Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25](O)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[C:17]([CH:23]=[CH2:24])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:34]=2[N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:36]2)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[C:17]([CH:23]=[CH2:24])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: C=Cc1cc2nc(C(=O)O)c(NC(=O)OCc3ccccc3)cc2cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[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: C=Cc1cc2nc(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OCc4ccccc4)C3)c(NC(=O)OCc3ccccc3)cc2cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-6-fluoro-7-vinylquinoline-2-carboxylic acid (153.2 mg, 0.4182 mmol), benzyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (151.1 mg, 0.4629 mmol) and HATU (485.8 mg, 1.278 mmol), DMF (4.0 mL) was added, followed by DIPEA (570.1 mg, 4.411 mmol). The reaction mixture was stirred at room temperature for 15 h, then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give the sub-title compound (242.7 mg, 86%). LCMS calc. for C38H36FN6O5(M+H)+: m/z=675.3. found 675.3.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:20])=[N:8][CH:9]=[C:10](/[CH:11]=[CH:12]/[CH:13](OCC)[O:14]CC)[C:5]=2[S:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O>[NH2:20][C:7]1[C:6]2[C:2]([Br:1])=[CH:3][S:4][C:5]=2[C:10](/[CH:11]=[CH:12]/[CH:13]=[O:14])=[CH:9][N:8]=1
Reactant: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: Nc1ncc(/C=C/C=O)c2scc(Br)c12
Yield: 164.3 %

Procedure:
A mixture of Example 176A (200 mg, 0.56 mmol), p-toluenesulfonic acid (10 mg), acetone (10 mL), and water (1 mL) at ambient temperature was stirred for 16 hours. The mixture was concentrated and washed with sodium bicarbonate (12 mL). The aqueous layer was extracted with dichloromethane/methanol (9:1). The combined organic extracts were concentrated to provide the desired product (160 mg, 0.92 mmol). Reverse phase HPLC (5% to 95% acetonitrile over 25 minutes, 1 mL/min, 254 nm, hypersil HS 100 Å, C18, 5 μm, 250×4.6 column) Rt=15.5 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(OP([N:34]=[N+:35]=[N-:36])(=O)OC2C=CC=CC=2)C=CC=CC=1.N1CCCN2CCCCCC=12>C1(C)C=CC=CC=1>[N:34]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OCc1cncc(Cl)c1COC1CCCCO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cncc(Cl)c1COC1CCCCO1

Procedure:
A solution of [5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-methanol (1.3 g, 4.9 mmol), phosphorazidic acid diphenyl ester (1.4 mL, 6.4 mmol) and 2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepine (0.96 mL, 6.4 mmol) in toluene (0.15 mL) was stirred at RT overnight. Solvents were concentrated in vacuo and the residue was partitioned between DCM (10 mL) and saturated NaCl solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexanes/EA 3:1) to give the title compound. MS (m/z): 282.9 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][O:16]C)=[CH:10][N:9]=2)=[CH:4][CH:3]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC=Cc1ccc(-c2ccc(Br)cc2)nc1
Solvent: C1CCOC1
Product: O=CCc1ccc(-c2ccc(Br)cc2)nc1

