Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]2[CH2:14][CH2:15][N:11]([CH:10]=[CH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:23][N:22]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])N=C1N(C=Cc2ccc(Cl)c(Cl)c2)CCN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture comprising 7.0 g of 1-{2-(3,4-dichlorophenyl)vinyl}-2-nitroiminoimidazolidine, 7.5 g of 2-chloro-5-chloromethylpyridine, 6.4 g of potassium carbonate and 50 ml of dimethylsulfoxide was stirred at 60° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgS04) and concentrated o give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate) to give 5.7 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(3,4-dichlorphenylvinyl) -imidazolidine.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:31]=3)[CH2:14][CH:13]=[CH:12][N:11]2[CH3:16])[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: CC1(C)OB(c2cccc(OCCC3CCCCC3)c2)OC1(C)C
Reactant: Cn1c(I)ccc1CC[C@]1(C)COC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1C=CCC1(CC[C@]1(C)COC(=O)N1)c1cccc(OCCC2CCCCC2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.8 %

Procedure:
(4R)-4-Methyl-4-[2-(5-iodo-1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (0.3101 g, 0.92 mmol) obtained in Example (40a), 2-[3-(2-cyclohexylethyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4646 g, 1.41 mmol), dichlorobis(triphenylphopsphine)palladium(II) (63.1 mg, 0.09 mmol) and cesium carbonate (0.6006 g, 1.81 mmol) were suspended in a mixed solvent of dimethoxyethane (8 ml) and water (2 ml) and stirred at 80° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:2) as the eluent to afford the crude product. Furthermore, the crude product thus obtained was purified using a preparative reversed phase HPLC column [Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (41.1 mg, yield: 11%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:4].[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=[O:40])([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)Cn1ccnc1C=O
Yield: 62.5 %

Procedure:
A solution of di-tert-butyl 4-(2-bromoacetamido)-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (1.397 g, 2.61 mmol), 1H-imidazole-2-carbaldehyde (0.30 g, 3.13 mmol), DIPEA (2.0 mL), and KI (0.30 g) in DMF (5.0 mL) was stirred at 80° C. for 5 hrs. The solvent was evaporated under reduced pressure to afford a residue, which was purified by biotage eluting with 20% EtOAc in hexanes to 100% EtOAc to give di-tert-butyl 4-(3-(tert-butoxy)-3-oxopropyl)-4-(2-(2-formyl-1H-imidazol-1-yl)acetamido)heptanedioate (0.90 g, 63%). 1H NMR (400 MHz, CDCl3) 9.78 (s, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 6.65 (s, 1H), 4.90 (s, 2H), 2.19 (t, J=7.8 Hz, 6H), 1.94 (t, J=7.8 Hz, 6H), 1.42 (s, 9H); MS (ESI), 552 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:14])[CH:3]=1.S(Cl)([Cl:17])=O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6][Cl:17])=[C:4]([F:14])[CH:3]=1
Reactant: CC(C)Oc1cc(CO)c(F)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)Oc1cc(CCl)c(F)cc1Cl
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Then, 6.7 g of 4-chloro-2-fluoro-5-isopropoxybenzylalcohol was dissolved in 70 ml of tetrahydrofuran, to which 1 ml of pyridine was added, and the mixture was cooled to 5° C. Then, 5 ml of thionyl chloride was slowly added dropwise at 5° to 10° C., and the mixture was stirred at 5° C. for 1.5 hours. After completion of the reaction, the reaction mixture was filtered to separate the precipitated crystals, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, which afforded 7.3 g of 4-chloro-2-fluoro-5-isopropoxybenzyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6]([CH:12]([C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[O:13][SiH:14]([CH3:16])[CH3:15])=[CH:5]2.[H-].[Na+].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@H:35]([CH3:37])OS1(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:36][C@H:35]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[C:6]1[CH:12]([C:17]([CH3:21])([CH3:22])[CH:18]([CH3:19])[CH3:20])[O:13][SiH:14]([CH3:15])[CH3:16])[CH3:37])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc2[nH]c(C(O[SiH](C)C)C(C)(C)C(C)C)cc2cc1Br
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Br)cc(C(O[SiH](C)C)C(C)(C)C(C)C)n2[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.95 g 5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-1H-indole in 10 mL N,N-dimethylformamide was added 0.143 g sodium hydride (55-65%, mineral oil) and the mixture was stirred 30 min at room temperature. To the resulting mixture was added (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (0.703 g) and the mixture was stirred 2 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 10% citric acid and brine, dried over magnesium sulfate and purified by chromatography on silica gel with 5:1 hexane:ethyl acetateto yield 0.789 g of the title compound as a slightly yellow oil. MS: M+H=541.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([NH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][NH2:11])[CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25].[K+].[Br-].CC#N>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([N:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:10][NH:11][C:24]2=[S:25])[CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1NC(=NN)c1ccc(C(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(Cl)cc1-n1c(-c2ccc(C(F)(F)F)cc2)n[nH]c1=S

