98 g, 20.88 mmol) were added consecutively at room temperature. The post-reaction mixture obtained after stirring the reaction mixture for 12 hours at room temperature was partitioned to distilled water (40 mL) and ethyl acetate (120 mL). The organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, and vacuum distilled to give 2-(2-(2-azidoethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (5.15 g, 90%). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, 2H, J=8.2 Hz), 7.33 (d, 2H, J=8.2 Hz), 4.15 (t, 2H, J=5.0 Hz), 3.69 (t, 2H, J=5.0 Hz), 3.63 (t, 2H, J=5.5 Hz), 3.59 (s, 4H), 3.36 (t, 2H, J=5.0 Hz), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 144.9, 133.0, 129.9 (2), 128.0 (2), 70.8, 70.7, 70.1, 69.3, 68.8, 50.7, 21.7.