Procedure:
A solution of 12.4 g of 2-(p-bromophenyl)-5-(2-methoxyvinyl)pyridine in 200 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) is heated to reflux for 1 hour while stirring. The reaction mixture is subsequently partitioned three times in diethyl ether/water. The organic extracts are washed twice with water, dried over magnesium sulphate, filtered and evaporated, whereby [2-(p-bromophenyl)-5-pyridyl]acetaldehyde is obtained as the residue.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1ccnc(Br)c1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3cc(C)ccn3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and 2-bromo-4-methylpyridine. HRMS (ESI+): m/z=388.1481 [M+H]
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]([F:19])([F:18])[C:8]1[C:16]2[C:11](=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1.[OH-].[Na+]>>[Cl:3][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:10][N:9]=[C:8]([C:7]([F:19])([F:18])[F:6])[C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2c(C(F)(F)F)n[nH]c21
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1n[nH]c2nccc(Cl)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Phosphorus oxychloride (76.4 g) was gradually added to compound (1b) (33.2 g), followed by stirring at 100° C. for 1 hr. The reaction solution was poured into ice water, and sodium hydroxide was added thereto to adjust the pH to 10. The precipitate was collected by filtration to obtain compound (1c) (9.76 g, 27%) as a light pink solid.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.C(P(CCCC)CCCC)CCC.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][S:60](=[O:64])(=[O:63])[CH2:59][CH2:58]1>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][S:60](=[O:64])(=[O:63])[CH2:59][CH2:58]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=S1(=O)CCN(CCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCS(=O)(=O)CC1
Reaction time: 18 h
Yield: 3.6 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (525 mg, 2.1 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol), (prepared as described for the starting material in Example 2), tributylphosphine (420 mg, 2.1 mmol) and 4-(2-hydroxyethyl)-1,1-dioxothiomorpholine (140 mg, 7.8 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (14 ml of a 1M solution, 14 mmol) and the precipitate was collected by filtration. The residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was triturated with ether/methylene chloride collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2-(1,1-dioxothiomorpholino)ethoxy)-6-methoxyquinazoline (120 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1([C:11]#[N:12])[CH2:7][CH2:6][N:5]([N:8]([CH3:10])[CH3:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[CH2:29][C:30](Cl)=[O:31].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O1CCCC1>[C:11]([C:2]1([NH:1][C:30](=[O:31])[CH2:29][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][C:23]=2[CH3:28])[CH2:3][CH2:4][N:5]([N:8]([CH3:9])[CH3:10])[CH2:6][CH2:7]1)#[N:12]
Reactant: CN(C)N1CCC(N)(C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CC(=O)NC2(C#N)CCN(N(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
920 mg 4-Amino-1-dimethylamino-piperidine-4-carbonitrile (from Step 1), 1.38 g triethylamine and 10 mg N,N-Dimethyl-4-aminopyridine are dissolved in 35 ml tetrahydrofuran. The mixture is cooled in an ice bath and a solution of 1.07 g (2,4,6-trimethyl-phenyl)-acetyl chloride in 15 ml tetrahydrofuran is added. The temperature is kept around 3° C. during addition. Then the mixture is allowed to warm to room temperature and stirred for 2 hours. Then saturated aqueous sodium bicarbonate is added, the mixture is extracted with t-butyl methyl ether, dried over sodium sulfate, and the solvent evaporated. Thus, 1.44 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-2-(2,4,6-trimethyl-phenyl)-acetamide is obtained as an off-white solid. 1H-NMR (CDCl3): 6.90 ppm (s, 2H), 5.20 ppm (s, 1H), 3.60 ppm (s, 2H), 2.70 ppm (m, 4H), 2.36 ppm (m, 2H), 2.33 ppm (s, 6H), 2.28 ppm (s, 3H), 2.23 ppm (s, 6H), 1.72 ppm (m, 2H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][CH:45]1[CH2:48][CH:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:46]1)=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][CH:45]2[CH2:46][CH:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:48]2)=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To a solution of PPh3 (7.9 g, 30.0 mmol) in dry DCM (60 mL) was added I2 (7.8 g, 30.0 mmol). After I2 was dissolved completely, TEA (10.5 mL, 75.0 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutyl-carbamate (4.9 g, 15.0 mmol) was added. The mixture was stirred at rt for 1 hr. The solvent was concentrated. EtOAc (300 mL) was added, and the solution was filtered to remove PPh3O. The filtrate was concentrated. The residue was purified by silica gel column chromatography (gradient elution 0˜50% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl-carbamate (6.2 g, 85%) as a white solid. ESI-MS (EI+, m/z): 484.0 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:34]=[CH:33][C:26]([CH2:27][CH2:28][PH:29](=[O:32])[O:30][CH3:31])=[CH:25][CH:24]=1)=[O:22])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][PH:29](=[O:32])[O:30][CH3:31])=[CH:33][CH:34]=1)=[O:22]
Reactant: CO[PH](=O)CCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[PH](=O)CCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl [4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]methyl-phosphinate (6.69 g, 13.37 mmol) was dissolved in CH2Cl2 (48 ml), and TFA (12 ml) was added. The solution was stirred at room temperature for 3 h and evaporated. The residue was dissolved in CH2Cl2, washed with saturated NaHCO3 and brine, dried (MgSO4), and evaporated. The crude was then slurried in CH2Cl2 and triturated with a small amount of hexanes to precipitate the title compound as a colorless solid. This material was subjected to chiral SFC to provide enantiopure samples of the two enantiomeric forms. Spectral data for racemate: 1H NMR (DMSO-d6) δ 9.68 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.44 (d, J=1.6 Hz, 1H), 7.38 (dd, J=8.1, 2.0 Hz, 2H), 7.32 (dd, J=5.2, 0.9 Hz, 1H), 7.27 (dd, J=8.3, 2.2 Hz, 1H), 7.21 (d, J=3.6 Hz, 1H), 7.01 (dd, J=5.0, 3.6 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 5.13 (s, 2H), 3.55 (d, J=11.0 Hz, 3H), 3.29 (d, J=18.0 Hz, 2H), 1.32 (d, J=13.7 Hz, 3H). MS: cal'd 401 (MH+), exp 401 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[N:11][OH:12].[CH3:13][N:14]=[C:15]=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[N:11][O:12][C:15](=[O:16])[NH:14][CH3:13]
Reactant: COCCN1C(=O)CSC1=NO
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)ON=C1SCC(=O)N1CCOC