Procedure:
N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzene carbohydrazonamide (2.5 g, 7.27 mmol) was dissolved in THF (450 ml) under N2 and 1,1′-thiocarbonyldiimidazole (1.95 g, 11.0 mmol) added. The solution was stirred at reflux for 18 h and solvent removed by rotary evaporation. The residue was taken up in ethyl acetate (400 ml) and washed with 0.1N HCl solution (100 ml), water (100 ml) and brine prior to drying over MgSO4. Recrystallization from acetonitrile gave 1.91 g (68%) mp 275-280° C.; IR(KBr, υ=cm−1) 3080, 3058, 3020, 2916, 1506, 1488, 1322, 1288, 1174, 1130, 1110; 1H NMR (300 MHz, DMSO-d6) δ 3.51 (3H, s), 7.17 (1H, d, J=9.0 Hz), 7.53-7.57 (3H, m), 7.69 (1H, d, J=2.6 Hz), 7.77 (2H, d, J=8.4 Hz.s), 14.29 (1H, s); MS(DCl)m/z: 386(MH+). Anal. calcd. for C16H11ClF3N3OS.0.06 CH3CN: C, 49.87; H, 2.90; N, 11.04. Found: C, 50.03; H, 2.94; N, 11.07.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:19][C:20]1([CH3:45])[CH:29]=[C:28]([CH3:30])[C:27]2[N:26]=[CH:25][N:24]=[C:23]([N:31]3[CH2:37][C:36]4[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:35]=4[O:34][CH2:33][CH2:32]3)[C:22]=2[CH2:21]1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:39]2[CH:40]=[CH:41][C:35]3[O:34][CH2:33][CH2:32][N:31]([C:23]4[C:22]5[CH2:21][C:20]([CH3:19])([CH3:45])[CH:29]=[C:28]([CH3:30])[C:27]=5[N:26]=[CH:25][N:24]=4)[CH2:37][C:36]=3[CH:38]=2)=[CH:4][N:3]=1
Reactant: CC1=CC(C)(C)Cc2c1ncnc2N1CCOc2ccc(B(O)O)cc2C1
Reactant: CN1CC[C@H](NS(=O)(=O)c2cc(Br)cnc2N)C1
Product: CC1=CC(C)(C)Cc2c1ncnc2N1CCOc2ccc(-c3cnc(N)c(S(=O)(=O)N[C@@H]4CCN(C)C4)c3)cc2C1