Procedure:
A solution of 5.4 g 3-(2-methoxyethyl)-2-oximino-4-thiazolidinone in 50 ml methylene chloride, 4.0 g of methylisocyanate and 4 drops of triethylamine was kept in a pressure bottle for 16 hours at ambient temperature. On concentration under reduced pressure the reddish brown liquid was dissolved in methanol, decolorized with charcoal and concentrated. The desired produced was crystallized from methanol. Weight 5.5 g., m.p. 153°-155°C.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9]CC)=O.C(O)(=O)C.[CH:16](N)=[NH:17]>CCO>[CH:5]1[N:4]=[C:3]2[C:7]([N:17]=[CH:16][NH:1][N:2]2[CH:6]=1)=[O:9]
Reactant: N=CN
Reactant: CCOC(=O)c1nccn1N
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1nc[nH]n2ccnc12
Temperature: 25 °C

Procedure:
A mixture of ethyl 1-amino-1H-imidazole-2-carboxylate (C-4) (800 mg, 5.16 mmol, 1.0 eq) and formamidine acetate (2.68 g, 25.78 mmol, 5.0 eq) in EtOH (100 mL) is stirred at reflux overnight. The resulting mixture is cooled to RT. The solid is collected by filtration, rinsed with EtOH (3×2 mL) and petroleum ether (2 mL×3), and then dried in vacuo to afford the product, imidazo[1,2-f][1,2,4]triazin-4-ol (C-5). Imidazo[1,2-f][1,2,4]triazin-4-ol (C-5) (400 mg, 2.94 mmol, 1.0 eq) is dissolved in POCl3 (10 mL, 109.2 mmol, 37.1 eq) and the resulting mixture is stirred at reflux for 2 h. The mixture is concentrated in vacuo to remove POCl3. The residue is poured into ice water (30 mL) and neutralized with saturated aqueous NaHCO3 solution to adjust the pH to 6-7 while keeping the temperature below 5° C. The mixture is extracted with ethyl acetate (30 mL×4). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (16% ethyl acetate in petro ether) to afford the product, 4-chloroimidazo[1,2-f][1,2,4]triazine (C-6).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[OH-].[Na+].[CH3:17]I>C(O)C.O>[CH3:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc2cc3ccccc3cc2[nH]1
Yield: 122.3 %

Procedure:
20.0 g of 1H-naphth[2,3-d]imidazole-2-thiol and 4.0 g of sodium hydroxide were heated for 1 hour under reflux and in 150 ml of ethanol with 6.5 g of methyl iodide. The reaction solution was diluted with 500 ml of water and the precipitated product was suction filtered. Crystallisation from dioxane provided 12.0 g of 2-methylthio-1H-naphth[2,3-d]imidazole haing a m.p. of 242°-244°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][S:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)(=[O:19])=[O:18].Cl>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:27][CH:26]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (200 mg, 819 μmol) in MeOH (5 mL) was added a suspension of 4-methylsulfonylbenzaldehyde (158 mg, 860 μmol) in acetic acid (75 μl) and MeOH (2 mL). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (140 mg, 1.31 mmol, Aldrich) was added and the stirring was continued for 3 days. The reaction mixture was diluted with MeOH (6 mL) and poured into 0.1N HCl solution (10 ml). The resulting suspension was filtered and washed with water to give an off white solid as desired product (228 mg, 67% yield). MS +m/z: 412 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11]2)=[CH:7][CH:6]=1.[C:30]1(=[O:40])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32][NH:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:40]=[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32][N:31]1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11]2)=[CH:28][CH:29]=1
Reactant: O=c1[nH]ncc2ccccc12
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCBr)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1cn(Cc2ccc(OCCn3ncc4ccccc4c3=O)cc2)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 128.6 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1050 mg), 1(2H)-phthalazinone (530 mg), potassium carbonate (1000 mg) and N,N-dimethylformamide (15 ml) was stirred at 90° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-[2-[1-oxophthalazin-2(1H)-yl]ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (1460 mg, yield 90%). This was recrystallized from acetone-hexane. Melting point: 155–156° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)[CH:35]=1)=[O:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J41) (347 mg, 1.0 mmol) and 3-(3-imidazol-1-yl-phenyl)-3-oxo-propionic acid tert-butyl ester (Example K26) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (430 mg, 77%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:26](=[O:28])(=[O:27])[N:25]([CH3:30])[CH3:24])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 67.7 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and dimethylsulfamoyl chloride (144 mg, 1.01 mmol) affords 92 mg (68%) of the title compound as a yellow oil. MS (ES) 427 (M+Na), 403 (M−H); HPLC shows 93% purity.