Procedure:
Synthesized according to the method of example 5 using (S)-2-amino-5-bromo-N-(1-methylpyrrolidin-3-yl)pyridine-3-sulfonamide (reagent preparation 25) and [4-(6,6,8-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.52 (d, 1H), 8.37 (s, 1H), 8.12 (s, H), 8.06 (d, 1H), 7.56 (d, 1H), 7.45 (dd, 1H), 7.02 (d, 1H), 6.69 (br s, 2H), 6.12 (s, 1H), 4.62 (s, 2H), 4.32 (br t, 2H), 3.84 (br m, 2H), 3.63 (br s, 1H), 2.68 (s, 2H), 2.44 (m, 2H), 2.26-2.16 (m, 2H), 2.14 (s, 3H), 1.88 (s, 3H), 1.86 (s, 2H), 1.48-1.42 (m, 1H), 0.91 (s, 6H); MS (EI) for C30H37N7O3S: 576 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[CH3:23][N:24]=[C:25]=S.C(O)C>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:23]([NH:24][CH3:25])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc(Cl)cc2)c1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(Cl)cc2)c1=O
Yield: 57 %

Procedure:
A solution of 3-butyl-1-(4-chlorobenzyl)-6-hydrazinouracil (3.0 g, 9.3 mM) and methyl isothiocyanate (2.0 ml, 29 mM) in DMF (30 ml) was stirred at 120° C. for 20 hours. To the solution was added ethanol (20 ml) and the mixture was cooled to give crude crystals. Recrystallization from DMF/ethanol gave pale yellow crystals (1.91 g, 57%), m.p. 292°-294° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=3)[CH:14]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])=[N:9]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)[CH:14]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:39])[F:40])([C:34]([F:35])([F:36])[F:37])[OH:33])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)c2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (350.0 mg, 0.58 mmol) prepared in Example 229 and trifluoroacetic acid (444.0 uL, 5.79 mmol) were slowly added to dichloromethane (5.8 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 400.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]=2[S:14][CH:13]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(C(C)C)CC)(C)C>C(OC(=O)C)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)[C:15]=2[S:14][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCNCC4)ncnc23)c(F)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(Oc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4F)csc23)CC1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
30 mg (0.0736 mmol) of 7-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidine was dissolved in 1 ml of dimethylchloride, and 20 (0.147 mmol) of acetyl chloride and 19 μl (0.110 mmol) of diisopropylethylamine were added thereto. The mixture was stirred at room temperature for 13 hr. The resulting mixture was dissolved in ethylacetate and washed with sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to obtain 17 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(-c2ccc(Cl)cc2)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a stirred solution of 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20.0 g, 79.8 mmol) in toluene (500 mL) was added Pd(PPh3)4 (5.5 g, 4.76 mmol) under an atmosphere of argon. 4-Chlorophenylboronic acid (18.7 g, 119.6 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (33.8 g, 318.9 mmol) pre-dissolved in water (90 mL) was added to the suspension. A stream of argon was bubbled through this suspension for 10 min. After this time, the flask was placed in an oil bath preheated at 120° C. The reaction was refluxed for 3 h. After this time, the reaction was cooled to RT The reaction mixture was then poured into water (200 mL). The layers were separated and the aqueous mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (2×200 mL) followed by saturated aqueous NaCl (2×100 mL). The organic layer was then concentrated under reduced pressure to obtain crude product. This crude product was purified by silica gel column chromatography eluting with 8% EtOAc/hexanes to give the title compound, 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one, (21.5 g, 82%) as a white solid. HPLC: 3.79 min; M+H=327. 1H NMR (CDCl3, 500 MHz): δ 7.76 (1H, s), 7.48 (2H, d, J=10.0 Hz), 7.40-7.45 (4H, m), 7.28-7.36 (3H, m), 5.35 (2H, s), 4.10 (3H, s).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[C:29]=2[CH3:30])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1.[H][H]>[Pd].CO.O1CCCC1>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[C:29]=2[CH3:30])=[CH:10][C:9]=1[OH:8]
Reactant: Cc1ccn2c(C)c(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1

Procedure:
10% Palladium on carbon (10 g) was added to a mixture of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-3,7-dimethylimidazo[1,2-a]pyridine (27.3 g) in methanol (200 ml) and tetrahydrofuran (200 ml) and the mixture was stirred at ambient temperature under atmospheric pressure of hydrogen gas. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with ethyl acetate and the precipitate was collected by filtration to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (13.8 ).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:23])([CH3:3])[CH3:2].O1CCOCC1.[Mn]([O-])(=O)(=O)=O.[K+].C=O>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)CCO3
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2cc3c(cc21)CCO3

Procedure:
To a stirred solution of 4.6 g. of 1-isopropyl-3,4,7,8-tetrahydro-4-phenyl-furo[2,3-g]quinazolin-2(1H)-one in 200 ml. of dioxane cooled to 5°±5°C. is added dropwise a solution of 3.0 g. of potassium permanganate in 140 ml. of water. After the addition is completed 1.5 ml. of formalin solution is added. The resulting precipitated solids are removed by filtration and the filtrate concentrated in vacuo to obtain an oil of 1-isopropyl-7,8-dihydro-4-phenyl-furo[2,3-g]quinazolin-2(1H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[N+:9]([C:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:6]=1)([O-:11])=[O:10]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 3,5-dinitro-1H-pyrazole (2.5 g, 15.81 mmol) and potassium carbonate (4.36 g, 31.62 mmol) in DMF (50 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (3.07 mL, 17.39 mmol) and the mixture was stirred at rt for 6 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography eluting with 0-20% EtOAc/hexane to afford 3,5-dinitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a colorless oil (2.7 g, 59%). 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 6.00 (s, 2H), 3.72-3.67 (m, 2H), 0.97-0.91 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[CH:57][C:56]([NH2:59])=[N:55]1>CN(C)C=O>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[CH:57][C:56]([NH:59][C:8]([C:7]2[C:6]([F:11])=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[O:10])=[N:55]1
Reactant: O=C(O)c1c(F)cncc1F
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
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: O=C(Nc1ccn(Cc2ccc(Cl)cc2Cl)n1)c1c(F)cncc1F
Reaction time: 0.08 h
Yield: 114.8 %

Procedure:
To a solution of 3,5-difluoro-4-pyridinecarboxylic acid (15.9 mg, 0.1 mmol, Frontier Scientific) in dimethylformamide (0.1 ml) was added HATU (38 mg, 0.1 mmol) in dimethylformamide (0.2 mL), followed by N,N-diisopropylethylamine (0.050 ml, 0.286 mmol) and the resulting solution left for 5 min. Finally, a solution of 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-amine (24.2 mg, 0.01 mmol, ChemCollect GmbH) in N,N-dimethylformamide (0.1 ml) was added and the resulting solution shaken for 10 min. The solution was then left to stand for 16 h at ambient temperature after which the solvent was removed. A 1:1 mixture of dimethylsulphoxide:methanol (0.6 ml) was added and the solution purified by MDAP on SUNFIRE C18 column (Method D). The appropriate fraction was concentrated in vacuo then under nitrogen flow to give the title compound (4.4 mg);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([CH2:16][C:17]([OH:19])=O)[C:6]1=[O:20].[NH2:22][C:23]1[CH:24]=[C:25]2[CH2:40][C:30]3([C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]3=[O:39])[CH2:29][C:26]2=[N:27][CH:28]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[C:9]2[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[C:6](=[O:20])[N:7]([CH2:16][C:17](=[O:19])[NH:22][C:23]3[CH:24]=[C:25]4[CH2:40][C:30]5([C:38]6[C:33](=[N:34][CH:35]=[CH:36][CH:37]=6)[NH:32][C:31]5=[O:39])[CH2:29][C:26]4=[N:27][CH:28]=3)[C:8]=2[CH:13]=1
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: COC(=O)Cn1c(=O)n(CC(=O)O)c2cc(C)cc(C)c21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1c(=O)n(CC(=O)Nc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c2cc(C)cc(C)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (67 mg, 0.23 mmol, described in Intermediate 9), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1>C(Cl)CCl.C(OCC)(=O)C>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nncs1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2nncs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 41 %

Procedure:
4-Hydroxy-2-methyl-N-(1,3,4-thiadiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-1,3,4-thiadiazole. Yield: 41% of theory; m.p.217°-219° C (decomp.; from ethylene chloride/ethyl acetate).